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Molecular Biology and Therapeutic Properties of Mesenchymal Stromal Cells

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

Deadline for manuscript submissions: closed (20 January 2024) | Viewed by 8321

Special Issue Editor


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Guest Editor
School of Biological and Medical Physics, Moscow Institute of Physics and Technology, National Research University, Dolgoprudny 141701, Russia
Interests: functional biomaterials; drug delivery systems; 3D multicellular models; stem cell biology; cancer biology; cell engineering

Special Issue Information

Dear Colleagues, 

Mesenchymal stromal cells (MSCs) are involved into regulation of stem cell niches in various tissues and play a pivotal role in tissue regeneration. In particular, MSCs are able to replenish stem cell pool at the site of injury via paracrine activity and exosome production. Moreover, MSCs significantly contribute to angiogenesis and extracellullar matrix production that provides mechanical support and nutrient supply to the cells in newly-formed tissue. Owing to the mentioned properties, MSCs and their derivatives have been used for numerous applications in regenerative medicine. It is believed that therapeutic effects of MSCs can be boosted via increase of survival rate and homing of the transplanted cells. It can be achieved due to different methods including chemical functionalization, pre-condition with biologically active molecules or genetic modification.

For this Special Issue, to be published in the International Journal of Molecular Science, researchers who are active in development of MSC-based therapies or in molecular mechanisms of therapeutic effects of MSC are invited to submit their latest results. Papers covering genetic and non-genetic modifications of MSC aiming at improvement of their regenerative properties, are also welcome.

Dr. Mikhail O. Durymanov
Guest Editor

Manuscript Submission Information

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Keywords

  • mesenchymal stromal cells
  • regenerative medicine
  • growth factor
  • immunomodulation
  • cell homing
  • hypoxia
  • wound healing
  • transfection

Published Papers (7 papers)

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Research

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14 pages, 3517 KiB  
Article
Novel Immortalized Human Multipotent Mesenchymal Stromal Cell Line for Studying Hormonal Signaling
by Alexandra Primak, Natalia Kalinina, Mariya Skryabina, Vladimir Usachev, Vadim Chechekhin, Maksim Vigovskiy, Elizaveta Chechekhina, Nikita Voloshin, Konstantin Kulebyakin, Maria Kulebyakina, Olga Grigorieva, Pyotr Tyurin-Kuzmin, Nataliya Basalova, Anastasia Efimenko, Stalik Dzhauari, Yulia Antropova, Ivan Plyushchii, Zhanna Akopyan, Veronika Sysoeva, Vsevolod Tkachuk and Maxim Karagyauradd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(4), 2421; https://doi.org/10.3390/ijms25042421 - 19 Feb 2024
Viewed by 806
Abstract
Multipotent mesenchymal stromal cells (MSCs) integrate hormone and neuromediator signaling to coordinate tissue homeostasis, tissue renewal and regeneration. To facilitate the investigation of MSC biology, stable immortalized cell lines are created (e.g., commercially available ASC52telo). However, the ASC52telo cell line has an impaired [...] Read more.
Multipotent mesenchymal stromal cells (MSCs) integrate hormone and neuromediator signaling to coordinate tissue homeostasis, tissue renewal and regeneration. To facilitate the investigation of MSC biology, stable immortalized cell lines are created (e.g., commercially available ASC52telo). However, the ASC52telo cell line has an impaired adipogenic ability and a depressed response to hormones, including 5-HT, GABA, glutamate, noradrenaline, PTH and insulin compared to primary cells. This markedly reduces the potential of the ASC52telo cell line in studying the mechanisms of hormonal control of MSC’s physiology. Here, we have established a novel immortalized culture of adipose tissue-derived MSCs via forced telomerase expression after lentiviral transduction. These immortalized cell cultures demonstrate high proliferative potential (up to 40 passages), delayed senescence, as well as preserved primary culture-like functional activity (sensitivity to hormones, ability to hormonal sensitization and differentiation) and immunophenotype up to 17–26 passages. Meanwhile, primary adipose tissue-derived MSCs usually irreversibly lose their properties by 8–10 passages. Observed characteristics of reported immortalized human MSC cultures make them a feasible model for studying molecular mechanisms, which regulate the functional activities of these cells, especially when primary cultures or commercially available cell lines are not appropriate. Full article
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17 pages, 2786 KiB  
Article
The Decellularized Cell-Derived Extracellular Matrix Enhances the Paracrine Function of Human Mesenchymal Stromal/Stem Cells
by Roman Ushakov, Andrey Ratushnyy, Ludmila Buravkova, Elena Tolkunova and Elena Burova
Int. J. Mol. Sci. 2024, 25(4), 2419; https://doi.org/10.3390/ijms25042419 - 19 Feb 2024
Viewed by 734
Abstract
The mesenchymal stromal/stem cells (MSCs) are known to secrete pleiotropic paracrine factors, contributing to tissue regeneration. This unique ability makes MSCs promising therapeutic tools for many diseases, including even those that were previously untreatable. Thus, the development of preconditioning approaches aimed at enhancing [...] Read more.
The mesenchymal stromal/stem cells (MSCs) are known to secrete pleiotropic paracrine factors, contributing to tissue regeneration. This unique ability makes MSCs promising therapeutic tools for many diseases, including even those that were previously untreatable. Thus, the development of preconditioning approaches aimed at enhancing the paracrine function of MSCs attracts great interest. In the present work, we studied how the extracellular matrix, the essential part of the native tissue microenvironment, affects the secretory capacity of MSCs of various origins. The MSC-derived decellularized extracellular matrix (dECM), used as the cell culture substrate, triggered strong upregulation of FGF-2, MMP-1, HGF, GRO-α, GRO-β, CXCL-5, CXCL-6, IL-6, IL-8, G-CSF and MCP-1. Functional in vitro tests revealed that conditioned media derived from MSCs cultured on dECM significantly improved 3T3 fibroblast and HaCaT keratinocyte scratch wound healing, stimulated THP-1 monocyte migration and promoted capillary-like HUVEC-based tube formation compared to conditioned media from MSCs grown on plastic. In addition, we found that FAK inhibition promoted dECM-induced upregulation of paracrine factors, suggesting that this kinase participates in the MSCs’ paracrine response to dECM. Together, these findings demonstrate that dECM provides cues that considerably enhance the secretory function of MSCs. Thus, dECM usage as a cell culture substrate alone or in combination with a FAK inhibitor may be viewed as a novel MSC preconditioning technique. Full article
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14 pages, 1719 KiB  
Article
Mesenchymal Stromal Cells Primed by Toll-like Receptors 3 and 4 Enhanced Anti-Inflammatory Effects against LPS-Induced Macrophages via Extracellular Vesicles
by Sein Hwang, Dong Kyung Sung, Young Eun Kim, Misun Yang, So Yoon Ahn, Se In Sung and Yun Sil Chang
Int. J. Mol. Sci. 2023, 24(22), 16264; https://doi.org/10.3390/ijms242216264 - 13 Nov 2023
Cited by 2 | Viewed by 1052
Abstract
Although it has been suggested that toll-like receptor (TLR) 3 and TLR4 activation alters mesenchymal stromal cells (MSCs)’ immunoregulatory function as anti- or pro-inflammatory phenotypes, we have previously confirmed that TLR4-primed hUCB-MSCs alleviate lung inflammation and tissue injury in an E. coli-induced [...] Read more.
Although it has been suggested that toll-like receptor (TLR) 3 and TLR4 activation alters mesenchymal stromal cells (MSCs)’ immunoregulatory function as anti- or pro-inflammatory phenotypes, we have previously confirmed that TLR4-primed hUCB-MSCs alleviate lung inflammation and tissue injury in an E. coli-induced acute lung injury (ALI) mouse model. Therefore, we hypothesized that strong stimulation of TLR3 or TLR4 prompts hUCB-MSCs to exhibit an anti-inflammatory phenotype mediated by extracellular vesicles (EVs). In this study, we compared the anti-inflammatory effect of TLR3-primed and TLR4-primed hUCB-MSCs against an LPS-induced ALI in vitro model by treating MSCs, MSC-derived conditioned medium (CM), and MSC-derived extracellular vesicles (EVs). LPS-induced rat primary alveolar macrophage and RAW 264.7 cells were treated with naïve, TLR3-, and TLR4-primed MSCs and their derived CM and EVs. Flow cytometry and ELISA were used to evaluate M1-M2 polarization of macrophages and pro-inflammatory cytokine levels, respectively. LPS-stimulated macrophages showed significantly increased pro-inflammatory cytokines compared to those of the normal control, and the percentage of M2 macrophage phenotype was predominantly low. In reducing the inflammatory cytokines and enhancing M2 polarization, TLR3- and TLR4-primed MSCs were significantly more effective than the naïve MSCs, and this finding was also observed with the treatment of MSC-derived CMs and EVs. No significant difference between the efficacy of TLR3- and TLR-primed MSCs was observed. Strong stimulation of TLR3- and TLR4-stimulated hUCB-MSCs significantly reduced pro-inflammatory cytokine secretion from LPS-induced macrophages and significantly enhanced the M2 polarization of macrophages. We further confirmed that TLR-primed MSC-derived EVs can exert anti-inflammatory and immunosuppressive effects alone comparable to MSC treatment. We hereby suggest that in the LPS-induced macrophage in vitro model, EVs derived from both TLR3 and TLR4-primed MSCs can be a therapeutic candidate by promoting the M2 phenotype. Full article
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18 pages, 5532 KiB  
Article
Labeling and Tracking of Individual Human Mesenchymal Stromal Cells Using Photoconvertible Fluorescent Microcapsules
by Olga A. Sindeeva, Polina A. Demina, Zhanna V. Kozyreva, Albert R. Muslimov, Olga I. Gusliakova, Valeriia O. Laushkina, Ekaterina A. Mordovina, Daria Tsyupka, Olga S. Epifanovskaya, Anastasiia Yu. Sapach, Irina Yu. Goryacheva and Gleb B. Sukhorukov
Int. J. Mol. Sci. 2023, 24(17), 13665; https://doi.org/10.3390/ijms241713665 - 04 Sep 2023
Viewed by 1128
Abstract
The behavior and migration of human mesenchymal stromal cells (hMSCs) are focal points of research in the biomedical field. One of the major aspects is potential therapy using hMCS, but at present, the safety of their use is still controversial owing to limited [...] Read more.
The behavior and migration of human mesenchymal stromal cells (hMSCs) are focal points of research in the biomedical field. One of the major aspects is potential therapy using hMCS, but at present, the safety of their use is still controversial owing to limited data on changes that occur with hMSCs in the long term. Fluorescent photoconvertible proteins are intensively used today as “gold standard” to mark the individual cells and study single-cell interactions, migration processes, and the formation of pure lines. A crucial disadvantage of this method is the need for genetic modification of the primary culture, which casts doubt on the possibility of exploring the resulting clones in personalized medicine. Here we present a new approach for labeling and tracking hMSCs without genetic modification based on the application of cell-internalizable photoconvertible polyelectrolyte microcapsules (size: 2.6 ± 0.5 μm). These capsules were loaded with rhodamine B, and after thermal treatment, exhibited fluorescent photoconversion properties. Photoconvertible capsules demonstrated low cytotoxicity, did not affect the immunophenotype of the hMSCs, and maintained a high level of fluorescent signal for at least seven days. The developed approach was tested for cell tracking for four days and made it possible to trace the destiny of daughter cells without the need for additional labeling. Full article
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9 pages, 1034 KiB  
Communication
The Potential Use of THP-1, a Monocytic Leukemia Cell Line, to Predict Immune-Suppressive Potency of Human Bone-Marrow Stromal Cells (BMSCs) In Vitro: A Pilot Study
by Jiaqiang Ren, Gergely Szombath, Lynn Vitale-Cross, David F. Stroncek, Pamela G. Robey, Anna Hajdara, Ildiko Szalayova, Balazs Mayer, Daniel Martin, Eva Mezey and Krisztian Nemeth
Int. J. Mol. Sci. 2023, 24(17), 13258; https://doi.org/10.3390/ijms241713258 - 26 Aug 2023
Cited by 1 | Viewed by 1243
Abstract
Adoptive transfer of cultured BMSCs was shown to be immune-suppressive in various inflammatory settings. Many factors play a role in the process, but no master regulator of BMSC-driven immunomodulation was identified. Consequently, an assay that might predict BMSC product efficacy is still unavailable. [...] Read more.
Adoptive transfer of cultured BMSCs was shown to be immune-suppressive in various inflammatory settings. Many factors play a role in the process, but no master regulator of BMSC-driven immunomodulation was identified. Consequently, an assay that might predict BMSC product efficacy is still unavailable. Below, we show that BMSC donor variability can be monitored by IL-10 production of monocytes/macrophages using THP-1 cells (immortalized monocytic leukemia cells) co-cultured with BMSCs. Using a mixed lymphocyte reaction (MLR) assay, we also compared the ability of the different donor BMSCs to suppress T-cell proliferation, another measure of their immune-suppressive ability. We found that the BMSCs from a donor that induced the most IL-10 production were also the most efficient in suppressing T-cell proliferation. Transcriptome studies showed that the most potent BMSC batch also had higher expression of several known key immunomodulatory molecules such as hepatocyte growth factor (HGF), PDL1, and numerous members of the PGE2 pathway, including PTGS1 and TLR4. Multiplex ELISA experiments revealed higher expression of HGF and IL6 by the most potent BMSC donor. Based on these findings, we propose that THP-1 cells may be used to assess BMSC immunosuppressive activity as a product characterization assay. Full article
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15 pages, 4551 KiB  
Article
Tissue-Oxygen-Adaptation of Bone Marrow-Derived Mesenchymal Stromal Cells Enhances Their Immunomodulatory and Pro-Angiogenic Capacity, Resulting in Accelerated Healing of Chemical Burns
by Marina V. Volkova, Ningfei Shen, Anna Polyanskaya, Xiaoli Qi, Valery V. Boyarintsev, Elena V. Kovaleva, Alexander V. Trofimenko, Gleb I. Filkov, Alexandre V. Mezentsev, Sergey P. Rybalkin and Mikhail O. Durymanov
Int. J. Mol. Sci. 2023, 24(4), 4102; https://doi.org/10.3390/ijms24044102 - 17 Feb 2023
Cited by 5 | Viewed by 1652
Abstract
Transplantation of mesenchymal stromal cells (MSCs) provides a powerful tool for the management of multiple tissue injuries. However, poor survival of exogenous cells at the site of injury is a major complication that impairs MSC therapeutic efficacy. It has been found that tissue-oxygen [...] Read more.
Transplantation of mesenchymal stromal cells (MSCs) provides a powerful tool for the management of multiple tissue injuries. However, poor survival of exogenous cells at the site of injury is a major complication that impairs MSC therapeutic efficacy. It has been found that tissue-oxygen adaptation or hypoxic pre-conditioning of MSCs could improve the healing process. Here, we investigated the effect of low oxygen tension on the regenerative potential of bone-marrow MSCs. It turned out that incubation of MSCs under a 5% oxygen atmosphere resulted in increased proliferative activity and enhanced expression of multiple cytokines and growth factors. Conditioned growth medium from low-oxygen-adapted MSCs modulated the pro-inflammatory activity of LPS-activated macrophages and stimulated tube formation by endotheliocytes to a much higher extent than conditioned medium from MSCs cultured in a 21% oxygen atmosphere. Moreover, we examined the regenerative potential of tissue-oxygen-adapted and normoxic MSCs in an alkali-burn injury model on mice. It has been revealed that tissue-oxygen adaptation of MSCs accelerated wound re-epithelialization and improved the tissue histology of the healed wounds in comparison with normoxic MSC-treated and non-treated wounds. Overall, this study suggests that MSC adaptation to ‘physiological hypoxia’ could be a promising approach for facilitating skin injuries, including chemical burns. Full article
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Review

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22 pages, 1303 KiB  
Review
Biology and Therapeutic Properties of Mesenchymal Stem Cells in Leukemia
by Cheng-Hsien Wu, Te-Fu Weng, Ju-Pi Li and Kang-Hsi Wu
Int. J. Mol. Sci. 2024, 25(5), 2527; https://doi.org/10.3390/ijms25052527 - 21 Feb 2024
Viewed by 719
Abstract
This comprehensive review delves into the multifaceted roles of mesenchymal stem cells (MSCs) in leukemia, focusing on their interactions within the bone marrow microenvironment and their impact on leukemia pathogenesis, progression, and treatment resistance. MSCs, characterized by their ability to differentiate into various [...] Read more.
This comprehensive review delves into the multifaceted roles of mesenchymal stem cells (MSCs) in leukemia, focusing on their interactions within the bone marrow microenvironment and their impact on leukemia pathogenesis, progression, and treatment resistance. MSCs, characterized by their ability to differentiate into various cell types and modulate the immune system, are integral to the BM niche, influencing hematopoietic stem cell maintenance and functionality. This review extensively explores the intricate relationship between MSCs and leukemic cells in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. This review also addresses the potential clinical applications of MSCs in leukemia treatment. MSCs’ role in hematopoietic stem cell transplantation, their antitumor effects, and strategies to disrupt chemo-resistance are discussed. Despite their therapeutic potential, the dual nature of MSCs in promoting and inhibiting tumor growth poses significant challenges. Further research is needed to understand MSCs’ biological mechanisms in hematologic malignancies and develop targeted therapeutic strategies. This in-depth exploration of MSCs in leukemia provides crucial insights for advancing treatment modalities and improving patient outcomes in hematologic malignancies. Full article
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