Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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32 pages, 1003 KiB  
Review
Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury
by Michał Szymoniuk, Jakub Litak, Leon Sakwa, Aleksandra Dryla, Wojciech Zezuliński, Wojciech Czyżewski, Piotr Kamieniak and Tomasz Blicharski
Cells 2023, 12(1), 120; https://doi.org/10.3390/cells12010120 - 28 Dec 2022
Cited by 14 | Viewed by 3709
Abstract
Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well as urinary complications, and a small number [...] Read more.
Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well as urinary complications, and a small number of patients experience a complete recovery. Current standard treatment modalities of the SCI aim to prevent secondary injury and provide limited recovery of lost neurological functions. Stem Cell Therapy (SCT) represents an emerging treatment approach using the differentiation, paracrine, and self-renewal capabilities of stem cells to regenerate the injured spinal cord. To date, multipotent stem cells including mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) represent the most investigated types of stem cells for the treatment of SCI in preclinical and clinical studies. The microenvironment of SCI has a significant impact on the survival, proliferation, and differentiation of transplanted stem cells. Therefore, a deep understanding of the pathophysiology of SCI and molecular mechanisms through which stem cells act may help improve the treatment efficacy of SCT and find new therapeutic approaches such as stem-cell-derived exosomes, gene-modified stem cells, scaffolds, and nanomaterials. In this literature review, the pathogenesis of SCI and molecular mechanisms of action of multipotent stem cells including MSCs, NSCs, and HSCs are comprehensively described. Moreover, the clinical efficacy of multipotent stem cells in SCI treatment, an optimal protocol of stem cell administration, and recent therapeutic approaches based on or combined with SCT are also discussed. Full article
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17 pages, 3144 KiB  
Article
Advanced Maternal Age Differentially Affects Embryonic Tissues with the Most Severe Impact on the Developing Brain
by Caroline Kokorudz, Bethany N. Radford, Wendy Dean and Myriam Hemberger
Cells 2023, 12(1), 76; https://doi.org/10.3390/cells12010076 - 24 Dec 2022
Cited by 1 | Viewed by 2012
Abstract
Advanced maternal age (AMA) poses the single greatest risk to a successful pregnancy. Apart from the impact of AMA on oocyte fitness, aged female mice often display defects in normal placentation. Placental defects in turn are tightly correlated with brain and cardiovascular abnormalities. [...] Read more.
Advanced maternal age (AMA) poses the single greatest risk to a successful pregnancy. Apart from the impact of AMA on oocyte fitness, aged female mice often display defects in normal placentation. Placental defects in turn are tightly correlated with brain and cardiovascular abnormalities. It therefore follows that placenta, brain and heart development may be particularly susceptible to the impact of AMA. In the current study, we compared global transcriptomes of placentas, brains, hearts, and facial prominences from mid-gestation mouse conceptuses developed in young control (7–13 wks) and aging (43–50 wks) females. We find that AMA increases transcriptional heterogeneity in all tissues, but particularly in fetal brain. Importantly, even overtly normally developed embryos from older females display dramatic expression changes in neurodevelopmental genes. These transcriptomic alterations in the brain are likely induced by defects in placental development. Using trophoblast stem cells (TSCs) as a model, we show that exposure to aging uterine stromal cell-conditioned medium interferes with normal TSC proliferation and causes precocious differentiation, recapitulating many of the defects observed in placentas from aged females. These data highlight the increased risk of AMA on reproductive outcome, with neurodevelopment being the most sensitive to such early perturbations and with potential for lifelong impact. Full article
(This article belongs to the Section Reproductive Cells and Development)
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20 pages, 3401 KiB  
Article
Impact of Mitochondrial A3243G Heteroplasmy on Mitochondrial Bioenergetics and Dynamics of Directly Reprogrammed MELAS Neurons
by Dar-Shong Lin, Yu-Wen Huang, Che-Sheng Ho, Tung-Sun Huang, Tsung-Han Lee, Tsu-Yen Wu, Zon-Darr Huang and Tuan-Jen Wang
Cells 2023, 12(1), 15; https://doi.org/10.3390/cells12010015 - 21 Dec 2022
Cited by 3 | Viewed by 1565
Abstract
The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the impact of various levels of m.A3243G heteroplasmy on CNS remains elusive due to the lack of a proper [...] Read more.
The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the impact of various levels of m.A3243G heteroplasmy on CNS remains elusive due to the lack of a proper neuronal model harboring m.A3243G mutation. We generated induced neurons (iNs) through the direct reprogramming of MELAS patients, with derived fibroblasts harboring high (>95%), intermediate (68%), and low (20%) m.A3243G mutation. iNs demonstrated neuronal morphology with neurite outgrowth, branching, and dendritic spines. The heteroplasmy and deficiency of respiratory chain complexes were retained in MELAS iNs. High heteroplasmy elicited the elevation in ROS levels and the disruption of mitochondrial membrane potential. Furthermore, high and intermediate heteroplasmy led to the impairment of mitochondrial bioenergetics and a change in mitochondrial dynamics toward the fission and fragmentation of mitochondria, with a reduction in mitochondrial networks. Moreover, iNs derived from aged individuals manifested with mitochondrial fission. These results help us in understanding the impact of various heteroplasmic levels on mitochondrial bioenergetics and mitochondrial dynamics in neurons as the underlying pathomechanism of neurological manifestations of MELAS syndrome. Furthermore, these findings provide targets for further pharmacological approaches of mitochondrial diseases and validate iNs as a reliable platform for studies in neuronal aspects of aging, neurodegenerative disorders, and mitochondrial diseases. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Dynamics and Neurodegeneration)
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28 pages, 5418 KiB  
Article
Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice
by Henna Jäntti, Minna Oksanen, Pinja Kettunen, Stella Manta, Lionel Mouledous, Hennariikka Koivisto, Johanna Ruuth, Kalevi Trontti, Hiramani Dhungana, Meike Keuters, Isabelle Weert, Marja Koskuvi, Iiris Hovatta, Anni-Maija Linden, Claire Rampon, Tarja Malm, Heikki Tanila, Jari Koistinaho and Taisia Rolova
Cells 2022, 11(24), 4116; https://doi.org/10.3390/cells11244116 - 18 Dec 2022
Cited by 1 | Viewed by 2592
Abstract
The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell [...] Read more.
The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell (iPSC)-derived astrocytes increases Aβ42 production and impairs cellular responses. Here, we injected PSEN1 ΔE9 mutant astrosphere-derived glial progenitors into newborn mice and investigated mouse behavior at the ages of 8, 12, and 16 months. While we did not find significant behavioral changes in younger mice, spatial learning and memory were paradoxically improved in 16-month-old PSEN1 ΔE9 glia-transplanted male mice as compared to age-matched isogenic control-transplanted animals. Memory improvement was associated with lower levels of soluble, but not insoluble, human Aβ42 in the mouse brain. We also found a decreased engraftment of PSEN1 ΔE9 mutant cells in the cingulate cortex and significant transcriptional changes in both human and mouse genes in the hippocampus, including the extracellular matrix-related genes. Overall, the presence of PSEN1 ΔE9 mutant glia exerted a more beneficial effect on aged mouse brain than the isogenic control human cells likely as a combination of several factors. Full article
(This article belongs to the Special Issue Glial Cells in Synaptic Plasticity)
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13 pages, 2045 KiB  
Article
Tumor Growth Remains Refractory to Myc Ablation in Host Macrophages
by Riley J. Morrow, Amr H. Allam, Josh Konecnik, David Baloyan, Christine Dijkstra, Moritz F. Eissmann, Saumya P. Jacob, Megan O’Brien, Ashleigh R. Poh and Matthias Ernst
Cells 2022, 11(24), 4104; https://doi.org/10.3390/cells11244104 - 17 Dec 2022
Viewed by 1621
Abstract
Aberrant expression of the oncoprotein c-Myc (Myc) is frequently observed in solid tumors and is associated with reduced overall survival. In addition to well-recognized cancer cell-intrinsic roles of Myc, studies have also suggested tumor-promoting roles for Myc in cells of the tumor microenvironment, [...] Read more.
Aberrant expression of the oncoprotein c-Myc (Myc) is frequently observed in solid tumors and is associated with reduced overall survival. In addition to well-recognized cancer cell-intrinsic roles of Myc, studies have also suggested tumor-promoting roles for Myc in cells of the tumor microenvironment, including macrophages and other myeloid cells. Here, we benchmark Myc inactivation in tumor cells against the contribution of its expression in myeloid cells of murine hosts that harbor endogenous or allograft tumors. Surprisingly, we observe that LysMCre-mediated Myc ablation in host macrophages does not attenuate tumor growth regardless of immunogenicity, the cellular origin of the tumor, the site it develops, or the stage along the tumor progression cascade. Likewise, we find no evidence for Myc ablation to revert or antagonize the polarization of alternatively activated immunosuppressive macrophages. Thus, we surmise that systemic targeting of Myc activity may confer therapeutic benefits primarily through limiting Myc activity in tumor cells rather than reinvigorating the anti-tumor activity of macrophages. Full article
(This article belongs to the Special Issue MYC Signaling in Cancer)
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15 pages, 1461 KiB  
Article
Pre-Transplant Prediction of Acute Graft-versus-Host Disease Using the Gut Microbiome
by Ramtin Zargari Marandi, Mette Jørgensen, Emma Elizabeth Ilett, Jens Christian Nørgaard, Marc Noguera-Julian, Roger Paredes, Jens D. Lundgren, Henrik Sengeløv and Cameron Ross MacPherson
Cells 2022, 11(24), 4089; https://doi.org/10.3390/cells11244089 - 16 Dec 2022
Cited by 2 | Viewed by 2377
Abstract
Gut microbiota is thought to influence host responses to allogeneic hematopoietic stem cell transplantation (aHSCT). Recent evidence points to this post-transplant for acute graft-versus-host disease (aGvHD). We asked whether any such association might be found pre-transplant and conducted a metagenome-wide association study (MWAS) [...] Read more.
Gut microbiota is thought to influence host responses to allogeneic hematopoietic stem cell transplantation (aHSCT). Recent evidence points to this post-transplant for acute graft-versus-host disease (aGvHD). We asked whether any such association might be found pre-transplant and conducted a metagenome-wide association study (MWAS) to explore. Microbial abundance profiles were estimated using ensembles of Kaiju, Kraken2, and DeepMicrobes calls followed by dimensionality reduction. The area under the curve (AUC) was used to evaluate classification of the samples (aGvHD vs. none) using an elastic net to test the relevance of metagenomic data. Clinical data included the underlying disease (leukemia vs. other hematological malignancies), recipient age, and sex. Among 172 aHSCT patients of whom 42 developed aGVHD post transplantation, a total of 181 pre-transplant tool samples were analyzed. The top performing model predicting risk of aGVHD included a reduced species profile (AUC = 0.672). Beta diversity (37% in Jaccard’s Nestedness by mean fold change, p < 0.05) was lower in those developing aGvHD. Ten bacterial species including Prevotella and Eggerthella genera were consistently found to associate with aGvHD in indicator species analysis, as well as relief and impurity-based algorithms. The findings support the hypothesis on potential associations between gut microbiota and aGvHD based on a data-driven approach to MWAS. This highlights the need and relevance of routine stool collection for the discovery of novel biomarkers. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Microenvironment)
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21 pages, 27931 KiB  
Article
Loss of Pex1 in Inner Ear Hair Cells Contributes to Cochlear Synaptopathy and Hearing Loss
by Stephanie A. Mauriac, Thibault Peineau, Aamir Zuberi, Cathleen Lutz and Gwénaëlle S. G. Géléoc
Cells 2022, 11(24), 3982; https://doi.org/10.3390/cells11243982 - 09 Dec 2022
Viewed by 2093
Abstract
Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic multisystem disorders that include hearing impairment and are associated with defects in peroxisome assembly, function, or both. Mutations in 13 peroxin (PEX) genes have been found to cause [...] Read more.
Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic multisystem disorders that include hearing impairment and are associated with defects in peroxisome assembly, function, or both. Mutations in 13 peroxin (PEX) genes have been found to cause PBD-ZSD with ~70% of patients harboring mutations in PEX1. Limited research has focused on the impact of peroxisomal disorders on auditory function. As sensory hair cells are particularly vulnerable to metabolic changes, we hypothesize that mutations in PEX1 lead to oxidative stress affecting hair cells of the inner ear, subsequently resulting in hair cell degeneration and hearing loss. Global deletion of the Pex1 gene is neonatal lethal in mice, impairing any postnatal studies. To overcome this limitation, we created conditional knockout mice (cKO) using Gfi1Creor VGlut3Cre expressing mice crossed to floxed Pex1 mice to allow for selective deletion of Pex1 in the hair cells of the inner ear. We find that Pex1 excision in inner hair cells (IHCs) leads to progressive hearing loss associated with significant decrease in auditory brainstem responses (ABR), specifically ABR wave I amplitude, indicative of synaptic defects. Analysis of IHC synapses in cKO mice reveals a decrease in ribbon synapse volume and functional alterations in exocytosis. Concomitantly, we observe a decrease in peroxisomal number, indicative of oxidative stress imbalance. Taken together, these results suggest a critical function of Pex1 in development and maturation of IHC-spiral ganglion synapses and auditory function. Full article
(This article belongs to the Special Issue Exclusive Review Papers in Autophagy)
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22 pages, 1310 KiB  
Review
The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology
by Isaure Vanmeerbeek, Jannes Govaerts, Raquel S. Laureano, Jenny Sprooten, Stefan Naulaerts, Daniel M. Borras, Damya Laoui, Massimiliano Mazzone, Jo A. Van Ginderachter and Abhishek D. Garg
Cells 2022, 11(23), 3890; https://doi.org/10.3390/cells11233890 - 02 Dec 2022
Cited by 11 | Viewed by 3803
Abstract
Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer [...] Read more.
Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies. Full article
(This article belongs to the Special Issue Immunogenic Cell Stress and Death)
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18 pages, 1837 KiB  
Review
A Review on Autophagy in Orofacial Neuropathic Pain
by Mayank Shrivastava and Liang Ye
Cells 2022, 11(23), 3842; https://doi.org/10.3390/cells11233842 - 30 Nov 2022
Cited by 4 | Viewed by 1698
Abstract
Orofacial neuropathic pain indicates pain caused by a lesion or diseases of the somatosensory nervous system. It is challenging for the clinician to diagnose and manage orofacial neuropathic pain conditions due to the considerable variability between individual clinical presentations and a lack of [...] Read more.
Orofacial neuropathic pain indicates pain caused by a lesion or diseases of the somatosensory nervous system. It is challenging for the clinician to diagnose and manage orofacial neuropathic pain conditions due to the considerable variability between individual clinical presentations and a lack of understanding of the mechanisms underlying the etiology and pathogenesis. In the last few decades, researchers have developed diagnostic criteria, questionnaires, and clinical assessment methods for the diagnosis of orofacial neuropathic pain. Recently, researchers have observed the role of autophagy in neuronal dysfunction as well as in the modulation of neuropathic pain. On this basis, in the present review, we highlight the characteristics, classification, and clinical assessment of orofacial neuropathic pain. Additionally, we introduce autophagy and its potential role in the modulation of orofacial neuropathic pain, along with a brief overview of the pathogenesis, which in future may reveal new possible targets for treating this condition. Full article
(This article belongs to the Special Issue Exclusive Review Papers in Autophagy)
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17 pages, 3633 KiB  
Article
High-Content RNAi Phenotypic Screening Unveils the Involvement of Human Ubiquitin-Related Enzymes in Late Cytokinesis
by Mikaël Boullé, Laurianne Davignon, Keïs Nabhane Saïd Halidi, Salomé Guez, Emilie Giraud, Marcel Hollenstein and Fabrice Agou
Cells 2022, 11(23), 3862; https://doi.org/10.3390/cells11233862 - 30 Nov 2022
Cited by 1 | Viewed by 1739
Abstract
CEP55 is a central regulator of late cytokinesis and is overexpressed in numerous cancers. Its post-translationally controlled recruitment to the midbody is crucial to the structural coordination of the abscission sequence. Our recent evidence that CEP55 contains two ubiquitin-binding domains was the first [...] Read more.
CEP55 is a central regulator of late cytokinesis and is overexpressed in numerous cancers. Its post-translationally controlled recruitment to the midbody is crucial to the structural coordination of the abscission sequence. Our recent evidence that CEP55 contains two ubiquitin-binding domains was the first structural and functional link between ubiquitin signaling and ESCRT-mediated severing of the intercellular bridge. So far, high-content screens focusing on cytokinesis have used multinucleation as the endpoint readout. Here, we report an automated image-based detection method of intercellular bridges, which we applied to further our understanding of late cytokinetic signaling by performing an RNAi screen of ubiquitin ligases and deubiquitinases. A secondary validation confirmed four candidate genes, i.e., LNX2, NEURL, UCHL1 and RNF157, whose downregulation variably affects interconnected phenotypes related to CEP55 and its UBDs, as follows: decreased recruitment of CEP55 to the midbody, increased number of midbody remnants per cell, and increased frequency of intercellular bridges or multinucleation events. This brings into question the Notch-dependent or independent contributions of LNX2 and NEURL proteins to late cytokinesis. Similarly, the role of UCHL1 in autophagy could link its function with the fate of midbody remnants. Beyond the biological interest, this high-content screening approach could also be used to isolate anticancer drugs that act by impairing cytokinesis and CEP55 functions. Full article
(This article belongs to the Special Issue Molecular Factors and Mechanisms Involved in Cytokinesis II)
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13 pages, 2027 KiB  
Article
4-Methylumebelliferone Enhances Radiosensitizing Effects of Radioresistant Oral Squamous Cell Carcinoma Cells via Hyaluronan Synthase 3 Suppression
by Kazuki Hasegawa, Ryo Saga, Kentaro Ohuchi, Yoshikazu Kuwahara, Kazuo Tomita, Kazuhiko Okumura, Tomoaki Sato, Manabu Fukumoto, Eichi Tsuruga and Yoichiro Hosokawa
Cells 2022, 11(23), 3780; https://doi.org/10.3390/cells11233780 - 25 Nov 2022
Cited by 1 | Viewed by 1482
Abstract
Radioresistant (RR) cells are poor prognostic factors for tumor recurrence and metastasis after radiotherapy. The hyaluronan (HA) synthesis inhibitor, 4-methylumbelliferone (4-MU), shows anti-tumor and anti-metastatic effects through suppressing HA synthase (HAS) expression in various cancer cells. We previously reported that the administration of [...] Read more.
Radioresistant (RR) cells are poor prognostic factors for tumor recurrence and metastasis after radiotherapy. The hyaluronan (HA) synthesis inhibitor, 4-methylumbelliferone (4-MU), shows anti-tumor and anti-metastatic effects through suppressing HA synthase (HAS) expression in various cancer cells. We previously reported that the administration of 4-MU with X-ray irradiation enhanced radiosensitization. However, an effective sensitizer for radioresistant (RR) cells is yet to be established, and it is unknown whether 4-MU exerts radiosensitizing effects on RR cells. We investigated the radiosensitizing effects of 4-MU in RR cell models. This study revealed that 4-MU enhanced intracellular oxidative stress and suppressed the expression of cluster-of-differentiation (CD)-44 and cancer stem cell (CSC)-like phenotypes. Interestingly, eliminating extracellular HA using HA-degrading enzymes did not cause radiosensitization, whereas HAS3 knockdown using siRNA showed similar effects as 4-MU treatment. These results suggest that 4-MU treatment enhances radiosensitization of RR cells through enhancing oxidative stress and suppressing the CSC-like phenotype. Furthermore, the radiosensitizing mechanisms of 4-MU may involve HAS3 or intracellular HA synthesized by HAS3. Full article
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17 pages, 7647 KiB  
Article
Dynamic Changes in the Extracellular Matrix in Primary, Metastatic, and Recurrent Ovarian Cancers
by Arkadiusz Gertych, Ann E. Walts, Keyi Cheng, Manyun Liu, Joshi John, Jenny Lester, Beth Y. Karlan and Sandra Orsulic
Cells 2022, 11(23), 3769; https://doi.org/10.3390/cells11233769 - 25 Nov 2022
Cited by 2 | Viewed by 1877
Abstract
Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational [...] Read more.
Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational image analyses of patient-matched primary high-grade serous ovarian carcinomas, synchronous pre-chemotherapy metastases, and metachronous post-chemotherapy metastases from 42 patients, we documented the dynamic spatiotemporal changes in the extracellular matrix, fibroblasts, epithelial cells, immune cells, and CAF subsets expressing different extracellular matrix components. Among the different CAF subsets, COL11A1+ CAFs were associated with linearized collagen fibers and exhibited the greatest enrichment in pre- and post-chemotherapy metastases compared to matched primary tumors. Although pre- and post-chemotherapy metastases were associated with increased CD8+ T cell infiltration, the infiltrate was not always evenly distributed between the stroma and cancer cells, leading to an increased frequency of the immune-excluded phenotype where the majority of CD8+ T cells are present in the tumor stroma but absent from the tumor parenchyma. Overall, most of the differences in the tumor microenvironment were observed between primary tumors and metastases, while fewer differences were observed between pre- and post-treatment metastases. These data suggest that the tumor microenvironment is largely determined by the primary vs. metastatic location of the tumor while chemotherapy does not have a significant impact on the host microenvironment. Full article
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31 pages, 3152 KiB  
Review
Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy
by Rashedul Alam, Mohammad Fazlul Kabir, Hyung-Ryong Kim and Han-Jung Chae
Cells 2022, 11(23), 3773; https://doi.org/10.3390/cells11233773 - 25 Nov 2022
Cited by 2 | Viewed by 2563
Abstract
Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged [...] Read more.
Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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15 pages, 7082 KiB  
Article
Low-Dose rIL-15 Protects from Nephrotoxic Serum Nephritis via CD8+ T Cells
by Agnes A. Mooslechner, Max Schuller, Katharina Artinger, Alexander H. Kirsch, Corinna Schabhüttl, Philipp Eller, Alexander R. Rosenkranz and Kathrin Eller
Cells 2022, 11(22), 3656; https://doi.org/10.3390/cells11223656 - 18 Nov 2022
Cited by 3 | Viewed by 1741
Abstract
Rapid progressive glomerulonephritis (GN) often leads to end-stage kidney disease, driving the need for renal replacement therapy and posing a global health burden. Low-dose cytokine-based immunotherapies provide a new strategy to treat GN. IL-15 is a strong candidate for the therapy of immune-mediated [...] Read more.
Rapid progressive glomerulonephritis (GN) often leads to end-stage kidney disease, driving the need for renal replacement therapy and posing a global health burden. Low-dose cytokine-based immunotherapies provide a new strategy to treat GN. IL-15 is a strong candidate for the therapy of immune-mediated kidney disease since it has proven to be tubular-protective before. Therefore, we set out to test the potential of low-dose rIL-15 treatment in a mouse model of nephrotoxic serum nephritis (NTS), mimicking immune complex-driven GN in humans. A single low-dose treatment with rIL-15 ameliorated NTS, reflected by reduced albuminuria, less tissue scarring, fewer myeloid cells in the kidney, and improved tubular epithelial cell survival. In addition, CD8+ T cells, a primary target of IL-15, showed altered gene expression and function corresponding with less cytotoxicity mediated by rIL-15. With the use of transgenic knock-out mice, antibody depletion, and adoptive cell transfer studies, we here show that the beneficial effects of rIL-15 treatment in NTS depended on CD8+ T cells, suggesting a pivotal role for them in the underlying mechanism. Our findings add to existing evidence of the association of IL-15 with kidney health and imply a potential for low-dose rIL-15 immunotherapies in GN. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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42 pages, 1992 KiB  
Review
Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology
by Aleš Cvekl and Michael John Camerino
Cells 2022, 11(21), 3516; https://doi.org/10.3390/cells11213516 - 06 Nov 2022
Cited by 5 | Viewed by 2951
Abstract
In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight into those cellular and molecular mechanisms regulating human development. Although normal embryonic eye development is a complex process, generation of ocular organoids [...] Read more.
In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight into those cellular and molecular mechanisms regulating human development. Although normal embryonic eye development is a complex process, generation of ocular organoids and specific ocular tissues from pluripotent stem cells has provided invaluable insights into the formation of lineage-committed progenitor cell populations, signal transduction pathways, and self-organization principles. This review provides a comprehensive summary of recent advances in generation of adenohypophyseal, olfactory, and lens placodes, lens progenitor cells and three-dimensional (3D) primitive lenses, “lentoid bodies”, and “micro-lenses”. These cells are produced alone or “community-grown” with other ocular tissues. Lentoid bodies/micro-lenses generated from human patients carrying mutations in crystallin genes demonstrate proof-of-principle that these cells are suitable for mechanistic studies of cataractogenesis. Taken together, current and emerging advanced in vitro differentiation methods pave the road to understand molecular mechanisms of cataract formation caused by the entire spectrum of mutations in DNA-binding regulatory genes, such as PAX6, SOX2, FOXE3, MAF, PITX3, and HSF4, individual crystallins, and other genes such as BFSP1, BFSP2, EPHA2, GJA3, GJA8, LIM2, MIP, and TDRD7 represented in human cataract patients. Full article
(This article belongs to the Special Issue New Advances in Lens Biology and Pathology)
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15 pages, 2879 KiB  
Article
The HSF1-CPT1a Pathway Is Differentially Regulated in NAFLD Progression
by Wiebke Breternitz, Friedrich Sandkühler, Frauke Grohmann, Jochen Hampe, Mario Brosch, Alexander Herrmann, Clemens Schafmayer, Christian Meinhardt, Stefan Schreiber, Alexander Arlt and Claudia Geismann
Cells 2022, 11(21), 3504; https://doi.org/10.3390/cells11213504 - 04 Nov 2022
Cited by 1 | Viewed by 1970
Abstract
Obesity and obesity-associated diseases represent one of the key health challenges of our time. In this context, aberrant hepatic lipid accumulation is a central pathological aspect of non-alcoholic fatty liver disease (NAFLD). By comparing methylation signatures of liver biopsies before and after bariatric [...] Read more.
Obesity and obesity-associated diseases represent one of the key health challenges of our time. In this context, aberrant hepatic lipid accumulation is a central pathological aspect of non-alcoholic fatty liver disease (NAFLD). By comparing methylation signatures of liver biopsies before and after bariatric surgery, we recently demonstrated the strong enrichment of differentially methylated heat shock factor 1 (HSF1) binding sites (>400-fold) in the process of liver remodeling, indicating a crucial role of HSF1 in modulating central aspects of NAFLD pathogenesis. Using cellular models of NAFLD, we were able to show that HSF1 is activated during fat accumulation in hepatocytes, mimicking conditions in patients before bariatric surgery. This induction was abolished by starving the cells, mimicking the situation after bariatric surgery. Regarding this connection, carnitine palmitoyltransferase 1 isoform A (CTP1a), a central regulator of lipid beta-oxidation, was identified as a HSF1 target gene by promoter analysis and HSF1 knockdown experiments. Finally, pharmacological activation of HSF1 through celastrol reduced fat accumulation in the cells in a HSF1-dependent manner. In conclusion, we were able to confirm the relevance of HSF1 activity and described a functional HSF1-CPT1a pathway in NAFLD pathogenesis. Full article
(This article belongs to the Special Issue Metabolic Regulation: Cell Growth and Proliferation)
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19 pages, 1416 KiB  
Review
A Linkage between Angiogenesis and Inflammation in Neovascular Age-Related Macular Degeneration
by Hanna Heloterä and Kai Kaarniranta
Cells 2022, 11(21), 3453; https://doi.org/10.3390/cells11213453 - 01 Nov 2022
Cited by 17 | Viewed by 3661
Abstract
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD (nAMD). Dry AMD is the most prevalent form (80–90%) of AMD cases. Neovascular AMD (10–20% of AMD cases) is treated with monthly or more sparsely given intravitreal anti-vascular endothelial growth factor inhibitors, but unfortunately, not all patients respond to the current treatments. A clinical hallmark of nAMD is choroidal neovascularization. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Cellular damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to advanced geographic atrophy and/or choroidal neovascularization and fibrosis. Currently, it is not fully known why different AMD phenotypes develop. In this review, we connect angiogenesis and inflammatory regulators in the development of nAMD and discuss therapy challenges and hopes. Full article
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27 pages, 3449 KiB  
Review
Mesenchymal Stem Cell-Derived Extracellular Vesicles for Therapeutic Use and in Bioengineering Applications
by Caroline McLaughlin, Pallab Datta, Yogendra P. Singh, Alexis Lo, Summer Horchler, Irina A. Elcheva, Ibrahim T. Ozbolat, Dino J. Ravnic and Srinivas V. Koduru
Cells 2022, 11(21), 3366; https://doi.org/10.3390/cells11213366 - 25 Oct 2022
Cited by 9 | Viewed by 2815
Abstract
Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth [...] Read more.
Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth factors, interleukins (ILs), transcription factors, and nucleic acids such as DNA, mRNAs, microRNAs, piRNAs, lncRNAs, sn/snoRNAs, mtRNAs and circRNAs; these EVs travel to predecided destinations to perform their functions. While mesenchymal stem cells (MSCs) have been shown to improve healing and facilitate treatments of various diseases, the allogenic use of these cells is often accompanied by serious adverse effects after transplantation. MSC-produced EVs are less immunogenic and can serve as an alternative to cellular therapies by transmitting signaling or delivering biomaterials to diseased areas of the body. This review article is focused on understanding the properties of EVs derived from different types of MSCs and MSC–EV-based therapeutic options. The potential of modern technologies such as 3D bioprinting to advance EV-based therapies is also discussed. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles)
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11 pages, 625 KiB  
Review
Morbidity and Mortality of Neutropenic Patients in Visceral Surgery: A Narrative Review
by Ann-Kathrin Lederer, Fabian Bartsch, Markus Moehler, Peter Gaßmann and Hauke Lang
Cells 2022, 11(20), 3314; https://doi.org/10.3390/cells11203314 - 21 Oct 2022
Cited by 2 | Viewed by 1959
Abstract
Leukocytes are essential for the function of the immune system and cell–cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are [...] Read more.
Leukocytes are essential for the function of the immune system and cell–cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are neutrophilic granulocytes, and leukopenia is, therefore, mostly characterized by a decrease in neutrophilic granulocytes. The consequence of neutropenia is increased susceptibility to infection, but also healing disorders are suggestable due to the disturbed cell–cell interaction. While there is no surgical treatment for leucocyte disorders, patients suffering from neutropenia are sometimes in need of surgery for other reasons. Less is known about the morbidity and mortality of this patients, which is why this narrative review critically summarizes the results of recent research in this particular field. The results of this review suggest that neutropenic patients in need of emergency surgery have a higher mortality risk compared to non-neutropenic patients. In contrast, in elective surgery, there was not a clear tendency for a higher mortality risk of neutropenic patients. The role of neutrophilic granulocytes in inflammation and immunity in surgical patients is emphasized by the results, but most of the evaluated studies showed methodological flaws due to small sample sizes or risk of bias. Further research has to evaluate the risk for postoperative complications, particularly of infectious complications such as surgical site infections, in neutropenic patients undergoing elective surgery, and should address the role of neutrophilic function in postoperative morbidity and mortality. Full article
(This article belongs to the Collection Emerging Roles of Neutrophil in Inflammation and Immunity)
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27 pages, 7126 KiB  
Article
Dendritic Cells or Macrophages? The Microenvironment of Human Clear Cell Renal Cell Carcinoma Imprints a Mosaic Myeloid Subtype Associated with Patient Survival
by Dorothee Brech, Anna S. Herbstritt, Sarah Diederich, Tobias Straub, Evangelos Kokolakis, Martin Irmler, Johannes Beckers, Florian A. Büttner, Elke Schaeffeler, Stefan Winter, Matthias Schwab, Peter J. Nelson and Elfriede Noessner
Cells 2022, 11(20), 3289; https://doi.org/10.3390/cells11203289 - 19 Oct 2022
Cited by 3 | Viewed by 2939
Abstract
Since their initial description by Elie Metchnikoff, phagocytes have sparked interest in a variety of biologic disciplines. These important cells perform central functions in tissue repair and immune activation as well as tolerance. Myeloid cells can be immunoinhibitory, particularly in the tumor microenvironment, [...] Read more.
Since their initial description by Elie Metchnikoff, phagocytes have sparked interest in a variety of biologic disciplines. These important cells perform central functions in tissue repair and immune activation as well as tolerance. Myeloid cells can be immunoinhibitory, particularly in the tumor microenvironment, where their presence is generally associated with poor patient prognosis. These cells are highly adaptable and plastic, and can be modulated to perform desired functions such as antitumor activity, if key programming molecules can be identified. Human clear cell renal cell carcinoma (ccRCC) is considered immunogenic; yet checkpoint blockades that target T cell dysfunction have shown limited clinical efficacy, suggesting additional layers of immunoinhibition. We previously described “enriched-in-renal cell carcinoma” (erc) DCs that were often found in tight contact with dysfunctional T cells. Using transcriptional profiling and flow cytometry, we describe here that ercDCs represent a mosaic cell type within the macrophage continuum co-expressing M1 and M2 markers. The polarization state reflects tissue-specific signals that are characteristic of RCC and renal tissue homeostasis. ErcDCs are tissue-resident with increasing prevalence related to tumor grade. Accordingly, a high ercDC score predicted poor patient survival. Within the profile, therapeutic targets (VSIG4, NRP1, GPNMB) were identified with promise to improve immunotherapy. Full article
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27 pages, 893 KiB  
Review
The Extracellular Matrix and Neuroblastoma Cell Communication—A Complex Interplay and Its Therapeutic Implications
by Irena Horwacik
Cells 2022, 11(19), 3172; https://doi.org/10.3390/cells11193172 - 10 Oct 2022
Cited by 6 | Viewed by 2270
Abstract
Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients [...] Read more.
Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients call for more research to further inter-relate treatment and molecular features of the disease. In this regard, it is well established that in the tumor microenvironment (TME), malignant cells are engaged in complex and dynamic interactions with the extracellular matrix (ECM) and stromal cells. The ECM can be a source of both pro- and anti-tumorigenic factors to regulate tumor cell fate, such as survival, proliferation, and resistance to therapy. Moreover, the ECM composition, organization, and resulting signaling networks are vastly remodeled during tumor progression and metastasis. This review mainly focuses on the molecular mechanisms and effects of interactions of selected ECM components with their receptors on neuroblastoma cells. Additionally, it describes roles of enzymes modifying and degrading ECM in NB. Finally, the article gives examples on how the knowledge is exploited for prognosis and to yield new treatment options for NB patients. Full article
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10 pages, 935 KiB  
Hypothesis
AIRE in Male Fertility: A New Hypothesis
by Jana Petrusová, Jasper Manning and Dominik Filipp
Cells 2022, 11(19), 3168; https://doi.org/10.3390/cells11193168 - 09 Oct 2022
Cited by 1 | Viewed by 1498
Abstract
Male infertility affects approximately 14% of all European men, of which ~44% are characterized as idiopathic. There is an urgency to identify the factors that affect male fertility. One such factor, Autoimmune Regulator (AIRE), a protein found in the thymus, has been studied [...] Read more.
Male infertility affects approximately 14% of all European men, of which ~44% are characterized as idiopathic. There is an urgency to identify the factors that affect male fertility. One such factor, Autoimmune Regulator (AIRE), a protein found in the thymus, has been studied in the context of central tolerance functioning as a nuclear transcription modulator, responsible for the expression of tissue-restricted antigens in specialized thymic cells that prevent autoimmunity. While its expression in the testes remains enigmatic, we recently observed that sterility in mice correlates with the absence of Aire in the testes, regardless of the deficient expression in medullary thymic epithelial cells or cells of the hematopoietic system. By assessing the Aire transcript levels, we discovered that Sertoli cells are the exclusive source of Aire in the testes, where it most likely plays a non-immune role, suggesting an unknown mechanism by which testicular Aire regulates fertility. Here, we discuss these results in the context of previous reports which have suggested that infertility observed in Aire deficient mice is of an autoimmune aetiology. We present an alternative point of view for the role of Aire in testes in respect to fertility altering the perspective of how Aire’s function in the testes is currently perceived. Full article
(This article belongs to the Section Reproductive Cells and Development)
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11 pages, 1632 KiB  
Article
Characterization of the Aquaporin-9 Inhibitor RG100204 In Vitro and in db/db Mice
by Marilina Florio, Angelica Engfors, Patrizia Gena, Jessica Larsson, Alessandro Massaro, Stella Timpka, Martina Kvist Reimer, Per Kjellbom, Eric Beitz, Urban Johanson, Michael Rützler and Giuseppe Calamita
Cells 2022, 11(19), 3118; https://doi.org/10.3390/cells11193118 - 04 Oct 2022
Cited by 6 | Viewed by 1789
Abstract
Aquaporin-9 (AQP9) is a facilitator of glycerol and other small neutral solute transmembrane diffusion. Identification of specific inhibitors for aquaporin family proteins has been difficult, due to high sequence similarity between the 13 human isoforms, and due to the limited channel surface areas [...] Read more.
Aquaporin-9 (AQP9) is a facilitator of glycerol and other small neutral solute transmembrane diffusion. Identification of specific inhibitors for aquaporin family proteins has been difficult, due to high sequence similarity between the 13 human isoforms, and due to the limited channel surface areas that permit inhibitor binding. The few AQP9 inhibitor molecules described to date were not suitable for in vivo experiments. We now describe the characterization of a new small molecule AQP9 inhibitor, RG100204 in cell-based calcein-quenching assays, and by stopped-flow light-scattering recordings of AQP9 permeability in proteoliposomes. Moreover, we investigated the effects of RG100204 on glycerol metabolism in mice. In cell-based assays, RG100204 blocked AQP9 water permeability and glycerol permeability with similar, high potency (~5 × 10−8 M). AQP9 channel blocking by RG100204 was confirmed in proteoliposomes. After oral gavage of db/db mice with RG100204, a dose-dependent elevation of plasma glycerol was observed. A blood glucose-lowering effect was not statistically significant. These experiments establish RG100204 as a direct blocker of the AQP9 channel, and suggest its use as an experimental tool for in vivo experiments on AQP9 function. Full article
(This article belongs to the Section Cellular Metabolism)
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17 pages, 5246 KiB  
Article
Proteomic and Phosphoproteomic Profiling Reveals the Oncogenic Role of Protein Kinase D Family Kinases in Cholangiocarcinoma
by Yun Lu, Xiangyu Li, Kai Zhao, Yuanxin Shi, Zhengdong Deng, Wei Yao and Jianming Wang
Cells 2022, 11(19), 3088; https://doi.org/10.3390/cells11193088 - 30 Sep 2022
Cited by 5 | Viewed by 1950
Abstract
Cholangiocarcinoma (CCA) is a lethal malignancy in the hepatobiliary system, with dysregulated protein expression and phosphorylation signaling. However, the protein and phosphorylation signatures of CCAs are little-known. Here, we performed the proteomic and phosphoproteomic profiling of tumors and normal adjacent tissues (NATs) from [...] Read more.
Cholangiocarcinoma (CCA) is a lethal malignancy in the hepatobiliary system, with dysregulated protein expression and phosphorylation signaling. However, the protein and phosphorylation signatures of CCAs are little-known. Here, we performed the proteomic and phosphoproteomic profiling of tumors and normal adjacent tissues (NATs) from patients with CCA and predicted eleven PKs high-potentially related to CCA with a comprehensive inference of the functional protein kinases (PKs) (CifPK) pipeline. Besides the two known CCA-associated PKs, we screened the remaining candidates and uncovered five PKs as novel regulators in CCA. Specifically, the protein kinase D (PKD) family members, including PRKD1, PRKD2, and PRKD3, were identified as critical regulators in CCA. Moreover, the pan-inhibitor of the PKD family, 1-naphthyl PP1 (1-NA-PP1), was validated as a potent agent for inhibiting the proliferation, migration, and invasion ability of CCA cells. This study reveals new PKs associated with CCA and suggests PRKD kinases as novel treatment targets for CCA. Full article
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15 pages, 2006 KiB  
Review
The Complex Relation between Atrial Cardiomyopathy and Thrombogenesis
by Elisa D’Alessandro, Joris Winters, Frans A. van Nieuwenhoven, Ulrich Schotten and Sander Verheule
Cells 2022, 11(19), 2963; https://doi.org/10.3390/cells11192963 - 22 Sep 2022
Cited by 3 | Viewed by 1827
Abstract
Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy [...] Read more.
Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability. Full article
(This article belongs to the Special Issue Molecular Biology of Atrial Myocardium)
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14 pages, 876 KiB  
Review
Molecular Regulators of Embryonic Diapause and Cancer Diapause-like State
by Abdiasis M. Hussein, Nanditaa Balachandar, Julie Mathieu and Hannele Ruohola-Baker
Cells 2022, 11(19), 2929; https://doi.org/10.3390/cells11192929 - 20 Sep 2022
Cited by 7 | Viewed by 4821
Abstract
Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and state of suspended development occurs in mice, bears, roe deer, and over 130 other mammals and favors the survival of [...] Read more.
Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and state of suspended development occurs in mice, bears, roe deer, and over 130 other mammals and favors the survival of newborns. Diapause arrests the embryo at the blastocyst stage, delaying the post-implantation development of the embryo. This months-long quiescence is reversible, in contrast to senescence that occurs in aging stem cells. Recent studies have revealed critical regulators of diapause. These findings are important since defects in the diapause state can cause a lack of regeneration and control of normal growth. Controlling this state may also have therapeutic applications since recent findings suggest that radiation and chemotherapy may lead some cancer cells to a protective diapause-like, reversible state. Interestingly, recent studies have shown the metabolic regulation of epigenetic modifications and the role of microRNAs in embryonic diapause. In this review, we discuss the molecular mechanism of diapause induction. Full article
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20 pages, 3466 KiB  
Article
Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies
by Lei Wang, Lieke E. J. van Iersel, Charlotte E. Pelgrim, Jingyi Lu, Ingrid van Ark, Thea Leusink-Muis, Harry R. Gosker, Ramon C. J. Langen, Annemie M. W. J. Schols, Josep M. Argilés, Ardy van Helvoort, Aletta D. Kraneveld, Johan Garssen, Paul A. J. Henricks, Gert Folkerts and Saskia Braber
Cells 2022, 11(18), 2893; https://doi.org/10.3390/cells11182893 - 16 Sep 2022
Cited by 7 | Viewed by 3759
Abstract
Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro [...] Read more.
Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis. Full article
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15 pages, 3542 KiB  
Article
Characterization of Three-Dimensional Trophoblast Spheroids: An Alternative Model to Study the Physiological Properties of the Placental Unit
by Violeta Stojanovska, Susanne Arnold, Mario Bauer, Hermann Voss, Stefan Fest and Ana Claudia Zenclussen
Cells 2022, 11(18), 2884; https://doi.org/10.3390/cells11182884 - 15 Sep 2022
Cited by 7 | Viewed by 2609
Abstract
It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized [...] Read more.
It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized three different 3D cultures (e.g., spheroids) derived from trophoblast cell lines and studied their functionality in comparison to primary fetal trophoblasts and placental tissue. The spheroid growth rates of JEG3, BeWo and HTR8/SVneo cell lines were similar among each other and were significantly larger in comparison to primary trophoblast spheroids. All spheroids exhibited migratory properties and shortest distances were registered for JEG3 spheroids. Even though all spheroids displayed invasive capabilities, only the invasive features of HTR8/SVneo spheroids resulted in specific branching. This was in agreement with the invasive properties of the spheroids obtained from primary trophoblasts. Human chorionic gonadotropin production was highest in JEG3 spheroids and only increased when stimulated with cAMP and forskolin in BeWo, but not HTR8/SVneo spheroids. The gene expression analysis confirmed that 3D trophoblast cell cultures and especially HTR8/SVneo spheroids showed considerable similarities with the gene expression profile of primary placental tissue. This study offers a broad characterization of 3D trophoblast spheroids that, in turn, can help in selecting the best model depending on the scientific question that needs to be answered. Full article
(This article belongs to the Special Issue Placental Development in Health and Disease)
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23 pages, 4047 KiB  
Article
The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism
by Sonia Spinelli, Lucrezia Guida, Tiziana Vigliarolo, Mario Passalacqua, Giulia Begani, Mirko Magnone, Laura Sturla, Andrea Benzi, Pietro Ameri, Edoardo Lazzarini, Claudia Bearzi, Roberto Rizzi and Elena Zocchi
Cells 2022, 11(18), 2888; https://doi.org/10.3390/cells11182888 - 15 Sep 2022
Cited by 10 | Viewed by 2388
Abstract
Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We [...] Read more.
Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia. Full article
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14 pages, 2204 KiB  
Article
Biological Pathway-Derived TMB Robustly Predicts the Outcome of Immune Checkpoint Blockade Therapy
by Ya-Ru Miao, Chun-Jie Liu, Hui Hu, Mei Yang and An-Yuan Guo
Cells 2022, 11(18), 2802; https://doi.org/10.3390/cells11182802 - 08 Sep 2022
Cited by 4 | Viewed by 2103
Abstract
Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response [...] Read more.
Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response in anti-PD1 treated melanoma. SERPINB3 was the most significant response-related gene in melanoma and mutations in either SERPINB3 or PEG3 can serve as an independent risk factor in melanoma. Some recurrent mutations in CSMD3 were only in responders or non-responders, indicating their diverse impacts on patient response. Enrichment scores (ES) of gene mutations in 12 biological pathways were significantly higher in responders or non-responders. Next, the P-TMB calculated from genes in these pathways was significantly related to patient response with prediction AUC 0.74–0.82 in all collected datasets. In conclusion, our work provides new insights into the application of TMB in predicting patient response, which will benefit to immunotherapy research. Full article
(This article belongs to the Special Issue Cutting Edge in Bioinformatics of Cancer Immunotherapy)
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15 pages, 1844 KiB  
Review
The Memory T Cell “Communication Web” in Context with Gastrointestinal Disorders—How Memory T Cells Affect Their Surroundings and How They Are Influenced by It
by Annkathrin Knauss, Michael Gabel, Markus F. Neurath and Benno Weigmann
Cells 2022, 11(18), 2780; https://doi.org/10.3390/cells11182780 - 06 Sep 2022
Cited by 3 | Viewed by 2624
Abstract
Gut-related diseases like ulcerative colitis, Crohn’s disease, or colorectal cancer affect millions of people worldwide. It is an ongoing process finding causes leading to the development and manifestation of those disorders. This is highly relevant since understanding molecular processes and signalling pathways offers [...] Read more.
Gut-related diseases like ulcerative colitis, Crohn’s disease, or colorectal cancer affect millions of people worldwide. It is an ongoing process finding causes leading to the development and manifestation of those disorders. This is highly relevant since understanding molecular processes and signalling pathways offers new opportunities in finding novel ways to interfere with and apply new pharmaceuticals. Memory T cells (mT cells) and their pro-inflammatory properties have been proven to play an important role in gastrointestinal diseases and are therefore increasingly spotlighted. This review focuses on mT cells and their subsets in the context of disease pathogenesis and maintenance. It illustrates the network of regulatory proteins and metabolites connecting mT cells with other cell types and tissue compartments. Furthermore, the crosstalk with various microbes will be a subject of discussion. Characterizing mT cell interactions will help to further elucidate the sophisticated molecular and cellular networking system in the intestine and may present new ideas for future research approaches to control gut-related diseases. Full article
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17 pages, 1724 KiB  
Review
Role of Microglia and Astrocytes in Alzheimer’s Disease: From Neuroinflammation to Ca2+ Homeostasis Dysregulation
by Giulia Di Benedetto, Chiara Burgaletto, Carlo Maria Bellanca, Antonio Munafò, Renato Bernardini and Giuseppina Cantarella
Cells 2022, 11(17), 2728; https://doi.org/10.3390/cells11172728 - 01 Sep 2022
Cited by 32 | Viewed by 6094
Abstract
Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a complex, poorly understood pathogenesis. Cerebral atrophy, amyloid-β (Aβ) plaques, and neurofibrillary tangles represent the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as a prominent feature [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a complex, poorly understood pathogenesis. Cerebral atrophy, amyloid-β (Aβ) plaques, and neurofibrillary tangles represent the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as a prominent feature of the AD brain and substantial evidence suggests that the inflammatory response modulates disease progression. Additionally, dysregulation of calcium (Ca2+) homeostasis represents another early factor involved in the AD pathogenesis, as intracellular Ca2+ concentration is essential to ensure proper cellular and neuronal functions. Although growing evidence supports the involvement of Ca2+ in the mechanisms of neurodegeneration-related inflammatory processes, scant data are available on its contribution in microglia and astrocytes functioning, both in health and throughout the AD continuum. Nevertheless, AD-related aberrant Ca2+ signalling in astrocytes and microglia is crucially involved in the mechanisms underpinning neuroinflammatory processes that, in turn, impact neuronal Ca2+ homeostasis and brain function. In this light, we attempted to provide an overview of the current understanding of the interactions between the glia cells-mediated inflammatory responses and the molecular mechanisms involved in Ca2+ homeostasis dysregulation in AD. Full article
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20 pages, 1610 KiB  
Review
Postnatal and Adult Neurogenesis in Mammals, Including Marsupials
by Katarzyna Bartkowska, Beata Tepper, Krzysztof Turlejski and Ruzanna Djavadian
Cells 2022, 11(17), 2735; https://doi.org/10.3390/cells11172735 - 01 Sep 2022
Cited by 12 | Viewed by 3130
Abstract
In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and [...] Read more.
In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and cerebellum of eutherian species. The formation of these structures starts during embryogenesis and continues postnatally. In both eutherians and marsupials, neurogenesis continues in the subventricular zone of the lateral ventricle (SVZ) and the dentate gyrus of the hippocampal formation throughout life. The majority of proliferated cells from the SVZ migrate to the olfactory bulb, whereas, in the dentate gyrus, cells reside within this structure after division and differentiation into neurons. A key aim of this review is to evaluate advances in understanding developmental neurogenesis that occurs postnatally in both marsupials and eutherians, with a particular emphasis on the generation of granule cells during the formation of the olfactory bulb, dentate gyrus, and cerebellum. We debate the significance of immature neurons in the piriform cortex of young mammals. We also synthesize the knowledge of adult neurogenesis in the olfactory bulb and the dentate gyrus of marsupials by considering whether adult-born neurons are essential for the functioning of a given area. Full article
(This article belongs to the Special Issue Frontiers in Neurogenesis)
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16 pages, 1852 KiB  
Article
BC-miR: Monitoring Breast Cancer-Related miRNA Profile in Blood Sera—A Prosperous Approach for Tumor Detection
by Barbara N. Borsos, Zoltán G. Páhi, Zsuzsanna Ujfaludi, Farkas Sükösd, Alíz Nikolényi, Sarolta Bankó, Gabriella Pankotai-Bodó, Orsolya Oláh-Németh and Tibor Pankotai
Cells 2022, 11(17), 2721; https://doi.org/10.3390/cells11172721 - 31 Aug 2022
Cited by 9 | Viewed by 1931
Abstract
Breast cancer is the most frequent cancer with a high fatality rate amongst women worldwide. Diagnosing at an early stage is challenging, and due to the limitations of the currently used techniques, including mammography and imaging diagnostics, it still remains unascertained. Serum biomarkers [...] Read more.
Breast cancer is the most frequent cancer with a high fatality rate amongst women worldwide. Diagnosing at an early stage is challenging, and due to the limitations of the currently used techniques, including mammography and imaging diagnostics, it still remains unascertained. Serum biomarkers can be a solution for this as they can be isolated in a less painful, more cost-effective, and minimally invasive manner. In this study, we shed light on the relevant role of multiple microRNAs (miRNAs) as potential biomarkers in breast cancer diagnosis. We monitored the expressional changes of 15 pre-selected miRNAs in a large cohort, including 65 patients with breast cancer and 42 healthy individuals. We performed thorough statistical analyses on the cohort sample set and determined the diagnostic accuracy of individual and multiple miRNAs. Our study reveals a potential improvement in diagnostics by implicating the monitoring of miR-15a+miR-16+miR-221 expression in breast cancer management. Full article
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18 pages, 1863 KiB  
Review
The CXCL13/CXCR5 Immune Axis in Health and Disease—Implications for Intrathecal B Cell Activities in Neuroinflammation
by Christine Harrer, Ferdinand Otto, Richard Friedrich Radlberger, Tobias Moser, Georg Pilz, Peter Wipfler and Andrea Harrer
Cells 2022, 11(17), 2649; https://doi.org/10.3390/cells11172649 - 25 Aug 2022
Cited by 12 | Viewed by 4884
Abstract
The chemokine C-X-C- ligand 13 (CXCL13) is a major B cell chemoattractant to B cell follicles in secondary lymphoid organs (SLO) that proposedly recruits B cells to the cerebrospinal fluid (CSF) during neuroinflammation. CXCR5, the cognate receptor of CXCL13, is expressed on B [...] Read more.
The chemokine C-X-C- ligand 13 (CXCL13) is a major B cell chemoattractant to B cell follicles in secondary lymphoid organs (SLO) that proposedly recruits B cells to the cerebrospinal fluid (CSF) during neuroinflammation. CXCR5, the cognate receptor of CXCL13, is expressed on B cells and certain T cell subsets, in particular T follicular helper cells (Tfh cells), enabling them to follow CXCL13 gradients towards B cell follicles for spatial proximity, a prerequisite for productive T cell–B cell interaction. Tfh cells are essential contributors to B cell proliferation, differentiation, and high-affinity antibody synthesis and are required for germinal center formation and maintenance. Circulating Tfh cells (cTfh) have been observed in the peripheral blood and CSF. Furthermore, CXCL13/CXCR5-associated immune activities organize and shape adaptive B cell-related immune responses outside of SLO via the formation of ectopic lymphoid structures in inflamed tissues, including the central nervous system (CNS). This review summarizes the recent advances in our understanding of the CXCL13/CXCR5 immune axis and its role in vaccination, autoimmunity, and infection with a special focus on its relevance for intrathecal B cell activities in inflammatory CNS diseases. Full article
(This article belongs to the Special Issue Frontiers in Neuroinflammation)
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25 pages, 6296 KiB  
Article
The Proteome Signatures of Fibroblasts from Patients with Severe, Intermediate and Mild Spinal Muscular Atrophy Show Limited Overlap
by Sharon J. Brown, Rachel A. Kline, Silvia A. Synowsky, Sally L. Shirran, Ian Holt, Kelly A. Sillence, Peter Claus, Brunhilde Wirth, Thomas M. Wishart and Heidi R. Fuller
Cells 2022, 11(17), 2624; https://doi.org/10.3390/cells11172624 - 23 Aug 2022
Cited by 5 | Viewed by 2751
Abstract
Most research to characterise the molecular consequences of spinal muscular atrophy (SMA) has focused on SMA I. Here, proteomic profiling of skin fibroblasts from severe (SMA I), intermediate (SMA II), and mild (SMA III) patients, alongside age-matched controls, was conducted using SWATH mass [...] Read more.
Most research to characterise the molecular consequences of spinal muscular atrophy (SMA) has focused on SMA I. Here, proteomic profiling of skin fibroblasts from severe (SMA I), intermediate (SMA II), and mild (SMA III) patients, alongside age-matched controls, was conducted using SWATH mass spectrometry analysis. Differentially expressed proteomic profiles showed limited overlap across each SMA type, and variability was greatest within SMA II fibroblasts, which was not explained by SMN2 copy number. Despite limited proteomic overlap, enriched canonical pathways common to two of three SMA severities with at least one differentially expressed protein from the third included mTOR signalling, regulation of eIF2 and eIF4 signalling, and protein ubiquitination. Network expression clustering analysis identified protein profiles that may discriminate or correlate with SMA severity. From these clusters, the differential expression of PYGB (SMA I), RAB3B (SMA II), and IMP1 and STAT1 (SMA III) was verified by Western blot. All SMA fibroblasts were transfected with an SMN-enhanced construct, but only RAB3B expression in SMA II fibroblasts demonstrated an SMN-dependent response. The diverse proteomic profiles and pathways identified here pave the way for studies to determine their utility as biomarkers for patient stratification or monitoring treatment efficacy and for the identification of severity-specific treatments. Full article
(This article belongs to the Special Issue Proteomic Applications in Ageing and Neurodegenerative Conditions)
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18 pages, 5314 KiB  
Article
Pathogenetic Mechanisms Underlying Spinocerebellar Ataxia Type 3 Are Altered in Primary Oligodendrocyte Culture
by Kristen H. Schuster, Alexandra F. Putka and Hayley S. McLoughlin
Cells 2022, 11(16), 2615; https://doi.org/10.3390/cells11162615 - 22 Aug 2022
Cited by 7 | Viewed by 2397
Abstract
Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of [...] Read more.
Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of the of the earliest and most robust changes in vulnerable regions of the SCA3 mouse brain. However, the cell- and disease-specific mechanisms that underlie oligodendrocyte dysfunction remain poorly understood and are difficult to isolate in vivo. In this study, we used primary oligodendrocyte cultures to determine how known pathogenic SCA3 mechanisms affect this cell type. We isolated oligodendrocyte progenitor cells from 5- to 7-day-old mice that overexpress human mutant ATXN3 or lack mouse ATXN3 and differentiated them for up to 5 days in vitro. Utilizing immunocytochemistry, we characterized the contributions of ATXN3 toxic gain-of-function and loss-of-function in oligodendrocyte maturation, protein quality pathways, DNA damage signaling, and methylation status. We illustrate the utility of primary oligodendrocyte culture for elucidating cell-specific pathway dysregulation relevant to SCA3. Given recent work demonstrating disease-associated oligodendrocyte signatures in other neurodegenerative diseases, this novel model has broad applicability in revealing mechanistic insights of oligodendrocyte contribution to pathogenesis. Full article
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15 pages, 2191 KiB  
Article
A Multi-Strain Probiotic Formulation Improves Intestinal Barrier Function by the Modulation of Tight and Adherent Junction Proteins
by Raffaella di Vito, Carmela Conte and Giovanna Traina
Cells 2022, 11(16), 2617; https://doi.org/10.3390/cells11162617 - 22 Aug 2022
Cited by 13 | Viewed by 4087
Abstract
In healthy individuals, tight junction proteins (TJPs) maintain the integrity of the intestinal barrier. Dysbiosis and increased intestinal permeability are observed in several diseases, such as inflammatory bowel disease. Many studies highlight the role of probiotics in preventing intestinal barrier dysfunction. The present [...] Read more.
In healthy individuals, tight junction proteins (TJPs) maintain the integrity of the intestinal barrier. Dysbiosis and increased intestinal permeability are observed in several diseases, such as inflammatory bowel disease. Many studies highlight the role of probiotics in preventing intestinal barrier dysfunction. The present study aims to investigate the effects of a commercially available probiotic formulation of L. rhamnosus LR 32, B. lactis BL 04, and B. longum BB 536 (Serobioma, Bromatech s.r.l., Milan, Italy) on TJPs and the integrity of the intestinal epithelial barrier, and the ability of this formulation to prevent lipopolysaccharide-induced, inflammation-associated damage. An in vitro model of the intestinal barrier was developed using a Caco-2 cell monolayer. The mRNA expression levels of the TJ genes were analyzed using real-time PCR. Changes in the amounts of proteins were assessed with Western blotting. The effect of Serobioma on the intestinal epithelial barrier function was assessed using transepithelial electrical resistance (TEER) measurements. The probiotic formulation tested in this study modulates the expression of TJPs and prevents inflammatory damage. Our findings provide new insights into the mechanisms by which probiotics are able to prevent damage to the gut epithelial barrier. Full article
(This article belongs to the Special Issue Gut Microbiota in Nutrition and Health)
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32 pages, 5494 KiB  
Article
Single Cell Analysis of Cultivated Fibroblasts from Chronic Pancreatitis and Pancreatic Cancer Patients
by Yoshiaki Sunami, Yijun Chen, Bogusz Trojanowicz, Matthias Sommerer, Monika Hämmerle, Roland Eils and Jörg Kleeff
Cells 2022, 11(16), 2583; https://doi.org/10.3390/cells11162583 - 19 Aug 2022
Cited by 3 | Viewed by 2876
Abstract
Cancer-associated fibroblasts (CAFs) play a major role in the progression and drug resistance of pancreatic cancer. Recent studies suggest that CAFs exhibit functional heterogeneity and distinct transcriptomic signatures in pancreatic cancer. Pancreatic fibroblasts also form an integral component in pancreatic diseases such as [...] Read more.
Cancer-associated fibroblasts (CAFs) play a major role in the progression and drug resistance of pancreatic cancer. Recent studies suggest that CAFs exhibit functional heterogeneity and distinct transcriptomic signatures in pancreatic cancer. Pancreatic fibroblasts also form an integral component in pancreatic diseases such as chronic pancreatitis named disease-associated fibroblasts (DAFs). However, intra-tumoral heterogeneity of CAFs in pancreatic cancer patients and their pivotal role in cancer-related mechanisms have not been fully elucidated. Further, it has not been elucidated whether CAF subtypes identified in pancreatic cancer also exist in chronic pancreatitis. In this study, we used primary isolated fibroblasts from pancreatic cancer and chronic pancreatitis patients using the outgrowth method. Single-cell RNA sequencing (scRNA-seq) was performed, and bioinformatics analysis identified highly variable genes, including factors associated with overall survival of pancreatic cancer patients. The majority of highly variable genes are involved in the cell cycle. Instead of previously classified myofibroblastic (myCAFs), inflammatory (iCAFs), and antigen-presenting (ap) CAFs, we identified a myCAFs-like subtype in all cases. Most interestingly, after cell cycle regression, we observed 135 highly variable genes commonly identified in chronic pancreatitis and pancreatic cancer patients. This study is the first to conduct scRNAseq and bioinformatics analyses to compare CAFs/DAFs from both chronic pancreatitis and pancreatic cancer patients. Further studies are required to select and identify stromal factors in DAFs from chronic pancreatitis cases, which are commonly expressed also in CAFs potentially contributing to pancreatic cancer development. Full article
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21 pages, 6615 KiB  
Review
Corneal Regeneration Using Adipose-Derived Mesenchymal Stem Cells
by Jorge L. Alió del Barrio, Ana De la Mata, María P. De Miguel, Francisco Arnalich-Montiel, Teresa Nieto-Miguel, Mona El Zarif, Marta Cadenas-Martín, Marina López-Paniagua, Sara Galindo, Margarita Calonge and Jorge L. Alió
Cells 2022, 11(16), 2549; https://doi.org/10.3390/cells11162549 - 16 Aug 2022
Cited by 14 | Viewed by 3568
Abstract
Adipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular [...] Read more.
Adipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular lineages, to show immunomodulatory properties, and to promote tissue regeneration by a paracrine action through the secretion of extracellular vesicles containing trophic factors. This secretome is currently being investigated as a potential source for a cell-free based regenerative therapy for human tissues, which would significantly reduce the involved costs, risks and law regulations, allowing for a broader application in real clinical practice. In the current article, we will review the existing preclinical and human clinical evidence regarding the use of such adipose-derived mesenchymal stem cells for the regeneration of the three main layers of the human cornea: the epithelium (derived from the surface ectoderm), the stroma (derived from the neural crest mesenchyme), and the endothelium (derived from the neural crest cells). Full article
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13 pages, 2474 KiB  
Article
Integrated Multi-Omics Signature Predicts Survival in Head and Neck Cancer
by Ilda Patrícia Ribeiro, Luísa Esteves, Francisco Caramelo, Isabel Marques Carreira and Joana Barbosa Melo
Cells 2022, 11(16), 2536; https://doi.org/10.3390/cells11162536 - 16 Aug 2022
Cited by 4 | Viewed by 1658
Abstract
Head and Neck Cancer (HNC) is characterized by phenotypic, biological, and clinical heterogeneity. Despite treatment modalities, approximately half of all patients will die of the disease. Several molecular biomarkers have been investigated, but until now, without clinical translation. Here, we identified an integrative [...] Read more.
Head and Neck Cancer (HNC) is characterized by phenotypic, biological, and clinical heterogeneity. Despite treatment modalities, approximately half of all patients will die of the disease. Several molecular biomarkers have been investigated, but until now, without clinical translation. Here, we identified an integrative nine-gene multi-omics signature correlated with HNC patients’ survival independently of relapses or metastasis development. This prognosis multi-omic signature comprises genes mapped in the chromosomes 1q, 3p, 8q, 17q, 19p, and 19q and encompasses alterations at copy number, gene expression, and methylation. Copy number alterations in LMCD1-A1S and GRM7, the methylation status of CEACAM19, KRT17, and ST18, and the expression profile of RPL29, UBA7, FCGR2C, and RPSAP58 can predict the HNC patients’ survival. The difference higher than two years observed in the survival of HNC patients that harbor this nine-gene multi-omics signature can represent a significant step forward to improve patients’ management and guide new therapeutic targets development. Full article
(This article belongs to the Special Issue Early Biomarkers of Cancer: Diagnosis and Progression)
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13 pages, 2934 KiB  
Article
Oxidative Stress Is Associated with Overgrowth in Drosophila l(3)mbt Mutant Imaginal Discs
by Paula Climent-Cantó, Cristina Molnar, Paula Santabárbara-Ruiz, Cristina Prieto, Josep F. Abril, Florenci Serras and Cayetano Gonzalez
Cells 2022, 11(16), 2542; https://doi.org/10.3390/cells11162542 - 16 Aug 2022
Viewed by 1783
Abstract
The loss-of-function conditions for an l(3)malignant brain tumour (l(3)mbt) in larvae reared at 29 °C results in malignant brain tumours and hyperplastic imaginal discs. Unlike the former that have been extensively characterised, little is known about the latter. Here we report [...] Read more.
The loss-of-function conditions for an l(3)malignant brain tumour (l(3)mbt) in larvae reared at 29 °C results in malignant brain tumours and hyperplastic imaginal discs. Unlike the former that have been extensively characterised, little is known about the latter. Here we report the results of a study of the hyperplastic l(3)mbt mutant wing imaginal discs. We identify the l(3)mbt wing disc tumour transcriptome and find it to include genes involved in reactive oxygen species (ROS) metabolism. Furthermore, we show the presence of oxidative stress in l(3)mbt hyperplastic discs, even in apoptosis-blocked conditions, but not in l(3)mbt brain tumours. We also find that chemically blocking oxidative stress in l(3)mbt wing discs reduces the incidence of wing disc overgrowths. Our results reveal the involvement of oxidative stress in l(3)mbt wing discs hyperplastic growth. Full article
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16 pages, 3108 KiB  
Article
Integration of Human Protein Sequence and Protein-Protein Interaction Data by Graph Autoencoder to Identify Novel Protein-Abnormal Phenotype Associations
by Yuan Liu, Ruirui He, Yingjie Qu, Yuan Zhu, Dianke Li, Xinping Ling, Simin Xia, Zhenqiu Li and Dong Li
Cells 2022, 11(16), 2485; https://doi.org/10.3390/cells11162485 - 10 Aug 2022
Cited by 4 | Viewed by 2215
Abstract
Understanding gene functions and their associated abnormal phenotypes is crucial in the prevention, diagnosis and treatment against diseases. The Human Phenotype Ontology (HPO) is a standardized vocabulary for describing the phenotype abnormalities associated with human diseases. However, the current HPO annotations are far [...] Read more.
Understanding gene functions and their associated abnormal phenotypes is crucial in the prevention, diagnosis and treatment against diseases. The Human Phenotype Ontology (HPO) is a standardized vocabulary for describing the phenotype abnormalities associated with human diseases. However, the current HPO annotations are far from completion, and only a small fraction of human protein-coding genes has HPO annotations. Thus, it is necessary to predict protein-phenotype associations using computational methods. Protein sequences can indicate the structure and function of the proteins, and interacting proteins are more likely to have same function. It is promising to integrate these features for predicting HPO annotations of human protein. We developed GraphPheno, a semi-supervised method based on graph autoencoders, which does not require feature engineering to capture deep features from protein sequences, while also taking into account the topological properties in the protein–protein interaction network to predict the relationships between human genes/proteins and abnormal phenotypes. Cross validation and independent dataset tests show that GraphPheno has satisfactory prediction performance. The algorithm is further confirmed on automatic HPO annotation for no-knowledge proteins under the benchmark of the second Critical Assessment of Functional Annotation, 2013–2014 (CAFA2), where GraphPheno surpasses most existing methods. Further bioinformatics analysis shows that predicted certain phenotype-associated genes using GraphPheno share similar biological properties with known ones. In a case study on the phenotype of abnormality of mitochondrial respiratory chain, top prioritized genes are validated by recent papers. We believe that GraphPheno will help to reveal more associations between genes and phenotypes, and contribute to the discovery of drug targets. Full article
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20 pages, 4849 KiB  
Article
Membrane Properties of Human Induced Pluripotent Stem Cell-Derived Cultured Red Blood Cells
by Claudia Bernecker, Eva Maria Matzhold, Dagmar Kolb, Afrim Avdili, Lisa Rohrhofer, Annika Lampl, Martin Trötzmüller, Heike Singer, Johannes Oldenburg, Peter Schlenke and Isabel Dorn
Cells 2022, 11(16), 2473; https://doi.org/10.3390/cells11162473 - 09 Aug 2022
Cited by 3 | Viewed by 3523
Abstract
Cultured red blood cells from human induced pluripotent stem cells (cRBC_iPSCs) are a promising source for future concepts in transfusion medicine. Before cRBC_iPSCs will have entrance into clinical or laboratory use, their functional properties and safety have to be carefully validated. Due to [...] Read more.
Cultured red blood cells from human induced pluripotent stem cells (cRBC_iPSCs) are a promising source for future concepts in transfusion medicine. Before cRBC_iPSCs will have entrance into clinical or laboratory use, their functional properties and safety have to be carefully validated. Due to the limitations of established culture systems, such studies are still missing. Improved erythropoiesis in a recently established culture system, closer simulating the physiological niche, enabled us to conduct functional characterization of enucleated cRBC_iPSCs with a focus on membrane properties. Morphology and maturation stage of cRBC_iPSCs were closer to native reticulocytes (nRETs) than to native red blood cells (nRBCs). Whereas osmotic resistance of cRBC_iPSCs was similar to nRETs, their deformability was slightly impaired. Since no obvious alterations in membrane morphology, lipid composition, and major membrane associated protein patterns were observed, reduced deformability might be caused by a more primitive nature of cRBC_iPSCs comparable to human embryonic- or fetal liver erythropoiesis. Blood group phenotyping of cRBC_iPSCs further confirmed the potency of cRBC_iPSCs as a prospective device in pre-transfusional routine diagnostics. Therefore, RBC membrane analyses obtained in this study underscore the overall prospects of cRBC_iPSCs for their future application in the field of transfusion medicine. Full article
(This article belongs to the Collection Advances in Red Blood Cells Research)
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11 pages, 2526 KiB  
Communication
PARA: A New Platform for the Rapid Assembly of gRNA Arrays for Multiplexed CRISPR Technologies
by Guoliang Yuan, Stanton Martin, Md Mahmudul Hassan, Gerald A. Tuskan and Xiaohan Yang
Cells 2022, 11(16), 2467; https://doi.org/10.3390/cells11162467 - 09 Aug 2022
Cited by 8 | Viewed by 2923
Abstract
Multiplexed CRISPR technologies have great potential for pathway engineering and genome editing. However, their applications are constrained by complex, laborious and time-consuming cloning steps. In this research, we developed a novel method, PARA, which allows for the one-step assembly of multiple guide RNAs [...] Read more.
Multiplexed CRISPR technologies have great potential for pathway engineering and genome editing. However, their applications are constrained by complex, laborious and time-consuming cloning steps. In this research, we developed a novel method, PARA, which allows for the one-step assembly of multiple guide RNAs (gRNAs) into a CRISPR vector with up to 18 gRNAs. Here, we demonstrate that PARA is capable of the efficient assembly of transfer RNA/Csy4/ribozyme-based gRNA arrays. To aid in this process and to streamline vector construction, we developed a user-friendly PARAweb tool for designing PCR primers and component DNA parts and simulating assembled gRNA arrays and vector sequences. Full article
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22 pages, 6182 KiB  
Article
Screening Biophysical Sensors and Neurite Outgrowth Actuators in Human Induced-Pluripotent-Stem-Cell-Derived Neurons
by Vaibhav P. Pai, Ben G. Cooper and Michael Levin
Cells 2022, 11(16), 2470; https://doi.org/10.3390/cells11162470 - 09 Aug 2022
Cited by 2 | Viewed by 2973
Abstract
All living cells maintain a charge distribution across their cell membrane (membrane potential) by carefully controlled ion fluxes. These bioelectric signals regulate cell behavior (such as migration, proliferation, differentiation) as well as higher-level tissue and organ patterning. Thus, voltage gradients represent an important [...] Read more.
All living cells maintain a charge distribution across their cell membrane (membrane potential) by carefully controlled ion fluxes. These bioelectric signals regulate cell behavior (such as migration, proliferation, differentiation) as well as higher-level tissue and organ patterning. Thus, voltage gradients represent an important parameter for diagnostics as well as a promising target for therapeutic interventions in birth defects, injury, and cancer. However, despite much progress in cell and molecular biology, little is known about bioelectric states in human stem cells. Here, we present simple methods to simultaneously track ion dynamics, membrane voltage, cell morphology, and cell activity (pH and ROS), using fluorescent reporter dyes in living human neurons derived from induced neural stem cells (hiNSC). We developed and tested functional protocols for manipulating ion fluxes, membrane potential, and cell activity, and tracking neural responses to injury and reinnervation in vitro. Finally, using morphology sensor, we tested and quantified the ability of physiological actuators (neurotransmitters and pH) to manipulate nerve repair and reinnervation. These methods are not specific to a particular cell type and should be broadly applicable to the study of bioelectrical controls across a wide range of combinations of models and endpoints. Full article
(This article belongs to the Special Issue Molecular Bioelectricity and Cell Behaviour)
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19 pages, 2110 KiB  
Article
Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1
by Ying Jiang, Vitalyi Senyuk, Ke Ma, Hui Chen, Xiang Qin, Shun Li, Yiyao Liu, Saverio Gentile and Richard D. Minshall
Cells 2022, 11(15), 2461; https://doi.org/10.3390/cells11152461 - 08 Aug 2022
Cited by 5 | Viewed by 2190
Abstract
The prevention of metastasis is a central goal of cancer therapy. Caveolin-1 (Cav-1) is a structural membrane and scaffolding protein shown to be a key regulator of late-stage breast cancer metastasis. However, therapeutic strategies targeting Cav-1 are still lacking. Here, we demonstrate that [...] Read more.
The prevention of metastasis is a central goal of cancer therapy. Caveolin-1 (Cav-1) is a structural membrane and scaffolding protein shown to be a key regulator of late-stage breast cancer metastasis. However, therapeutic strategies targeting Cav-1 are still lacking. Here, we demonstrate that the pharmacological activation of potassium channel Kv11.1, which is uniquely expressed in MDA-MB-231 triple negative breast cancer cells (TNBCs) but not in normal MCF-10A cells, induces the dephosphorylation of Cav-1 Tyr-14 by promoting the Ca2+-dependent stimulation of protein tyrosine phosphatase 1B (PTP1B). Consequently, the dephosphorylation of Cav-1 resulted in its disassociation from β-catenin, which enabled the accumulation of β-catenin at cell borders, where it facilitated the formation of cell–cell adhesion complexes via interactions with R-cadherin and desmosomal proteins. Kv11.1 activation-dependent Cav-1 dephosphorylation induced with NS1643 also reduced cell migration and invasion, consistent with its ability to regulate focal adhesion dynamics. Thus, this study sheds light on a novel pharmacological mechanism of promoting Cav-1 dephosphorylation, which may prove to be effective at reducing metastasis and promoting contact inhibition. Full article
(This article belongs to the Collection Feature Papers in Cell Motility and Adhesion)
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12 pages, 2223 KiB  
Article
Spectral Library-Based Single-Cell Proteomics Resolves Cellular Heterogeneity
by Lakmini Senavirathna, Cheng Ma, Ru Chen and Sheng Pan
Cells 2022, 11(15), 2450; https://doi.org/10.3390/cells11152450 - 07 Aug 2022
Cited by 6 | Viewed by 2547
Abstract
Dissecting the proteome of cell types and states at single-cell resolution, while being highly challenging, has significant implications in basic science and biomedicine. Mass spectrometry (MS)-based single-cell proteomics represents an emerging technology for system-wide, unbiased profiling of proteins in single cells. However, significant [...] Read more.
Dissecting the proteome of cell types and states at single-cell resolution, while being highly challenging, has significant implications in basic science and biomedicine. Mass spectrometry (MS)-based single-cell proteomics represents an emerging technology for system-wide, unbiased profiling of proteins in single cells. However, significant challenges remain in analyzing an extremely small amount of proteins collected from a single cell, as a proteome-wide amplification of proteins is not currently feasible. Here, we report an integrated spectral library-based single-cell proteomics (SLB-SCP) platform that is ultrasensitive and well suited for a large-scale analysis. To overcome the low MS/MS signal intensity intrinsically associated with a single-cell analysis, this approach takes an alternative approach by extracting a breadth of information that specifically defines the physicochemical characteristics of a peptide from MS1 spectra, including monoisotopic mass, isotopic distribution, and retention time (hydrophobicity), and uses a spectral library for proteomic identification. This conceptually unique MS platform, coupled with the DIRECT sample preparation method, enabled identification of more than 2000 proteins in a single cell to distinguish different proteome landscapes associated with cellular types and heterogeneity. We characterized individual normal and cancerous pancreatic ductal cells (HPDE and PANC-1, respectively) and demonstrated the substantial difference in the proteomes between HPDE and PANC-1 at the single-cell level. A significant upregulation of multiple protein networks in cancer hallmarks was identified in the PANC-1 cells, functionally discriminating the PANC-1 cells from the HPDE cells. This integrated platform can be built on high-resolution MS and widely accepted proteomic software, making it possible for community-wide applications. Full article
(This article belongs to the Collection Deciphering the Proteome in Cell Biology and Diseases)
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15 pages, 2955 KiB  
Article
Cytosolic HMGB1 Mediates LPS-Induced Autophagy in Microglia by Interacting with NOD2 and Suppresses Its Proinflammatory Function
by Seung-Woo Kim, Sang-A Oh, Song-I Seol, Dashdulam Davaanyam and Ja-Kyeong Lee
Cells 2022, 11(15), 2410; https://doi.org/10.3390/cells11152410 - 04 Aug 2022
Cited by 7 | Viewed by 2695
Abstract
The high mobility group box 1 (HMGB1), a well-known danger-associated molecule pattern (DAMP) molecule, is a non-histone chromosomal protein localized in the nucleus under normal physiological conditions. HMGB1 exhibits diverse functions depending on its subcellular location. In the present study, we investigated the [...] Read more.
The high mobility group box 1 (HMGB1), a well-known danger-associated molecule pattern (DAMP) molecule, is a non-histone chromosomal protein localized in the nucleus under normal physiological conditions. HMGB1 exhibits diverse functions depending on its subcellular location. In the present study, we investigated the role of HMGB1-induced autophagy in the lipopolysaccharide (LPS)-treated BV2 microglial cell line in mediating the transition between the inflammatory and autophagic function of the nucleotide-binding oligomerization domain-containing 2 (NOD2), a cytoplasmic pattern-recognition receptor. The induction of the microtubule-associated protein 1 light chain 3 (LC3), an autophagy biomarker, was detected slowly in BV2 cells after the LPS treatment, and peak induction was detected at 12 h. Under these conditions, NOD2 level was significantly increased and the binding between HMGB1 and NOD2 and between HMGB1 and ATG16L1 was markedly enhanced and the temporal profiles of the LC3II induction and HMGB1-NOD2 and HMGB1-ATG16L1 complex formation coincided with the cytosolic accumulation of HMGB1. The LPS-mediated autophagy induction was significantly suppressed in BV2 cells after HMGB1 or NOD2 knock-down (KD), indicating that HMGB1 contributes to NOD2-mediated autophagy induction in microglia. Moreover, NOD2-RIP2 interaction-mediated pro-inflammatory cytokine induction and NF-κB activity were significantly enhanced in BV2 cells after HMGB1 KD, indicating that HMGB1 plays a critical role in the modulation of NOD2 function between pro-inflammation and pro-autophagy in microglia. The effects of the cell-autonomous pro-autophagic pathway operated by cytoplasmic HMGB1 may be beneficial, whereas those from the paracrine pro-inflammatory pathway executed by extracellularly secreted HMGB1 can be detrimental. Thus, the overall functional significance of HMGB1-induced autophagy is different, depending on its temporal activity. Full article
(This article belongs to the Special Issue Autophagy in the Nervous System)
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47 pages, 7312 KiB  
Review
BMP Signaling Pathway in Dentin Development and Diseases
by Mengmeng Liu, Graham Goldman, Mary MacDougall and Shuo Chen
Cells 2022, 11(14), 2216; https://doi.org/10.3390/cells11142216 - 16 Jul 2022
Cited by 25 | Viewed by 6553
Abstract
BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction [...] Read more.
BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described. Full article
(This article belongs to the Special Issue Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases)
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