International Journal of Molecular Sciences

Editorial

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4 pages, 211 KiB

Open AccessEditorial

Special Issue “Stem Cell Biology & Regenerative Medicine”

by Rivka Ofir

Int. J. Mol. Sci. 2023, 24(16), 12855; https://doi.org/10.3390/ijms241612855 - 16 Aug 2023

Cited by 1 | Viewed by 750

Abstract

More than 50% of pre-clinical studies fail despite a long and expensive journey of drug discovery using animal models [...] Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

Research

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17 pages, 10750 KiB

Open AccessArticle

Hypoimmunogenic Human Pluripotent Stem Cells as a Powerful Tool for Liver Regenerative Medicine

by Piera Trionfini, Elena Romano, Marco Varinelli, Lorena Longaretti, Paola Rizzo, Roberta Giampietro, Annalina Caroli, Sistiana Aiello, Marta Todeschini, Federica Casiraghi, Giuseppe Remuzzi, Ariela Benigni and Susanna Tomasoni

Int. J. Mol. Sci. 2023, 24(14), 11810; https://doi.org/10.3390/ijms241411810 - 22 Jul 2023

Cited by 3 | Viewed by 1877

Abstract

Induced pluripotent stem cells (iPSC) have huge potential as cell therapy for various diseases, given their potential for unlimited self-renewal and capability to differentiate into a wide range of cell types. Although autologous iPSCs represents the ideal source for patient-tailored regenerative medicine, the [...] Read more.

Induced pluripotent stem cells (iPSC) have huge potential as cell therapy for various diseases, given their potential for unlimited self-renewal and capability to differentiate into a wide range of cell types. Although autologous iPSCs represents the ideal source for patient-tailored regenerative medicine, the high costs of the extensive and time-consuming production process and the impracticability for treating acute conditions hinder their use for broad applications. An allogeneic iPSC-based strategy may overcome these issues, but it carries the risk of triggering an immune response. So far, several approaches based on genome-editing techniques to silence human leukocyte antigen class I (HLA-I) or II (HLA-II) expression have been explored to overcome the immune rejection of allogeneic iPSCs. In this study, we employed the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9) system to delete the β2-Microglobulin (B2M) and the Class II Major Histocompatibility Complex Transactivator (CIITA) genes, essential for the correct surface expression of HLA-I and HLA-II proteins. The resulting hypoimmunogenic iPSC line has a normal karyotype, expresses the pluripotency stem cell markers, and is capable of differentiating into the three embryonic germ layers. Furthermore, we showed that it specifically retains the ability to differentiate towards different liver cells, such as endothelial-like cells, hepatocyte-like cells, and hepatic stellate-like cells. Our results indicate that hypoimmunogenic iPSCs could give a new cost-effective and off-the-shelf opportunity for cell therapy in liver diseases. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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20 pages, 3051 KiB

Open AccessArticle

The Air–Liquid Interface Reorganizes Membrane Lipids and Enhances the Recruitment of Slc26a3 to Lipid-Rich Domains in Human Colonoid Monolayers

by C. Ming Tse, Zixin Zhang, Ruxian Lin, Rafiquel Sarker, Mark Donowitz and Varsha Singh

Int. J. Mol. Sci. 2023, 24(9), 8273; https://doi.org/10.3390/ijms24098273 - 05 May 2023

Cited by 1 | Viewed by 1308

Abstract

Cholesterol-rich membrane domains, also called lipid rafts (LRs), are specialized membrane domains that provide a platform for intracellular signal transduction. Membrane proteins often cluster in LRs that further aggregate into larger platform-like structures that are enriched in ceramides and are called ceramide-rich platforms [...] Read more.

Cholesterol-rich membrane domains, also called lipid rafts (LRs), are specialized membrane domains that provide a platform for intracellular signal transduction. Membrane proteins often cluster in LRs that further aggregate into larger platform-like structures that are enriched in ceramides and are called ceramide-rich platforms (CRPs). The role of CRPs in the regulation of intestinal epithelial functions remains unknown. Down-regulated in adenoma (DRA) is an intestinal Cl⁻/HCO₃⁻ antiporter that is enriched in LRs. However, little is known regarding the mechanisms involved in the regulation of DRA activity. The air–liquid interface (ALI) was created by removing apical media for a specified number of days; from 12–14 days post-confluency, Caco-2/BBe cells or a colonoid monolayer were grown as submerged cultures. Confocal imaging was used to examine the dimensions of membrane microdomains that contained DRA. DRA expression and activity were enhanced in Caco-2/BBe cells and human colonoids using an ALI culture method. ALI causes an increase in acid sphingomyelinase (ASMase) activity, an enzyme responsible for enhancing ceramide content in the plasma membrane. ALI cultures expressed a larger number of DRA-containing platforms with dimensions >2 µm compared to cells grown as submerged cultures. ASMase inhibitor, desipramine, disrupted CRPs and reduced the ALI-induced increase in DRA expression in the apical membrane. Exposing normal human colonoid monolayers to ALI increased the ASMase activity and enhanced the differentiation of colonoids along with basal and forskolin-stimulated DRA activities. ALI increases DRA activity and expression by increasing ASMase activity and platform formation in Caco-2/BBe cells and by enhancing the differentiation of colonoids. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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16 pages, 5580 KiB

Open AccessArticle

Sevoflurane Induces a Cyclophilin D-Dependent Decrease of Neural Progenitor Cells Migration

by Pan Lu, Feng Liang, Yuanlin Dong, Zhongcong Xie and Yiying Zhang

Int. J. Mol. Sci. 2023, 24(7), 6746; https://doi.org/10.3390/ijms24076746 - 04 Apr 2023

Cited by 3 | Viewed by 1453

Abstract

Clinical studies have suggested that repeated exposure to anesthesia and surgery at a young age may increase the risk of cognitive impairment. Our previous research has shown that sevoflurane can affect neurogenesis and cognitive function in young animals by altering cyclophilin D (CypD) [...] Read more.

Clinical studies have suggested that repeated exposure to anesthesia and surgery at a young age may increase the risk of cognitive impairment. Our previous research has shown that sevoflurane can affect neurogenesis and cognitive function in young animals by altering cyclophilin D (CypD) levels and mitochondrial function. Neural progenitor cells (NPCs) migration is associated with cognitive function in developing brains. However, it is unclear whether sevoflurane can regulate NPCs migration via changes in CypD. To address this question, we treated NPCs harvested from wild-type (WT) and CypD knockout (KO) mice and young WT and CypD KO mice with sevoflurane. We used immunofluorescence staining, wound healing assay, transwell assay, mass spectrometry, and Western blot to assess the effects of sevoflurane on CypD, reactive oxygen species (ROS), doublecortin levels, and NPCs migration. We showed that sevoflurane increased levels of CypD and ROS, decreased levels of doublecortin, and reduced migration of NPCs harvested from WT mice in vitro and in WT young mice. KO of CypD attenuated these effects, suggesting that a sevoflurane-induced decrease in NPCs migration is dependent on CypD. Our findings have established a system for future studies aimed at exploring the impacts of sevoflurane anesthesia on the impairment of NPCs migration. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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21 pages, 52286 KiB

Open AccessArticle

Characterization and Safety Profile of a New Combined Advanced Therapeutic Medical Product Platelet Lysate-Based Fibrin Hydrogel for Mesenchymal Stromal Cell Local Delivery in Regenerative Medicine

by Thibault Canceill, Géraldine Jourdan, Philippe Kémoun, Christophe Guissard, Yanad Abou Monsef, Marion Bourdens, Benoit Chaput, Sandrine Cavalie, Louis Casteilla, Valérie Planat-Bénard, Paul Monsarrat and Isabelle Raymond-Letron

Int. J. Mol. Sci. 2023, 24(3), 2206; https://doi.org/10.3390/ijms24032206 - 22 Jan 2023

Cited by 2 | Viewed by 1809

Abstract

Adipose-derived mesenchymal stromal cells (ASC) transplant to recover the optimal tissue structure/function relationship is a promising strategy to regenerate tissue lesions. Because filling local tissue defects by injection alone is often challenging, designing adequate cell carriers with suitable characteristics is critical for in [...] Read more.

Adipose-derived mesenchymal stromal cells (ASC) transplant to recover the optimal tissue structure/function relationship is a promising strategy to regenerate tissue lesions. Because filling local tissue defects by injection alone is often challenging, designing adequate cell carriers with suitable characteristics is critical for in situ ASC delivery. The aim of this study was to optimize the generation phase of a platelet–lysate-based fibrin hydrogel (PLFH) as a proper carrier for in situ ASC implantation and (1) to investigate in vitro PLFH biomechanical properties, cell viability, proliferation and migration sustainability, and (2) to comprehensively assess the local in vivo PLFH/ASC safety profile (local tolerance, ASC fate, biodistribution and toxicity). We first defined the experimental conditions to enhance physicochemical properties and microscopic features of PLFH as an adequate ASC vehicle. When ASC were mixed with PLFH, in vitro assays exhibited hydrogel supporting cell migration, viability and proliferation. In vivo local subcutaneous and subgingival PLFH/ASC administration in nude mice allowed us to generate biosafety data, including biodegradability, tolerance, ASC fate and engraftment, and the absence of biodistribution and toxicity to non-target tissues. Our data strongly suggest that this novel combined ATMP for in situ administration is safe with an efficient local ASC engraftment, supporting the further development for human clinical cell therapy. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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17 pages, 3353 KiB

Open AccessArticle

Therapeutic Potency of Induced Pluripotent Stem-Cell-Derived Corneal Endothelial-like Cells for Corneal Endothelial Dysfunction

by Seongjun So, Yoonkyung Park, Soon Suk Kang, Jongsuk Han, Jeong Hye Sunwoo, Whanseo Lee, Jin Kim, Eun Ah Ye, Jae Yong Kim, Hungwon Tchah, Eunju Kang and Hun Lee

Int. J. Mol. Sci. 2023, 24(1), 701; https://doi.org/10.3390/ijms24010701 - 31 Dec 2022

Cited by 19 | Viewed by 2554

Abstract

Corneal endothelial cells (CECs) do not proliferate or recover after illness or injury, resulting in decreased cell density and loss of pump/barrier function. Considering the shortage of donor cornea, it is vital to establish robust methods to generate CECs from induced pluripotent stem [...] Read more.

Corneal endothelial cells (CECs) do not proliferate or recover after illness or injury, resulting in decreased cell density and loss of pump/barrier function. Considering the shortage of donor cornea, it is vital to establish robust methods to generate CECs from induced pluripotent stem cells (iPSCs). We investigated the efficacy and safety of transplantation of iPSC-derived CECs into a corneal endothelial dysfunction (CED) rabbit model. iPSCs were generated from human fibroblasts. We characterized iPSCs by demonstrating the gene expression of the PSC markers OCT4, SOX2, TRA-1-60, and NANOG, teratoma formation, and differentiation into three germ layers. Differentiation of iPSCs into CECs was induced via neural crest cell (NCC) induction. CEC markers were detected using immunofluorescence and gene expression was analyzed using quantitative real-time PCR (qRT-PCR). After culturing iPSC-derived NCCs, we found the expression of zona occludens-1 (ZO-1) and Na⁺/K⁺ ATPase and a hexagonal morphology. ATP1A1, COL8A1, and AQP1 mRNA expression was higher in iPSC-derived CECs than in iPSCs and NCCs. We performed an injection of iPSC-derived CECs into the anterior chamber of a CED rabbit model and found improved levels of corneal transparency. We also found increased numbers of ZO-1- and ATP1A1-positive cells in rabbit corneas in the iPSC-derived CEC transplantation group. Usage of the coating material vitronectin (VTN) and fasudil resulted in good levels of CEC marker expression, demonstrated with Western blotting and immunocytochemistry. Combination of the VTN coating material and fasudil, instead of FNC mixture and Y27632, afforded the best results in terms of CEC differentiation’s in vitro and in vivo efficacy. Successful transplantation of CEC-like cells into a CED animal model confirms the therapeutic efficacy of these cells, demonstrated by the restoration of corneal clarity. Our results suggest that iPSC-derived CECs can be a promising cellular resource for the treatment of CED. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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27 pages, 5125 KiB

Open AccessArticle

iPSC-Derived Macrophages: The Differentiation Protocol Affects Cell Immune Characteristics and Differentiation Trajectories

by Anna Klepikova, Tatiana Nenasheva, Olga Sheveleva, Elena Protasova, Daniil Antonov, Anastasiia Gainullina, Evgeniia Chikina, Olga Sakovnich, Tatiana Gerasimova, Irina Nikitina, Dmitry Shevalie and Irina Lyadova

Int. J. Mol. Sci. 2022, 23(24), 16087; https://doi.org/10.3390/ijms232416087 - 16 Dec 2022

Cited by 6 | Viewed by 4314

Abstract

The generation of human macrophages from induced pluripotent stem cells (iMacs) is a rapidly developing approach used to create disease models, screen drugs, study macrophage–pathogen interactions and develop macrophage-based cell therapy. To generate iMacs, different types of protocols have been suggested, all thought [...] Read more.

The generation of human macrophages from induced pluripotent stem cells (iMacs) is a rapidly developing approach used to create disease models, screen drugs, study macrophage–pathogen interactions and develop macrophage-based cell therapy. To generate iMacs, different types of protocols have been suggested, all thought to result in the generation of similar iMac populations. However, direct comparison of iMacs generated using different protocols has not been performed. We have compared the productivity, the differentiation trajectories and the characteristics of iMacs generated using two widely used protocols: one based on the formation of embryoid bodies and the induction of myeloid differentiation by only two cytokines, interleukin-3 and macrophage colony-stimulating factor, and the other utilizing multiple exogenous factors for iMac generation. We report inter-protocol differences in the following: (i) protocol productivity; (ii) dynamic changes in the expression of genes related to inflammation and lipid homeostasis following iMac differentiation and (iii) the transcriptomic profiles of terminally differentiated iMacs, including the expression of genes involved in inflammatory response, antigen presentation and lipid homeostasis. The results document the dependence of fine iMac characteristics on the type of differentiation protocol, which is important for further development of the field, including the development of iMac-based cell therapy. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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19 pages, 4377 KiB

Open AccessArticle

Neural Stem Cells Overexpressing Arginine Decarboxylase Improve Functional Recovery from Spinal Cord Injury in a Mouse Model

by Yu Mi Park, Jae Hwan Kim and Jong Eun Lee

Int. J. Mol. Sci. 2022, 23(24), 15784; https://doi.org/10.3390/ijms232415784 - 13 Dec 2022

Cited by 4 | Viewed by 2133

Abstract

Current therapeutic strategies for spinal cord injury (SCI) cannot fully facilitate neural regeneration or improve function. Arginine decarboxylase (ADC) synthesizes agmatine, an endogenous primary amine with neuroprotective effects. Transfection of human ADC (hADC) gene exerts protective effects after injury in murine brain-derived neural [...] Read more.

Current therapeutic strategies for spinal cord injury (SCI) cannot fully facilitate neural regeneration or improve function. Arginine decarboxylase (ADC) synthesizes agmatine, an endogenous primary amine with neuroprotective effects. Transfection of human ADC (hADC) gene exerts protective effects after injury in murine brain-derived neural precursor cells (mNPCs). Following from these findings, we investigated the effects of hADC-mNPC transplantation in SCI model mice. Mice with experimentally damaged spinal cords were divided into three groups, separately transplanted with fluorescently labeled (1) control mNPCs, (2) retroviral vector (pLXSN)-infected mNPCs (pLXSN-mNPCs), and (3) hADC-mNPCs. Behavioral comparisons between groups were conducted weekly up to 6 weeks after SCI, and urine volume was measured up to 2 weeks after SCI. A subset of animals was euthanized each week after cell transplantation for molecular and histological analyses. The transplantation groups experienced significantly improved behavioral function, with the best recovery occurring in hADC-mNPC mice. Transplanting hADC-mNPCs improved neurological outcomes, induced oligodendrocyte differentiation and remyelination, increased neural lineage differentiation, and decreased glial scar formation. Moreover, locomotor and bladder function were both rehabilitated. These beneficial effects are likely related to differential BMP-2/4/7 expression in neuronal cells, providing an empirical basis for gene therapy as a curative SCI treatment option. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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19 pages, 5948 KiB

Open AccessArticle

Comparative Efficiency of Gene-Activated Matrices Based on Chitosan Hydrogel and PRP Impregnated with BMP2 Polyplexes for Bone Regeneration

by Irina Alekseevna Nedorubova, Tatiana Borisovna Bukharova, Viktoria Olegovna Mokrousova, Maria Aleksandrovna Khvorostina, Andrey Vyacheslavovich Vasilyev, Andrey Anatolevich Nedorubov, Timofei Evgenevich Grigoriev, Yuriy Dmitrievich Zagoskin, Sergei Nicolaevich Chvalun, Sergey Ivanovich Kutsev and Dmitry Vadimovich Goldshtein

Int. J. Mol. Sci. 2022, 23(23), 14720; https://doi.org/10.3390/ijms232314720 - 25 Nov 2022

Cited by 7 | Viewed by 1590

Abstract

Gene therapy is one of the most promising approaches in regenerative medicine. Gene-activated matrices provide stable gene expression and the production of osteogenic proteins in situ to stimulate osteogenesis and bone repair. In this study, we developed new gene-activated matrices based on polylactide [...] Read more.

Gene therapy is one of the most promising approaches in regenerative medicine. Gene-activated matrices provide stable gene expression and the production of osteogenic proteins in situ to stimulate osteogenesis and bone repair. In this study, we developed new gene-activated matrices based on polylactide granules (PLA) impregnated with BMP2 polyplexes and included in chitosan hydrogel or PRP-based fibrin hydrogel. The matrices showed high biocompatibility both in vitro with mesenchymal stem cells and in vivo when implanted intramuscularly in rats. The use of porous PLA granules allowed the inclusion of a high concentration of polyplexes, and the introduction of the granules into hydrogel provided the gradual release of the plasmid constructs. All gene-activated matrices showed transfecting ability and ensured long-term gene expression and the production of target proteins in vitro. At the same time, the achieved concentration of BMP-2 was sufficient to induce osteogenic differentiation of MSCs. When implanted into critical-size calvarial defects in rats, all matrices with BMP2 polyplexes led to new bone formation. The most significant effect on osteoinduction was observed for the PLA/PRP matrices. Thus, the developed gene-activated matrices were shown to be safe and effective osteoplastic materials. PLA granules and PRP-based fibrin hydrogel containing BMP2 polyplexes were shown to be the most promising for future applications in bone regeneration. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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12 pages, 3064 KiB

Open AccessArticle

The Inhibition of the Inducible Nitric Oxide Synthase Enhances the DPSC Mineralization under LPS-Induced Inflammation

by Amelia Cataldi, Rosa Amoroso, Viviana di Giacomo, Susi Zara, Cristina Maccallini and Marialucia Gallorini

Int. J. Mol. Sci. 2022, 23(23), 14560; https://doi.org/10.3390/ijms232314560 - 23 Nov 2022

Cited by 5 | Viewed by 1357

Abstract

Nitric oxide (NO) is a key messenger in physiological and pathological processes in mammals. An excessive NO production is associated with pathological conditions underlying the inflammation response as a trigger. Among others, dental pulp inflammation results from the invasion of dentin by pathogenic [...] Read more.

Nitric oxide (NO) is a key messenger in physiological and pathological processes in mammals. An excessive NO production is associated with pathological conditions underlying the inflammation response as a trigger. Among others, dental pulp inflammation results from the invasion of dentin by pathogenic bacteria. Vital functions of pulp mesenchymal stem cells (DPSCs, dental pulp stem cells), such as mineralization, might be affected by the inducible NOS (iNOS) upregulation. In this context, the iNOS selective inhibition can be considered an innovative therapeutic strategy to counteract inflammation and to promote the regeneration of the dentin-pulp complex. The present work aims at evaluating two acetamidines structurally related to the selective iNOS inhibitor 1400W, namely CM544 and FAB1020, in a model of LPS-stimulated primary DPSCs. Our data reveal that CM544 and even more FAB1020 are promising anti-inflammatory compounds, decreasing IL-6 secretion by enhancing CD73 expression-levels, a protein involved in innate immunity processes and thus confirming an immunomodulatory role of DPSCs. In parallel, cell mineralization potential is retained in the presence of compounds as well as VEGF secretion, and thus their angiogenetic potential. Data presented lay the ground for further investigation on the anti-inflammatory potential of acetamidines selectively targeting iNOS in a clinical context. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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18 pages, 2277 KiB

Open AccessArticle

A Bionic Testbed for Cardiac Ablation Tools

by Wei-Han Lin, Zhijie Zhu, Vasanth Ravikumar, Vinod Sharma, Elena G. Tolkacheva, Michael C. McAlpine and Brenda M. Ogle

Int. J. Mol. Sci. 2022, 23(22), 14444; https://doi.org/10.3390/ijms232214444 - 21 Nov 2022

Cited by 1 | Viewed by 2059

Abstract

Bionic-engineered tissues have been proposed for testing the performance of cardiovascular medical devices and predicting clinical outcomes ex vivo. Progress has been made in the development of compliant electronics that are capable of monitoring treatment parameters and being coupled to engineered tissues; however, [...] Read more.

Bionic-engineered tissues have been proposed for testing the performance of cardiovascular medical devices and predicting clinical outcomes ex vivo. Progress has been made in the development of compliant electronics that are capable of monitoring treatment parameters and being coupled to engineered tissues; however, the scale of most engineered tissues is too small to accommodate the size of clinical-grade medical devices. Here, we show substantial progress toward bionic tissues for evaluating cardiac ablation tools by generating a centimeter-scale human cardiac disk and coupling it to a hydrogel-based soft-pressure sensor. The cardiac tissue with contiguous electromechanical function was made possible by our recently established method to 3D bioprint human pluripotent stem cells in an extracellular matrix-based bioink that allows for in situ cell expansion prior to cardiac differentiation. The pressure sensor described here utilized electrical impedance tomography to enable the real-time spatiotemporal mapping of pressure distribution. A cryoablation tip catheter was applied to the composite bionic tissues with varied pressure. We found a close correlation between the cell response to ablation and the applied pressure. Under some conditions, cardiomyocytes could survive in the ablated region with more rounded morphology compared to the unablated controls, and connectivity was disrupted. This is the first known functional characterization of living human cardiomyocytes following an ablation procedure that suggests several mechanisms by which arrhythmia might redevelop following an ablation. Thus, bionic-engineered testbeds of this type can be indicators of tissue health and function and provide unique insight into human cell responses to ablative interventions. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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20 pages, 5587 KiB

Open AccessArticle

Oxidative Stress Response in Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells

by Tawakalitu Okikiola Waheed, Olga Hahn, Kaarthik Sridharan, Caroline Mörke, Günter Kamp and Kirsten Peters

Int. J. Mol. Sci. 2022, 23(21), 13435; https://doi.org/10.3390/ijms232113435 - 03 Nov 2022

Cited by 8 | Viewed by 2109

Abstract

Reactive oxygen species (ROS) can irreversibly damage biological molecules, a process known as oxidative stress. Elevated ROS levels are associated with immune cell activation. Sustained immune system activation can affect many different cells in the environment. One cell type that has been detected [...] Read more.

Reactive oxygen species (ROS) can irreversibly damage biological molecules, a process known as oxidative stress. Elevated ROS levels are associated with immune cell activation. Sustained immune system activation can affect many different cells in the environment. One cell type that has been detected in almost all tissues of the body is mesenchymal stem/stromal cells (MSC). MSC possess proliferation and differentiation potential, thus facilitating regeneration processes. However, the regenerative capacity of MSC might be impaired by oxidative stress, and the effects of long-term oxidative stress on MSC functions are sparsely described. The examination of oxidative stress is often performed by exposure to H₂O₂. Since H₂O₂ is rapidly degraded, we additionally exposed the cell cultures to glucose oxidase (GOx), resulting in sustained exposure to H₂O₂. Using these model systems, we have focused on the effects of short- and long-term oxidative stress on viability, migration, differentiation, and signaling. All cellular functions examined were affected by the applied oxidative stress. The differences that occur between pulsed and sustained oxidative stress indicated higher oxidative stress in MSC upon direct H₂O₂ exposure, whereas the GOx-induced prolonged exposure to H₂O₂ seems to allow for better cellular adaptation. The mechanisms underlying these different responses are currently unknown. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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15 pages, 1809 KiB

Open AccessArticle

The Manufacture of Xeno- and Feeder-Free Clinical-Grade Human Embryonic Stem Cell Lines: First Step for Cell Therapy

by Tereza Souralova, Daniela Rehakova, Michal Jeseta, Lenka Tesarova, Jindrich Beranek, Pavel Ventruba, Ales Hampl and Irena Koutna

Int. J. Mol. Sci. 2022, 23(20), 12500; https://doi.org/10.3390/ijms232012500 - 18 Oct 2022

Cited by 6 | Viewed by 2356

Abstract

Human embryonic stem cells (hESCs) are increasingly used in clinical trials as they can change the outcome of treatment for many human diseases. They are used as a starting material for further differentiation into specific cell types and to achieve the desirable result [...] Read more.

Human embryonic stem cells (hESCs) are increasingly used in clinical trials as they can change the outcome of treatment for many human diseases. They are used as a starting material for further differentiation into specific cell types and to achieve the desirable result of the cell therapy; thus, the quality of hESCs has to be taken into account. Therefore, current good manufacturing practice (cGMP) has to be implemented in the transport of embryos, derivation of inner cell mass to xeno-free, feeder-free and defined hESC culture, and cell freezing. The in-depth characterization of hESC lines focused on safety, pluripotency, differentiation potential and genetic background has to complement this process. In this paper, we show the derivation of three clinical-grade hESC lines, MUCG01, MUCG02, and MUCG03, following these criteria. We developed and validated the system for the manufacture of xeno-free and feeder-free clinical-grade hESC lines that present high-quality starting material suitable for cell therapy according to cGMP. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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10 pages, 2123 KiB

Open AccessArticle

Successful Derivation of Hepatoblasts, Cholangiocytes and Hepatocytes from Simian Induced Pluripotent Stem Cells

by Eleanor Luce, Clara Steichen, Soumeya Abed, Anne Weber, Philippe Leboulch, Leila Maouche-Chrétien and Anne Dubart-Kupperschmitt

Int. J. Mol. Sci. 2022, 23(18), 10861; https://doi.org/10.3390/ijms231810861 - 17 Sep 2022

Cited by 1 | Viewed by 1608

Abstract

The use of primary cells in human liver therapy is limited by a lack of cells. Induced pluripotent stem cells (iPSCs) represent an alternative to primary cells as they are infinitely expandable and can be differentiated into different liver cell types. The aim [...] Read more.

The use of primary cells in human liver therapy is limited by a lack of cells. Induced pluripotent stem cells (iPSCs) represent an alternative to primary cells as they are infinitely expandable and can be differentiated into different liver cell types. The aim of our work was to demonstrate that simian iPSCs (siPSCs) could be used as a new source of liver cells to be used as a large animal model for preclinical studies. We first differentiated siPSCs into a homogenous population of hepatoblasts (siHBs). We then separately differentiated them into hepatocytes (siHeps) and cholangiocytes (siChols) expressing respective specific markers and displaying epithelial polarity. Moreover, we showed that polarized siChols can self-organize into 3D structures. These results should facilitate the deciphering of liver development and open the way to exploring co-culture systems that could be assessed during preclinical studies, including in autologous monkey donors, for regenerative medicine purposes. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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13 pages, 2733 KiB

Open AccessArticle

Full-Length Dystrophin Restoration via Targeted Exon Addition in DMD-Patient Specific iPSCs and Cardiomyocytes

by Rou Xiao, Miaojin Zhou, Peiyun Wang, Baitao Zeng, Lingqian Wu, Zhiqing Hu and Desheng Liang

Int. J. Mol. Sci. 2022, 23(16), 9176; https://doi.org/10.3390/ijms23169176 - 16 Aug 2022

Cited by 3 | Viewed by 1980

Abstract

Duchenne muscular dystrophy (DMD) is the most common fatal muscle disease, with an estimated incidence of 1/3500–1/5000 male births, and it is associated with mutations in the X-linked DMD gene encoding dystrophin, the largest known human gene. There is currently no cure for [...] Read more.

Duchenne muscular dystrophy (DMD) is the most common fatal muscle disease, with an estimated incidence of 1/3500–1/5000 male births, and it is associated with mutations in the X-linked DMD gene encoding dystrophin, the largest known human gene. There is currently no cure for DMD. The large size of the DMD gene hampers exogenous gene addition and delivery. The genetic correction of DMD patient-derived induced pluripotent stem cells (DMD-iPSCs) and differentiation into suitable cells for transplantation is a promising autologous therapeutic strategy for DMD. In this study, using CRISPR/Cas9, the full-length dystrophin coding sequence was reconstructed in an exon-50-deleted DMD-iPSCs by the targeted addition of exon 50 at the junction of exon 49 and intron 49 via homologous-directed recombination (HDR), with a high targeting efficiency of 5/15, and the genetically corrected iPSCs were differentiated into cardiomyocytes (iCMs). Importantly, the full-length dystrophin expression and membrane localization were restored in genetically corrected iPSCs and iCMs. Thus, this is the first study demonstrating that full-length dystrophin can be restored in iPSCs and iCMs via targeted exon addition, indicating potential clinical prospects for DMD gene therapy. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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16 pages, 4218 KiB

Open AccessArticle

Hematopoietic–Mesenchymal Signals Regulate the Properties of Mesenchymal Stem Cells

by Sanshiro Kanazawa, Hiroyuki Okada, Dan Riu, Yo Mabuchi, Chihiro Akazawa, Junichi Iwata, Kazuto Hoshi and Atsuhiko Hikita

Int. J. Mol. Sci. 2022, 23(15), 8238; https://doi.org/10.3390/ijms23158238 - 26 Jul 2022

Cited by 4 | Viewed by 1917

Abstract

It is well known that the properties of hematopoietic stem/progenitor cells (HSCs), such as their self-renewal ability and multipotency, are maintained through interactions with mesenchymal stem/stromal cells (MSCs). MSCs are rare cells that are present in the bone marrow and are useful for [...] Read more.

It is well known that the properties of hematopoietic stem/progenitor cells (HSCs), such as their self-renewal ability and multipotency, are maintained through interactions with mesenchymal stem/stromal cells (MSCs). MSCs are rare cells that are present in the bone marrow and are useful for clinical applications due to their functional ability. To obtain the necessary number of cells, MSCs must be cultured to expand, but this causes a remarkable decrease in stem cell properties, such as multipotency and proliferation ability. In this study, we show that the c-Mpl signal, which is related to the maintenance of hematopoietic stem cells, has an important effect on the proliferation and differentiation ability of MSCs. Utilizing a co-culture system comprising MSCs and HSCs, it is suggested that signaling from hematopoietic cells to MSCs supports cell proliferation. Interestingly, the enhanced proliferation ability of the HSCs was decreased in c-Mpl knock-out HSCs (c-Mpl-KO). In addition, the MSCs co-cultured with c-Mpl-KO HSCs had reduced MSC marker expression (PDGFRa and Sca-1) compared to the MSCs co-cultured with c-Mpl-wild-type HSCs. These results suggest that a hematopoietic–mesenchymal signal exists, and that the state of the HSCs is important for the stability of MSC properties. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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27 pages, 9076 KiB

Open AccessArticle

Conditioned Medium of Human Pluripotent Stem Cell-Derived Neural Precursor Cells Exerts Neurorestorative Effects against Ischemic Stroke Model

by Hye-Jin Hur, Ji Yong Lee, Do-Hun Kim, Myung Soo Cho, Sangsik Lee, Han-Soo Kim and Dong-Wook Kim

Int. J. Mol. Sci. 2022, 23(14), 7787; https://doi.org/10.3390/ijms23147787 - 14 Jul 2022

Cited by 6 | Viewed by 2801

Abstract

Previous studies have shown that early therapeutic events of neural precursor cells (NPCs) transplantation to animals with acute ischemic stroke readily protected neuronal cell damage and improved behavioral recovery through paracrine mechanisms. In this study, we tested the hypothesis that administration of conditioned [...] Read more.

Previous studies have shown that early therapeutic events of neural precursor cells (NPCs) transplantation to animals with acute ischemic stroke readily protected neuronal cell damage and improved behavioral recovery through paracrine mechanisms. In this study, we tested the hypothesis that administration of conditioned medium from NPCs (NPC-CMs) could recapitulate the beneficial effects of cell transplantation. Rats with permanent middle cerebral artery occlusion (pMCAO) were randomly assigned to one of the following groups: PBS control, Vehicle (medium) controls, single (NPC-CM(S)) or multiple injections of NPC-CM(NPC-CM(M)) groups. A single intravenous injection of NPC-CM exhibited strong neuroregenerative potential to induce behavioral recovery, and multiple injections enhanced this activity further by suppressing inflammatory damage and inducing endogenous neurogenesis leading to histopathological and functional recovery. Proteome analysis of NPC-CM identified a number of proteins that are known to be associated with nervous system development, neurogenesis, and angiogenesis. In addition, transcriptome analysis revealed the importance of the inflammatory response during stroke recovery and some of the key hub genes in the interaction network were validated. Thus, our findings demonstrated that NPC-CM promoted functional recovery and reduced cerebral infarct and inflammation with enhanced endogenous neurogenesis, and the results highlighted the potency of NPC-CM in stroke therapy. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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12 pages, 3423 KiB

Open AccessArticle

Human Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote Neural Differentiation of Neural Progenitor Cells

by So-Yeon Park, Da-Seul Kim, Hyun-Mun Kim, Jun-Kyu Lee, Dong-Youn Hwang, Tae-Hyung Kim, Seungkwon You and Dong Keun Han

Int. J. Mol. Sci. 2022, 23(13), 7047; https://doi.org/10.3390/ijms23137047 - 24 Jun 2022

Cited by 13 | Viewed by 2364

Abstract

Mesenchymal stem cells (MSCs) have been adopted in various preclinical and clinical studies because of their multipotency and low immunogenicity. However, numerous obstacles relating to safety issues remain. Therefore, MSC-derived extracellular vesicles (EVs) have been recently employed. EVs are nano-sized endoplasmic reticulum particles [...] Read more.

Mesenchymal stem cells (MSCs) have been adopted in various preclinical and clinical studies because of their multipotency and low immunogenicity. However, numerous obstacles relating to safety issues remain. Therefore, MSC-derived extracellular vesicles (EVs) have been recently employed. EVs are nano-sized endoplasmic reticulum particles generated and released in cells that have similar biological functions to their origin cells. EVs act as cargo for bioactive molecules such as proteins and genetic materials and facilitate tissue regeneration. EVs obtained from adipose-derived MSC (ADMSC) also have neuroprotective and neurogenesis effects. On the basis of the versatile effects of EVs, we aimed to enhance the neural differentiation ability of ADMSC-derived EVs by elucidating the neurogenic-differentiation process. ADMSC-derived EVs isolated from neurogenesis conditioned media (differentiated EVs, dEVs) increased neurogenic ability by altering innate microRNA expression and cytokine composition. Consequently, dEVs promoted neuronal differentiation of neural progenitor cells in vitro, suggesting that dEVs are a prospective candidate for EV-based neurological disorder regeneration therapy. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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16 pages, 3539 KiB

Open AccessArticle

Human IL12p80 Promotes Murine Oligodendrocyte Differentiation to Repair Nerve Injury

by Yu-Fen Chung, Jong-Hang Chen, Ching-Wen Li, Hui-Yu Hsu, Ya-Ping Chen, Chiao-Chan Wang and Ing-Ming Chiu

Int. J. Mol. Sci. 2022, 23(13), 7002; https://doi.org/10.3390/ijms23137002 - 23 Jun 2022

Cited by 3 | Viewed by 1791

Abstract

Nerve injury of the central nervous system and the peripheral nervous system still poses a major challenge in modern clinics. Understanding the roles of neurotrophic factors and their molecular mechanisms on neuro-regeneration will not only benefit patients with neural damage but could potentially [...] Read more.

Nerve injury of the central nervous system and the peripheral nervous system still poses a major challenge in modern clinics. Understanding the roles of neurotrophic factors and their molecular mechanisms on neuro-regeneration will not only benefit patients with neural damage but could potentially treat neurodegenerative disorders, such as amyotrophic lateral sclerosis. In this study, we showed that human IL12 p40-p40 homodimer (hIL12p80) within PLA and PLGA conduits improved sciatic nerve regeneration in mice. As such, the group of conduits with NSCs and hIL12p80 (CNI) showed the best recovery among the groups in the sciatic functional index (SFI), compound muscle action potential (CMAP), and Rotarod performance analyses. In addition, the CNI group had a faster recovery and outperformed the other groups in SFI and Rotarod performance tests beginning in the fourth week post-surgery. Immunohistochemistry showed that the CNI group increased the diameter of the newly regenerated nerve by two-fold (p < 0.01). In vitro studies showed that hIL12p80 stimulated differentiation of mouse NSCs to oligodendrocyte lineages through phosphorylation of Stat3 at Y705 and S727. Furthermore, implantation using PLGA conduits (C2.0 and C2.1) showed better recovery in the Rotarod test and CMAP than using PLA conduits in FVB mice. In B6 mice, the group with C2.1 + NSCs + hIL12p80 (C2.1NI) not only promoted sciatic functional recovery but also reduced the rate of experimental autotomy. These results suggested that hIL12p80, combined with NSCs, enhanced the functional recovery and accelerated the regeneration of damaged nerves in the sciatic nerve injury mice. Our findings could further shed light on IL12′s application not only in damaged nerves but also in rectifying the oligodendrocytes’ defects in neurodegenerative diseases, such as amyotrophic lateral sclerosis and multiple sclerosis. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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13 pages, 1353 KiB

Open AccessArticle

Fluctuations in Corneal Endothelial LAP2 Expression Levels Correlate with Passage Dependent Declines in Their Cell Proliferative Activity

by Eleonora Maurizi, Alessia Merra, Davide Schiroli, Benedetta Ghezzi, Claudio Macaluso and Graziella Pellegrini

Int. J. Mol. Sci. 2022, 23(10), 5859; https://doi.org/10.3390/ijms23105859 - 23 May 2022

Cited by 5 | Viewed by 2068

Abstract

The corneal endothelium is the inner corneal mono-layered epithelium, fundamental for preserving corneal hydration and transparency. However, molecular mechanisms that regulate corneal endothelial cells (CEnCs), in particular regarding their proliferative capacity, have been only partially elucidated. CEnCs are quiescent in vivo and they [...] Read more.

The corneal endothelium is the inner corneal mono-layered epithelium, fundamental for preserving corneal hydration and transparency. However, molecular mechanisms that regulate corneal endothelial cells (CEnCs), in particular regarding their proliferative capacity, have been only partially elucidated. CEnCs are quiescent in vivo and they easily undergo endothelial to mesenchymal transition (EnMT) in vitro. This study aims to analyze CEnCs behavior and expression in vitro, either in sub-confluent growing (S) or confluent (C) CEnCs cultures. Primary rabbit and human CEnCs were cultured and used for RT-PCR, immunofluorescence or western blot analysis. These methods allowed identifying a novel molecular marker, LAP2, that is upregulated in S while downregulated in C human or rabbit CEnCs. Those results were observed for several subsequent passages in culture and this, together with the correlation between ki67 and LAP2 expression, suggested LAP2 as a novel possible indicator for culture ageing. Finally, treatment with FGF and TGFβ in rCEnCs highlighted how LAP2 can vary as the cells regulate their proliferative state. In conclusion, we have identified a novel marker for CEnCs, LAP2, that regulates its expression depending on the cells sub/confluent state and that correlates with CEnCs proliferation. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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Review

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18 pages, 4899 KiB

Open AccessReview

Insights into the Molecular Mechanisms Regulating Cell Behavior in Response to Magnetic Materials and Magnetic Stimulation in Stem Cell (Neurogenic) Differentiation

by Alexandra-Elena Mocanu-Dobranici, Marieta Costache and Sorina Dinescu

Int. J. Mol. Sci. 2023, 24(3), 2028; https://doi.org/10.3390/ijms24032028 - 19 Jan 2023

Cited by 6 | Viewed by 2000

Abstract

Magnetic materials and magnetic stimulation have gained increasing attention in tissue engineering (TE), particularly for bone and nervous tissue reconstruction. Magnetism is utilized to modulate the cell response to environmental factors and lineage specifications, which involve complex mechanisms of action. Magnetic fields and [...] Read more.

Magnetic materials and magnetic stimulation have gained increasing attention in tissue engineering (TE), particularly for bone and nervous tissue reconstruction. Magnetism is utilized to modulate the cell response to environmental factors and lineage specifications, which involve complex mechanisms of action. Magnetic fields and nanoparticles (MNPs) may trigger focal adhesion changes, which are further translated into the reorganization of the cytoskeleton architecture and have an impact on nuclear morphology and positioning through the activation of mechanotransduction pathways. Mechanical stress induced by magnetic stimuli translates into an elongation of cytoskeleton fibers, the activation of linker in the nucleoskeleton and cytoskeleton (LINC) complex, and nuclear envelope deformation, and finally leads to the mechanical regulation of chromatin conformational changes. As such, the internalization of MNPs with further magnetic stimulation promotes the evolution of stem cells and neurogenic differentiation, triggering significant changes in global gene expression that are mediated by histone deacetylases (e.g., HDAC 5/11), and the upregulation of noncoding RNAs (e.g., miR-106b~25). Additionally, exposure to a magnetic environment had a positive influence on neurodifferentiation through the modulation of calcium channels’ activity and cyclic AMP response element-binding protein (CREB) phosphorylation. This review presents an updated and integrated perspective on the molecular mechanisms that govern the cellular response to magnetic cues, with a special focus on neurogenic differentiation and the possible utility of nervous TE, as well as the limitations of using magnetism for these applications. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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17 pages, 1265 KiB

Open AccessReview

Mesenchymal Stem Cells in Burn Wound Management

by Agnieszka Surowiecka, Anna Chrapusta, Maria Klimeczek-Chrapusta, Tomasz Korzeniowski, Justyna Drukała and Jerzy Strużyna

Int. J. Mol. Sci. 2022, 23(23), 15339; https://doi.org/10.3390/ijms232315339 - 05 Dec 2022

Cited by 8 | Viewed by 3589

Abstract

Mesenchymal stem cells have a known regenerative potential and are used in many indications. They secrete many growth factors, including for fibroblasts (FGF), endothelium (VEGF), as well as 14 anti-inflammatory cytokines, and they stimulate tissue regeneration, promoting the secretion of proteins and glycosaminoglycans [...] Read more.

Mesenchymal stem cells have a known regenerative potential and are used in many indications. They secrete many growth factors, including for fibroblasts (FGF), endothelium (VEGF), as well as 14 anti-inflammatory cytokines, and they stimulate tissue regeneration, promoting the secretion of proteins and glycosaminoglycans of extracellular matrices, such as collagen I, II, III, and V, elastin, and also metalloproteinases. They secrete exosomes that contain proteins, nucleic acids, lipids, and enzymes. In addition, they show the activity of inactivating free radicals. The aim of this study was an attempt to collect the existing literature on the use of stem cells in the treatment of a burn wound. There were 81 studies included in the analysis. The studies differed in terms of the design, burn wound model, source of stem cells, and methods of cellular therapy application. No major side effects were reported, and cellular therapy reduced the healing time of the burn wound. Few case reports on human models did not report any serious adverse events. However, due to the heterogeneity of the evidence, cellular therapy in burn wound treatment remains an experimental method. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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29 pages, 1506 KiB

Open AccessReview

Decellularized Extracellular Matrix Scaffolds for Cardiovascular Tissue Engineering: Current Techniques and Challenges

by Greta Ionela Barbulescu, Florina Maria Bojin, Valentin Laurentiu Ordodi, Iacob Daniel Goje, Andreea Severina Barbulescu and Virgil Paunescu

Int. J. Mol. Sci. 2022, 23(21), 13040; https://doi.org/10.3390/ijms232113040 - 27 Oct 2022

Cited by 21 | Viewed by 5718

Abstract

Cardiovascular diseases are the leading cause of global mortality. Over the past two decades, researchers have tried to provide novel solutions for end-stage heart failure to address cardiac transplantation hurdles such as donor organ shortage, chronic rejection, and life-long immunosuppression. Cardiac decellularized extracellular [...] Read more.

Cardiovascular diseases are the leading cause of global mortality. Over the past two decades, researchers have tried to provide novel solutions for end-stage heart failure to address cardiac transplantation hurdles such as donor organ shortage, chronic rejection, and life-long immunosuppression. Cardiac decellularized extracellular matrix (dECM) has been widely explored as a promising approach in tissue-regenerative medicine because of its remarkable similarity to the original tissue. Optimized decellularization protocols combining physical, chemical, and enzymatic agents have been developed to obtain the perfect balance between cell removal, ECM composition, and function maintenance. However, proper assessment of decellularized tissue composition is still needed before clinical translation. Recellularizing the acellular scaffold with organ-specific cells and evaluating the extent of cardiomyocyte repopulation is also challenging. This review aims to discuss the existing literature on decellularized cardiac scaffolds, especially on the advantages and methods of preparation, pointing out areas for improvement. Finally, an overview of the state of research regarding the application of cardiac dECM and future challenges in bioengineering a human heart suitable for transplantation is provided. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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19 pages, 996 KiB

Open AccessReview

Physical, Mechanical, and Biological Properties of Fibrin Scaffolds for Cartilage Repair

by Juan Antonio Rojas-Murillo, Mario A. Simental-Mendía, Nidia K. Moncada-Saucedo, Paulina Delgado-Gonzalez, José Francisco Islas, Jorge A. Roacho-Pérez and Elsa N. Garza-Treviño

Int. J. Mol. Sci. 2022, 23(17), 9879; https://doi.org/10.3390/ijms23179879 - 30 Aug 2022

Cited by 14 | Viewed by 3758

Abstract

Articular cartilage is a highly organized tissue that provides remarkable load-bearing and low friction properties, allowing for smooth movement of diarthrodial joints; however, due to the avascular, aneural, and non-lymphatic characteristics of cartilage, joint cartilage has self-regeneration and repair limitations. Cartilage tissue engineering [...] Read more.

Articular cartilage is a highly organized tissue that provides remarkable load-bearing and low friction properties, allowing for smooth movement of diarthrodial joints; however, due to the avascular, aneural, and non-lymphatic characteristics of cartilage, joint cartilage has self-regeneration and repair limitations. Cartilage tissue engineering is a promising alternative for chondral defect repair. It proposes models that mimic natural tissue structure through the use of cells, scaffolds, and signaling factors to repair, replace, maintain, or improve the specific function of the tissue. In chondral tissue engineering, fibrin is a biocompatible biomaterial suitable for cell growth and differentiation with adequate properties to regenerate damaged cartilage. Additionally, its mechanical, biological, and physical properties can be enhanced by combining it with other materials or biological components. This review addresses the biological, physical, and mechanical properties of fibrin as a biomaterial for cartilage tissue engineering and as an element to enhance the regeneration or repair of chondral lesions. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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28 pages, 2146 KiB

Open AccessReview

Stem Cell-Based Therapies for Inflammatory Bowel Disease

by Hua-Min Zhang, Shuo Yuan, Huan Meng, Xiao-Ting Hou, Jiao Li, Jia-Chen Xue, You Li, Qi Wang, Ji-Xing Nan, Xue-Jun Jin and Qing-Gao Zhang

Int. J. Mol. Sci. 2022, 23(15), 8494; https://doi.org/10.3390/ijms23158494 - 31 Jul 2022

Cited by 20 | Viewed by 3934

Abstract

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients’ quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal [...] Read more.

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients’ quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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24 pages, 3255 KiB

Open AccessReview

Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease

by Yifang Li, Sharon D. Ricardo and Chrishan S. Samuel

Int. J. Mol. Sci. 2022, 23(11), 6035; https://doi.org/10.3390/ijms23116035 - 27 May 2022

Cited by 5 | Viewed by 2786

Abstract

Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even [...] Read more.

Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed. Full article

(This article belongs to the Special Issue Stem Cell Biology & Regenerative Medicine)

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