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Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition
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Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition

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 (20 September 2024) | Viewed by 17994

Special Issue Editor

Dr. Joan Oliva

E-Mail Website
Guest Editor
Department of Clinical Research, Emmaus Medical, Inc., Torrance, CA 90503, USA
Interests: stem cells; tissue regeneration; cell therapy; vitrification
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the last two decades, the scientific and medical communities have focused on mesenchymal stem cells (MSCs) and their potential to treat diseases. MSCs can be isolated from many adult tissues, such as bone marrow, adipose tissue, umbilical cords, and dental pulp. MSCs may regenerate tissue through their differentiation potential (myoblast, epithelial cells, neurons, and beta-cells) to lessen inflammatory reactions. They can also be used as anti-cancer therapies and to deliver compounds to targeted organs (nucleic acids, exogenous or endogenous proteins, and drugs). MSCs can be transplanted; alternatively, the vesicles produced by MSCs can be injected. Great efforts are still required to improve the therapeutical properties of MSCs in order to decrease their variability among studies and to improve the outcomes.

This Special Issue will accept original research articles, reviews, and methods from leading scientists and clinicians around the world who are studying and developing MSC-based therapies. The topics of submissions should focus on the therapeutic applications of MSCs, including, but not limited to, the following: cell/gene therapy, exosomes and extracellular vesicles, mechanisms of action, bioprinting, GM manufacturing, and regulatory guidelines.

Dr. Joan Oliva
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • mesenchymal stem cells
  • regenerating tissue
  • anti-cancer therapies
  • therapeutic applications

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Published Papers (7 papers)

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20 pages, 5280 KiB  
Article
Stem Cells Derived from Human Exfoliated Deciduous Teeth Functional Assessment: Exploring the Changes of Free Fatty Acids Composition during Cultivation
by Alexandra Ivan, Mirabela I. Cristea, Ada Telea, Camelia Oprean, Atena Galuscan, Calin A. Tatu and Virgil Paunescu
Int. J. Mol. Sci. 2023, 24(24), 17249; https://doi.org/10.3390/ijms242417249 - 8 Dec 2023
Cited by 5 | Viewed by 1913
Abstract
The metabolic regulation of stemness is widely recognized as a crucial factor in determining the fate of stem cells. When transferred to a stimulating and nutrient-rich environment, mesenchymal stem cells (MSCs) undergo rapid proliferation, accompanied by a change in protein expression and a [...] Read more.
The metabolic regulation of stemness is widely recognized as a crucial factor in determining the fate of stem cells. When transferred to a stimulating and nutrient-rich environment, mesenchymal stem cells (MSCs) undergo rapid proliferation, accompanied by a change in protein expression and a significant reconfiguration of central energy metabolism. This metabolic shift, from quiescence to metabolically active cells, can lead to an increase in the proportion of senescent cells and limit their regenerative potential. In this study, MSCs from human exfoliated deciduous teeth (SHEDs) were isolated and expanded in vitro for up to 10 passages. Immunophenotypic analysis, growth kinetics, in vitro plasticity, fatty acid content, and autophagic capacity were assessed throughout cultivation to evaluate the functional characteristics of SHEDs. Our findings revealed that SHEDs exhibit distinctive patterns of cell surface marker expression, possess high self-renewal capacity, and have a unique potential for neurogenic differentiation. Aged SHEDs exhibited lower proliferation rates, reduced potential for chondrogenic and osteogenic differentiation, an increasing capacity for adipogenic differentiation, and decreased autophagic potential. Prolonged cultivation of SHEDs resulted in changes in fatty acid composition, signaling a transition from anti-inflammatory to proinflammatory pathways. This underscores the intricate connection between metabolic regulation, stemness, and aging, crucial for optimizing therapeutic applications. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition)
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28 pages, 12636 KiB  
Article
The Immunoregulatory and Regenerative Potential of Activated Human Stem Cell Secretome Mitigates Acute-on-Chronic Liver Failure in a Rat Model
by Barbara Cuadra, Veronica Silva, Ya-Lin Huang, Yael Diaz, Claudio Rivas, Cristobal Molina, Valeska Simon, Maria Rosa Bono, Bernardo Morales, Mario Rosemblatt, Sebastian Silva, Rodrigo Acuña, Fernando Ezquer and Marcelo Ezquer
Int. J. Mol. Sci. 2024, 25(4), 2073; https://doi.org/10.3390/ijms25042073 - 8 Feb 2024
Cited by 2 | Viewed by 5520
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome marked by sudden liver function decline and multiorgan failure, predominantly acute kidney injury (AKY), in patients with chronic liver disease. Unregulated inflammation is a hallmark of ACLF; however, the key drivers of ACLF are not fully [...] Read more.
Acute-on-chronic liver failure (ACLF) is a syndrome marked by sudden liver function decline and multiorgan failure, predominantly acute kidney injury (AKY), in patients with chronic liver disease. Unregulated inflammation is a hallmark of ACLF; however, the key drivers of ACLF are not fully understood. This study explores the therapeutic properties of human mesenchymal stem cell (MSC) secretome, particularly focusing on its enhanced anti-inflammatory and pro-regenerative properties after the in vitro preconditioning of the cells. We evaluated the efficacy of the systemic administration of MSC secretome in preventing liver failure and AKI in a rat ACLF model where chronic liver disease was induced using by the administration of porcine serum, followed by D-galN/LPS administration to induce acute failure. After ACLF induction, animals were treated with saline (ACLF group) or MSC-derived secretome (ACLF-secretome group). The study revealed that MSC-secretome administration strongly reduced liver histological damage in the ACLF group, which was correlated with higher hepatocyte proliferation, increased hepatic and systemic anti-inflammatory molecule levels, and reduced neutrophil and macrophage infiltration. Additionally, renal examination revealed that MSC-secretome treatment mitigated tubular injuries, reduced apoptosis, and downregulated injury markers. These improvements were linked to increased survival rates in the ACLF-secretome group, endorsing MSC secretomes as a promising therapy for multiorgan failure in ACLF. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition)
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15 pages, 958 KiB  
Review
Molecular Mechanisms Responsible for the Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Lung Fibrosis
by Carl Randall Harrell, Valentin Djonov, Ana Volarevic, Aleksandar Arsenijevic and Vladislav Volarevic
Int. J. Mol. Sci. 2024, 25(8), 4378; https://doi.org/10.3390/ijms25084378 - 16 Apr 2024
Cited by 6 | Viewed by 3018
Abstract
Mesenchymal stem cell-derived exosomes (MSC-Exos) are nano-sized extracellular vesicles which contain various MSC-sourced anti-fibrotic, immunoregulatory and angio-modulatory proteins (growth factors, immunoregulatory cytokines, chemokines), lipids, and nucleic acids (messenger RNA and microRNAs). Due to their lipid envelope, MSC-Exos easily by-pass all barriers in the [...] Read more.
Mesenchymal stem cell-derived exosomes (MSC-Exos) are nano-sized extracellular vesicles which contain various MSC-sourced anti-fibrotic, immunoregulatory and angio-modulatory proteins (growth factors, immunoregulatory cytokines, chemokines), lipids, and nucleic acids (messenger RNA and microRNAs). Due to their lipid envelope, MSC-Exos easily by-pass all barriers in the body and deliver their cargo directly in target cells, modulating their viability, proliferation, phenotype and function. The results obtained in recently published experimental studies demonstrated beneficial effects of MSC-Exos in the treatment of lung fibrosis. MSC-Exos reduced activation of fibroblasts and prevented their differentiation in myofibroblasts. By delivering MSC-sourced immunoregulatory factors in lung-infiltrated monocytes and T cells, MSC-Exos modulate their function, alleviating on-going inflammation and fibrosis. MSC-Exos may also serve as vehicles for the target delivery of anti-fibrotic and immunomodulatory agents, enabling enhanced attenuation of lung fibrosis. Although numerous pre-clinical studies have demonstrated the therapeutic potential of MSC-Exos in the treatment of pulmonary fibrosis, there are several challenges that currently hinder their clinical implementation. Therefore, in this review article, we summarized current knowledge and we discussed future perspectives regarding molecular and cellular mechanisms which were responsible for the anti-fibrotic, anti-inflammatory and immunoregulatory properties of MSC-Exos, paving the way for their clinical use in the treatment of lung fibrosis. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition)
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21 pages, 1385 KiB  
Review
Cell Therapies for Acute Radiation Syndrome
by Barbara A. Christy, Maryanne C. Herzig, Xiaowu Wu, Arezoo Mohammadipoor, Jennifer S. McDaniel and James A. Bynum
Int. J. Mol. Sci. 2024, 25(13), 6973; https://doi.org/10.3390/ijms25136973 - 26 Jun 2024
Cited by 2 | Viewed by 2890
Abstract
The risks of severe ionizing radiation exposure are increasing due to the involvement of nuclear powers in combat operations, the increasing use of nuclear power, and the existence of terrorist threats. Exposure to a whole-body radiation dose above about 0.7 Gy results in [...] Read more.
The risks of severe ionizing radiation exposure are increasing due to the involvement of nuclear powers in combat operations, the increasing use of nuclear power, and the existence of terrorist threats. Exposure to a whole-body radiation dose above about 0.7 Gy results in H-ARS (hematopoietic acute radiation syndrome), which is characterized by damage to the hematopoietic system; higher doses result in further damage to the gastrointestinal and nervous systems. Only a few medical countermeasures for ARS are currently available and approved for use, although others are in development. Cell therapies (cells or products produced by cells) are complex therapeutics that show promise for the treatment of radiation injury and have been shown to reduce mortality and morbidity in animal models. Since clinical trials for ARS cannot be ethically conducted, animal testing is extremely important. Here, we describe cell therapies that have been tested in animal models. Both cells and cell products appear to promote survival and lessen tissue damage after whole-body irradiation, although the mechanisms are not clear. Because radiation exposure often occurs in conjunction with other traumatic injuries, animal models of combined injury involving radiation and future countermeasure testing for these complex medical problems are also discussed. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition)
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16 pages, 14920 KiB  
Article
miR-9-5p and miR-221-3p Promote Human Mesenchymal Stem Cells to Alleviate Carbon Tetrachloride-Induced Liver Injury by Enhancing Human Mesenchymal Stem Cell Engraftment and Inhibiting Hepatic Stellate Cell Activation
by Lihong He, Jianwei Xu, Ping Huang, Yu Bai, Huanhuan Chen, Xiaojing Xu, Ya’nan Hu, Jinming Liu and Huanxiang Zhang
Int. J. Mol. Sci. 2024, 25(13), 7235; https://doi.org/10.3390/ijms25137235 - 30 Jun 2024
Cited by 2 | Viewed by 1644
Abstract
Mesenchymal stem cells (MSCs) have shown great potential for the treatment of liver injuries, and the therapeutic efficacy greatly depends on their homing to the site of injury. In the present study, we detected significant upregulation of hepatocyte growth factor (HGF) in the [...] Read more.
Mesenchymal stem cells (MSCs) have shown great potential for the treatment of liver injuries, and the therapeutic efficacy greatly depends on their homing to the site of injury. In the present study, we detected significant upregulation of hepatocyte growth factor (HGF) in the serum and liver in mice with acute or chronic liver injury. In vitro study revealed that upregulation of miR-9-5p or miR-221-3p promoted the migration of human MSCs (hMSCs) toward HGF. Moreover, overexpression of miR-9-5p or miR-221-3p promoted hMSC homing to the injured liver and resulted in significantly higher engraftment upon peripheral infusion. hMSCs reduced hepatic necrosis and inflammatory infiltration but showed little effect on extracellular matrix (ECM) deposition. By contrast, hMSCs overexpressing miR-9-5p or miR-221-3p resulted in not only less centrilobular necrosis and venous congestion but also a significant reduction of ECM deposition, leading to obvious improvement of hepatocyte morphology and alleviation of fibrosis around central vein and portal triads. Further studies showed that hMSCs inhibited the activation of hepatic stellate cells (HSCs) but could not decrease the expression of TIMP-1 upon acute injury and the expression of MCP-1 and TIMP-1 upon chronic injury, while hMSCs overexpressing miR-9-5p or miR-221-3p led to further inactivation of HSCs and downregulation of all three fibrogenic and proinflammatory factors TGF-β, MCP-1, and TIMP-1 upon both acute and chronic injuries. Overexpression of miR-9-5p or miR-221-3p significantly downregulated the expression of α-SMA and Col-1α1 in activated human hepatic stellate cell line LX-2, suggesting that miR-9-5p and miR-221-3p may partially contribute to the alleviation of liver injury by preventing HSC activation and collagen expression, shedding light on improving the therapeutic efficacy of hMSCs via microRNA modification. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition)
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17 pages, 3157 KiB  
Article
Epigenetic Reprogramming and Inheritance of the Cellular Differentiation Status Following Transient Expression of a Nonfunctional Dominant-Negative Retinoblastoma Mutant in Murine Mesenchymal Stem Cells
by Mikhail Baryshev, Irina Maksimova and Ilona Sasoveca
Int. J. Mol. Sci. 2024, 25(19), 10678; https://doi.org/10.3390/ijms251910678 - 3 Oct 2024
Viewed by 1316
Abstract
The retinoblastoma gene product (Rb1), a master regulator of the cell cycle, plays a prominent role in cell differentiation. Previously, by analyzing the differentiation of cells transiently overexpressing the ΔS/N DN Rb1 mutant, we demonstrated that these cells fail to differentiate into mature [...] Read more.
The retinoblastoma gene product (Rb1), a master regulator of the cell cycle, plays a prominent role in cell differentiation. Previously, by analyzing the differentiation of cells transiently overexpressing the ΔS/N DN Rb1 mutant, we demonstrated that these cells fail to differentiate into mature adipocytes and that they constitutively silence Pparγ2 through CpG methylation. Here, we demonstrate that the consequences of the transient expression of ΔS/N DN Rb1 are accompanied by the retention of Cebpa promoter methylation near the TSS under adipogenic differentiation, thereby preventing its expression. The CGIs of the promoters of the Rb1, Ezh2, Mll4, Utx, and Tet2 genes, which are essential for adipogenic differentiation, have an unmethylated status regardless of the cell differentiation state. Moreover, Dnmt3a, a de novo DNA methyltransferase, is overexpressed in undifferentiated ΔS/N cells compared with wild-type cells and, in addition to Dnmt1, Dnmt3a is significantly upregulated by adipogenic stimuli in both wild-type and ΔS/N cells. Notably, the chromatin modifier Ezh2, which is also involved in epigenetic reprogramming, is highly induced in ΔS/N cells. Overall, we demonstrate that two major genes, Pparγ2 and Cebpa, which are responsible for terminal adipocyte differentiation, are selectively epigenetically reprogrammed to constitutively silent states. We hypothesize that the activation of Dnmt3a, Rb1, and Ezh2 observed in ΔS/N cells may be a consequence of a stress response caused by the accumulation and malfunctioning of Rb1-interacting complexes for the epigenetic reprogramming of Pparγ2/Cebpa and prevention of adipogenesis in an inappropriate cellular context. The failure of ΔS/N cells to differentiate and express Pparγ2 and Cebpa in culture following the expression of the DN Rb1 mutant may indicate the creation of epigenetic memory for new reprogrammed epigenetic states of genes. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition)
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22 pages, 5401 KiB  
Article
Adipose-Derived Stromal Cells Exposed to RGD Motifs Enter an Angiogenic Stage Regulating Endothelial Cells
by Nicolo-Constantino Brembilla, Sanae El-Harane, Stéphane Durual, Karl-Heinz Krause and Olivier Preynat-Seauve
Int. J. Mol. Sci. 2025, 26(3), 867; https://doi.org/10.3390/ijms26030867 - 21 Jan 2025
Viewed by 904
Abstract
Adipose-derived stromal cells (ASCs) possess significant regenerative potential, playing a key role in tissue repair and angiogenesis. During wound healing, ASC interacts with the extracellular matrix by recognizing arginylglycylaspartic acid (RGD) motifs, which are crucial for mediating these functions. This study investigates how [...] Read more.
Adipose-derived stromal cells (ASCs) possess significant regenerative potential, playing a key role in tissue repair and angiogenesis. During wound healing, ASC interacts with the extracellular matrix by recognizing arginylglycylaspartic acid (RGD) motifs, which are crucial for mediating these functions. This study investigates how RGD exposure influences ASC behavior, with a focus on angiogenesis. To mimic the wound-healing environment, ASC were cultured in a porcine gelatin sponge, an RGD-exposing matrix. Transcriptomics revealed that ASC cultured in gelatin exhibited an upregulated expression of genes associated with inflammation, angiogenesis, and tissue repair compared to ASC in suspension. Pro-inflammatory and pro-angiogenic factors, including IL-1, IL-6, IL-8, and VEGF, were significantly elevated. Functional assays further demonstrated that ASC-conditioned media enhanced endothelial cell migration, tubulogenesis, and reduced endothelial permeability, all critical processes in angiogenesis. Notably, ASC-conditioned media also promoted vasculogenesis in human vascular organoids. The inhibition of ASC-RGD interactions using the cyclic peptide cilengitide reversed these effects, underscoring the essential role of RGD-integrin interactions in ASC-mediated angiogenesis. These findings suggest that gelatin sponges enhance ASC’s regenerative and angiogenic properties via RGD-dependent mechanisms, offering promising therapeutic potential for tissue repair and vascular regeneration. Understanding how RGD modulates ASC behavior provides valuable insights into advancing cell-based regenerative therapies. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Therapeutic Application : 2nd Edition)
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