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Stem Cell Activation in Adult Organism 2023

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 17547

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Prof. Dr. Daniela Salvatori

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Department of Clinical Sciences, Anatomy and Physiology, Faculty of Veterinary Medicine, Utrecht University, 3584 Utrecht, The Netherlands
Interests: pluripotent stem cells; cardiology; mouse models; gene therapy; nuclear reprogramming
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Dear Colleagues,

Research on stem cells has developed as a promising area of biology in the last few decades. Meanwhile, the potential of stem cell-based tissue regeneration in adult organisms is recognized for nearly all organs and tissues, such as muscle, heart, brain, lung, mesenchymal, epithelial, and connective tissues. At the beginning of stem cell research for regeneration and repair in adults, strong focus was placed on embryonic stem cells, followed by a search for adult stem cell populations, which can be used to replace specific organ and tissue cell types due to their high differentiation potential. In the last few years, it has been recognized that the stem cell potential of terminal, differentiated cells can be rescued by reprogramming. While initial strategies were orientated toward the ex vivo reprogramming of terminal differentiated cells into multipotent stem cells, increasing knowledge about the reprogramming mechanisms and the influencing factors supporting mobilization of tissue stem cells, or the reprogramming of tissue specific cells to stem and progenitor cells, is also currently allowing us to develop strategies for the endogenous mobilization of stem cells and the reprogramming of differentiated cells from different tissues. Local and systemic factors, such as cytokines, the extracellular matrix, and supporting cells, are crucial for understanding mobilization strategies. These strategies can be used for systemic and local stem cell-based therapy.

This Special Issue will cover a selection of recent research topics and current review articles in the field of stem cell research for the regeneration and repair of different tissues and organs in adult organisms. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Prof. Dr. Daniela Salvatori
Guest Editor

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Keywords

adult stem cell
reprogramming
stem cell therapy
signaling and mechanism
growth factors
extra cellular matrix
homing
transdifferentiation

Related Special Issue

Stem Cell Activation in Adult Organism 2.0 in International Journal of Molecular Sciences (31 articles)

Published Papers (10 papers)

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Research

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25 pages, 4150 KiB

Open AccessArticle

Adult Neurogenesis of the Medial Geniculate Body: In Vitro and Molecular Genetic Analyses Reflect the Neural Stem Cell Capacity of the Rat Auditory Thalamus over Time

by Jonas Engert, Bjoern Spahn, Sabine Sommerer, Totta Ehret Kasemo, Stephan Hackenberg, Kristen Rak and Johannes Voelker

Int. J. Mol. Sci. 2024, 25(5), 2623; https://doi.org/10.3390/ijms25052623 - 23 Feb 2024

Viewed by 506

Abstract

Neural stem cells (NSCs) have been recently identified in the neonatal rat medial geniculate body (MGB). NSCs are characterized by three cardinal features: mitotic self-renewal, formation of progenitors, and differentiation into all neuroectodermal cell lineages. NSCs and the molecular factors affecting them are particularly interesting, as they present a potential target for treating neurologically based hearing disorders. It is unclear whether an NSC niche exists in the rat MGB up to the adult stage and which neurogenic factors are essential during maturation. The rat MGB was examined on postnatal days 8, 12, and 16, and at the adult stadium. The cardinal features of NSCs were detected in MGB cells of all age groups examined by neurosphere, passage, and differentiation assays. In addition, real-time quantitative polymerase chain reaction arrays were used to compare the mRNA levels of 84 genes relevant to NSCs and neurogenesis. In summary, cells of the MGB display the cardinal features of NSCs up to the adult stage with a decreasing NSC potential over time. Neurogenic factors with high importance for MGB neurogenesis were identified on the mRNA level. These findings should contribute to a better understanding of MGB neurogenesis and its regenerative capacity. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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19 pages, 6134 KiB

Open AccessArticle

Serum-Induced Proliferation of Human Cardiac Stem Cells Is Modulated via TGFβRI/II and SMAD2/3

by Kazuko E. Schmidt, Anna L. Höving, Sina Kiani Zahrani, Katerina Trevlopoulou, Barbara Kaltschmidt, Cornelius Knabbe and Christian Kaltschmidt

Int. J. Mol. Sci. 2024, 25(2), 959; https://doi.org/10.3390/ijms25020959 - 12 Jan 2024

Cited by 1 | Viewed by 790

Abstract

The ageing phenotype is strongly driven by the exhaustion of adult stem cells (ASCs) and the accumulation of senescent cells. Cardiovascular diseases (CVDs) and heart failure (HF) are strongly linked to the ageing phenotype and are the leading cause of death. As the human heart is considered as an organ with low regenerative capacity, treatments targeting the rejuvenation of human cardiac stem cells (hCSCs) are of great interest. In this study, the beneficial effects of human blood serum on proliferation and senescence of hCSCs have been investigated at the molecular level. We show the induction of a proliferation-related gene expression response by human blood serum at the mRNA level. The concurrent differential expression of the TGFβ target and inhibitor genes indicates the participation of TGFβ signalling in this context. Surprisingly, the application of TGFβ1 as well as the inhibition of TGFβ type I and type II receptor (TGFβRI/II) signalling strongly increased the proliferation of hCSCs. Likewise, both human blood serum and TGFβ1 reduced the senescence in hCSCs. The protective effect of serum on senescence in hCSCs was enhanced by simultaneous TGFβRI/II inhibition. These results strongly indicate a dual role of TGFβ signalling in terms of the serum-mediated effects on hCSCs. Further analysis via RNA sequencing (RNA-Seq) revealed the participation of Ras-inactivating genes wherefore a prevention of hyperproliferation upon serum-treatment in hCSCs via TGFβ signalling and Ras-induced senescence is suggested. These insights may improve treatments of heart failure in the future. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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21 pages, 7264 KiB

Open AccessArticle

CRISPR/Cas9 Directed Reprogramming of iPSC for Accelerated Motor Neuron Differentiation Leads to Dysregulation of Neuronal Fate Patterning and Function

by Katie Davis-Anderson, Sofiya Micheva-Viteva, Emilia Solomon, Blake Hovde, Elisa Cirigliano, Jennifer Harris, Scott Twary and Rashi Iyer

Int. J. Mol. Sci. 2023, 24(22), 16161; https://doi.org/10.3390/ijms242216161 - 10 Nov 2023

Viewed by 1170

Abstract

Neurodegeneration causes a significant disease burden and there are few therapeutic interventions available for reversing or slowing the disease progression. Induced pluripotent stem cells (iPSCs) hold significant potential since they are sourced from adult tissue and have the capacity to be differentiated into numerous cell lineages, including motor neurons. This differentiation process traditionally relies on cell lineage patterning factors to be supplied in the differentiation media. Genetic engineering of iPSC with the introduction of recombinant master regulators of motor neuron (MN) differentiation has the potential to shorten and streamline cell developmental programs. We have established stable iPSC cell lines with transient induction of exogenous LHX3 and ISL1 from the Tet-activator regulatory region and have demonstrated that induction of the transgenes is not sufficient for the development of mature MNs in the absence of neuron patterning factors. Comparative global transcriptome analysis of MN development from native and Lhx-ISL1 modified iPSC cultures demonstrated that the genetic manipulation helped to streamline the neuronal patterning process. However, leaky gene expression of the exogenous MN master regulators in iPSC resulted in the premature activation of genetic pathways characteristic of the mature MN function. Dysregulation of metabolic and regulatory pathways within the developmental process affected the MN electrophysiological responses. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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17 pages, 12270 KiB

Open AccessArticle

AKAP1 Regulates Mitochondrial Dynamics during the Fatty-Acid-Promoted Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Indicated by Proteomics Sequencing

by Han Xiang, Hao Xu, Bin Tan, Qin Yi, Xinyuan Zhang, Rui Wang, Tangtian Chen, Qiumin Xie, Jie Tian and Jing Zhu

Int. J. Mol. Sci. 2023, 24(9), 8112; https://doi.org/10.3390/ijms24098112 - 30 Apr 2023

Viewed by 1492

Abstract

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are cells with promising applications. However, their immaturity has restricted their use in cell therapy, disease modeling, and other studies. Therefore, the current study focused on inducing the maturation of CMs. We supplemented hiPSC-CMs with fatty acids (FAs) to promote their phenotypic maturity. Proteomic sequencing was performed to identify regulators critical for promoting the maturation of hiPSC-CMs. AKAP1 was found to be significantly increased in FA-treated hiPSC-CMs, and the results were verified. Therefore, we inhibited AKAP1 expression in the FA-treated cells and analyzed the outcomes. FA supplementation promoted the morphological and functional maturation of the hiPSC-CMs, which was accompanied by the development of a mitochondrial network. Proteomic analysis results revealed that AKAP1 expression was significantly higher in FA-treated hiPSC-CMs than in control cells. In addition, increased phosphorylation of the mitochondrial dynamin Drp1 and an increased mitochondrial fusion rate were found in FA-treated hiPSC-CMs. After AKAP1 was knocked down, the level of DRP1 phosphorylation in the cell was decreased, and the mitochondrial fusion rate was reduced. FA supplementation effectively promoted the maturation of hiPSC-CMs, and in these cells, AKAP1 regulated mitochondrial dynamics, possibly playing a significant role. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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13 pages, 4367 KiB

Open AccessArticle

Effects of Exosomes Derived from Adipose-Derived Mesenchymal Stem Cells on Pyroptosis and Regeneration of Injured Liver

by Chenxi Piao, Jinfang Sang, Zhipeng Kou, Yue Wang, Tao Liu, Xiangyu Lu, Zhihui Jiao and Hongbin Wang

Int. J. Mol. Sci. 2022, 23(20), 12065; https://doi.org/10.3390/ijms232012065 - 11 Oct 2022

Cited by 15 | Viewed by 1873

Abstract

Although accumulating evidence indicates that exosomes have a positive therapeutic effect on hepatic ischemia–reperfusion injury (HIRI), studies focusing on the alleviation of liver injury by exosomes derived from adipose-derived mesenchymal stem cells (ADSCs-Exo) based on the inhibition of cell pyroptosis have not yet been reported. Exosomes contain different kinds of biologically active substances such as proteins, lipids, mRNAs, miRNAs, and signaling molecules. These molecules are widely involved in cell–cell communication, cell signal transmission, proliferation, migration, and apoptosis. Therefore, we investigated the positive effects exerted by ADSCs-Exo after hepatic ischemia–reperfusion with partial resection injury in rats. In this study, we found that the post-operative tail vein injection of ADSCs-Exo could effectively inhibit the expression of pyroptosis-related factors such as NLRP3, ASC, caspase-1, and GSDMD-N, and promote the expression of regeneration-related factors such as Cyclin D1 and VEGF. Moreover, we found that the above cellular activities were associated with the NF-κB and Wnt/β-catenin signaling pathways. According to the results, ADSCs and ADSCs-Exo can reduce pyroptosis in the injured liver and promote the expression of those factors related to liver regeneration, while they can inhibit the NF-κB pathway and activate the Wnt/β-catenin pathway. However, although adipose-derived mesenchymal stem cell (ADSC) transplantation can reduce liver injury, it leads to a significant increase in the pyroptosis-related protein GSDMD-N expression. In conclusion, our study shows that ADSCs-Exo has unique advantages and significance as a cell-free therapy to replace stem cells and still has a broad research prospect in the clinical diagnosis and treatment of liver injuries. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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15 pages, 8271 KiB

Open AccessArticle

Damaged DNA Is an Early Event of Neurodegeneration in Induced Pluripotent Stem Cell-Derived Motoneurons with UBQLN2^P497H Mutation

by Yiti Zhang, Baitao Zeng, Ao Gu, Qinyu Kang, Mingri Zhao, Guangnan Peng, Miaojin Zhou, Wanxi Liu, Min Liu, Lingjie Ding, Desheng Liang, Xionghao Liu and Mujun Liu

Int. J. Mol. Sci. 2022, 23(19), 11333; https://doi.org/10.3390/ijms231911333 - 26 Sep 2022

Cited by 1 | Viewed by 1867

Abstract

Ubiquilin-2 (UBQLN2) mutations lead to familial amyotrophic lateral sclerosis (FALS)/and frontotemporal dementia (FTLD) through unknown mechanisms. The combination of iPSC technology and CRISPR-mediated genome editing technology can generate an iPSC-derived motor neuron (iPSC-MN) model with disease-relevant mutations, which results in increased opportunities for disease mechanism research and drug screening. In this study, we introduced a UBQLN2-P497H mutation into a healthy control iPSC line using CRISPR/Cas9, and differentiated into MNs to study the pathology of UBQLN2-related ALS. Our in vitro MN model faithfully recapitulated specific aspects of the disease, including MN apoptosis. Under sodium arsenite (SA) treatment, we found differences in the number and the size of UBQLN2⁺ inclusions in UBQLN2^P497H MNs and wild-type (WT) MNs. We also observed cytoplasmic TAR DNA-binding protein (TARDBP, also known as TDP-43) aggregates in UBQLN2^P497H MNs, but not in WT MNs, as well as the recruitment of TDP-43 into stress granules (SGs) upon SA treatment. We noted that UBQLN2-P497H mutation induced MNs DNA damage, which is an early event in UBQLN2-ALS. Additionally, DNA damage led to an increase in compensation for FUS, whereas UBQLN2-P497H mutation impaired this function. Therefore, FUS may be involved in DNA damage repair signaling. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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16 pages, 3451 KiB

Open AccessArticle

Osteogenic Efficacy of Human Trophoblasts-Derived Conditioned Medium on Mesenchymal Stem Cells

by Yoon-Young Go, Chan-Mi Lee, Sung-Won Chae and Jae-Jun Song

Int. J. Mol. Sci. 2022, 23(17), 10196; https://doi.org/10.3390/ijms231710196 - 05 Sep 2022

Cited by 2 | Viewed by 1875

Abstract

Trophoblasts play an important role in the regulation of the development and function of the placenta. Our recent study demonstrated the skin regeneration capacity of trophoblast-derived extracellular vesicles (EV). Here, we aimed to determine the potential of trophoblast-derived conditioned medium (TB-CM) in enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). We found that TB-CM promoted the osteogenic differentiation of MSCs in a dose-dependent manner. Furthermore, it inhibited adipogenesis of MSCs. We also found that the primary trophoblast-derived conditioned medium (PTB-CM) significantly enhanced the proliferation and osteogenic differentiation of human MSCs. Our study demonstrated the regulatory mechanisms underlying the TB-CM-induced osteogenesis in MSCs. An upregulation of genes associated with cytokines/chemokines was observed. The treatment of MSCs with TB-CM stimulated osteogenesis by activating several biological processes, such as mitogen-activated protein kinase (MAPK) and bone morphogenetic protein 2 (BMP2) signaling. This study demonstrated the proliferative and osteogenic efficacies of the trophoblast-derived secretomes, suggesting their potential for use in clinical interventions for bone regeneration and treatment. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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14 pages, 2675 KiB

Open AccessArticle

Fused Cells between Human-Adipose-Derived Mesenchymal Stem Cells and Monocytes Keep Stemness Properties and Acquire High Mobility

by Karla Montalbán-Hernández, Cesar Casado-Sánchez, José Avendaño-Ortiz, José Carlos Casalvilla-Dueñas, Gloria C. Bonel-Pérez, Julia Prado-Montero, Jaime Valentín-Quiroga, Roberto Lozano-Rodríguez, Verónica Terrón-Arcos, Fátima Ruiz de la Bastida, Laura Córdoba, Fernando Laso-García, Luke Diekhorst, Carlos del Fresno and Eduardo López-Collazo

Int. J. Mol. Sci. 2022, 23(17), 9672; https://doi.org/10.3390/ijms23179672 - 26 Aug 2022

Cited by 2 | Viewed by 1705

Abstract

Human-adipose-derived mesenchymal stem cells (hADMSCs) are multipotent stem cells which have become of great interest in stem-cell therapy due to their less invasive isolation. However, they have limited migration and short lifespans. Therefore, understanding the mechanisms by which these cells could migrate is of critical importance for regenerative medicine. Methods: Looking for novel alternatives, herein, hADMSCs were isolated from adipose tissue and co-cultured with human monocytes ex vivo. Results: A new fused hybrid entity, a foam hybrid cell (FHC), which was CD90⁺CD14⁺, resulted from this co-culture and was observed to have enhanced motility, proliferation, immunomodulation properties, and maintained stemness features. Conclusions: Our study demonstrates the generation of a new hybrid cellular population that could provide migration advantages to MSCs, while at the same time maintaining stemness properties. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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12 pages, 3074 KiB

Open AccessArticle

Human Pluripotent Stem Cell-Derived Alveolar Organoid with Macrophages

by Ha-Rim Seo, Hyeong-Jun Han, Youngsun Lee, Young-Woock Noh, Seung-Ju Cho and Jung-Hyun Kim

Int. J. Mol. Sci. 2022, 23(16), 9211; https://doi.org/10.3390/ijms23169211 - 16 Aug 2022

Cited by 9 | Viewed by 2928

Abstract

Alveolar organoids (AOs), derived from human pluripotent stem cells (hPSCs) exhibit lung-specific functions. Therefore, the application of AOs in pulmonary disease modeling is a promising tool for understanding disease pathogenesis. However, the lack of immune cells in organoids limits the use of human AOs as models of inflammatory diseases. In this study, we generated AOs containing a functional macrophage derived from hPSCs based on human fetal lung development using biomimetic strategies. We optimized culture conditions to maintain the iMACs (induced hPSC-derived macrophages) AOs for up to 14 days. In lipopolysaccharide (LPS)-induced inflammatory conditions, IL-1β, MCP-1 and TNF-α levels were significantly increased in iMAC-AOs, which were not detected in AOs. In addition, chemotactic factor IL-8, which is produced by mononuclear phagocytic cells, was induced by LPS treatment in iMACs-AOs. iMACs-AOs can be used to understand pulmonary infectious diseases and is a useful tool in identifying the mechanism of action of therapeutic drugs in humans. Our study highlights the importance of immune cell presentation in AOs for modeling inflammatory pulmonary diseases. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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Review

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13 pages, 1462 KiB

Open AccessReview

Teratoma Assay for Testing Pluripotency and Malignancy of Stem Cells: Insufficient Reporting and Uptake of Animal-Free Methods—A Systematic Review

by Joaquin Montilla-Rojo, Monika Bialecka, Kimberley E. Wever, Christine L. Mummery, Leendert H. J. Looijenga, Bernard A. J. Roelen and Daniela C. F. Salvatori

Int. J. Mol. Sci. 2023, 24(4), 3879; https://doi.org/10.3390/ijms24043879 - 15 Feb 2023

Cited by 1 | Viewed by 2615

Abstract

Pluripotency describes the ability of stem cells to differentiate into derivatives of the three germ layers. In reporting new human pluripotent stem cell lines, their clonal derivatives or the safety of differentiated derivatives for transplantation, assessment of pluripotency is essential. Historically, the ability to form teratomas in vivo containing different somatic cell types following injection into immunodeficient mice has been regarded as functional evidence of pluripotency. In addition, the teratomas formed can be analyzed for the presence of malignant cells. However, use of this assay has been subject to scrutiny for ethical reasons on animal use and due to the lack of standardization in how it is used, therefore questioning its accuracy. In vitro alternatives for assessing pluripotency have been developed such as ScoreCard and PluriTest. However, it is unknown whether this has resulted in reduced use of the teratoma assay. Here, we systematically reviewed how the teratoma assay was reported in publications between 1998 (when the first human embryonic stem cell line was described) and 2021. Our analysis of >400 publications showed that in contrast to expectations, reporting of the teratoma assay has not improved: methods are not yet standardized, and malignancy was examined in only a relatively small percentage of assays. In addition, its use has not decreased since the implementation of the ARRIVE guidelines on reduction of animal use (2010) or the introduction of ScoreCard (2015) and PluriTest (2011). The teratoma assay is still the preferred method to assess the presence of undifferentiated cells in a differentiated cell product for transplantation since the in vitro assays alone are not generally accepted by the regulatory authorities for safety assessment. This highlights the remaining need for an in vitro assay to test malignancy of stem cells. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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