Mesenchymal Stem/Stromal Cells in Immunity and Disease

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (5 March 2021) | Viewed by 84976

Special Issue Editor


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Guest Editor
Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Campus Erasme, Bâtiment de Transfusion (Level +1), 1070 Brussels, Belgium
Interests: mesenchymal stem/stromal cells (MSCs); tissue sources of MSCs; immunomodulation properties; extracellular vesicles (EVs); environmental challenges; efficient MSC immunotherapy
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Special Issue Information

Dear Colleagues,

Due to their simple and easier isolation procedure as well as their great expansion potential, mesenchymal stem/stromal cells (MSCs) are increasingly considered as ideal candidates for different therapeutic applications. MSCs are multipotent fibroblast-like cells that can be virtually found in almost all tissues. The therapeutic effect of MSCs is mainly a result of their potent immunomodulatory functions. MSCs are not true immune cells but tissue precursor cells harboring a spectrum of therapeutically active molecules. Moreover, MSCs are environmentally responsive as they can actively sense their surroundings (inflammation, infection, and tissue damage) and modulate in consequence their fate and behavior. By nature, MSCs demonstrate plasticity in their immunomodulatory effects as a way of responding to these challenges. Accordingly, their use as immunotherapeutic strategies will present new hopes for treating patients with immunological and inflammatory diseases. A better understanding of the molecular mechanisms underlying the immunomodulatory effects of MSCs and, in particular, the influence of the local environment on their immuno-biology will improve the safety and efficiency of MSC-based therapy as well as help to achieve the appropriate therapeutic effect. Another strategy to enhance the therapeutic value of MSCs is to use their extracellular vesicles (EVs) as an alternative to cellular products. EVs can mediate the immunomodulatory effects of MSCs by transferring their cytokines, mRNA, or miRNA to the target cells. By selectively isolating these MSC-derived vesicles, they can be infused instead of the cells for different immunotherapy purposes.

In this Special Issue, we propose to present updates about the MSC immunomodulatory properties including their extracellular vesicles (EVs) and to discuss different opinions related to MSC source and type, and the effects of environmental signals on their immuno-biology. Your potential contribution based on your expertise in the field would certainly enrich this Special Issue.

Dr. Mehdi Najar
Guest Editor

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Keywords

  • Mesenchymal stem/stromal cells (MSCs) of different origins
  • Immunological and inflammatory diseases
  • MSCs and MSCs-free-based immunotherapeutic strategies
  • Immunomodulatory mechanisms
  • Local environment conditioning
  • Improved MSC strategies

Published Papers (17 papers)

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Editorial

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4 pages, 211 KiB  
Editorial
Mesenchymal Stem/Stromal Cells in Immunity and Disease: A Better Understanding for an Improved Use
by Makram Merimi, Laurence Lagneaux, Douâa Moussa Agha, Philippe Lewalle, Nathalie Meuleman, Arsène Burny, Hassan Fahmi and Mehdi Najar
J. Clin. Med. 2020, 9(5), 1516; https://doi.org/10.3390/jcm9051516 - 18 May 2020
Cited by 7 | Viewed by 1770
Abstract
In this Special Issue, directed and supervised by Dr. Mehdi Najar, a collection of basic research articles and reviews, on the state of the art of Mesenchymal Stem/Stromal Cells (MSCs) immune biology, is presented. Among the major goals of this Special Issue is [...] Read more.
In this Special Issue, directed and supervised by Dr. Mehdi Najar, a collection of basic research articles and reviews, on the state of the art of Mesenchymal Stem/Stromal Cells (MSCs) immune biology, is presented. Among the major goals of this Special Issue is the presentation of an update about the immunomodulatory properties of MSCs and their capacity to respond to tissue microenvironment changes. MSCs hold great promise in the field of immunotherapy and regenerative medicine. Accordingly, a better understanding of MSC immune biology will improve their therapeutic value and use. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
8 pages, 221 KiB  
Editorial
Mesenchymal Stromal Cell-Based Therapy: New Perspectives and Challenges
by Mehdi Najar, Fatima Bouhtit, Rahma Melki, Hassan Afif, Abdellah Hamal, Hassan Fahmi, Makram Merimi and Laurence Lagneaux
J. Clin. Med. 2019, 8(5), 626; https://doi.org/10.3390/jcm8050626 - 8 May 2019
Cited by 65 | Viewed by 5474
Abstract
Stem cells have been the focus of intense research opening up new possibilities for the treatment of various diseases. Mesenchymal stromal cells (MSCs) are multipotent cells with relevant immunomodulatory properties and are thus considered as a promising new strategy for immune disease management. [...] Read more.
Stem cells have been the focus of intense research opening up new possibilities for the treatment of various diseases. Mesenchymal stromal cells (MSCs) are multipotent cells with relevant immunomodulatory properties and are thus considered as a promising new strategy for immune disease management. To enhance their efficiency, several issues related to both MSC biology and functions are needed to be identified and, most importantly, well clarified. The sources from which MSCs are isolated are diverse and might affect their properties. Both clinicians and scientists need to handle a phenotypic-characterized population of MSCs, particularly regarding their immunological profile. Moreover, it is now recognized that the tissue-reparative effects of MSCs are based on their immunomodulatory functions that are activated following a priming/licensing step. Thus, finding the best ways to pre-conditionate MSCs before their injection will strengthen their activity potential. Finally, soluble elements derived from MSC-secretome, including extracellular vesicles (EVs), have been proposed as a cell-free alternative tool for therapeutic medicine. Collectively, these features have to be considered and developed to ensure the efficiency and safety of MSC-based therapy. By participating to this Special Issue “Mesenchymal Stem/Stromal Cells in Immunity and Disease”, your valuable contribution will certainly enrich the content and discussion related to the thematic of MSCs. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)

Research

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16 pages, 2490 KiB  
Article
The Impact of Cell-Expansion and Inflammation on The Immune-Biology of Human Adipose Tissue-Derived Mesenchymal Stromal Cells
by Karolien Buyl, Makram Merimi, Robim M. Rodrigues, Douâa Moussa Agha, Rahma Melki, Tamara Vanhaecke, Dominique Bron, Philippe Lewalle, Nathalie Meuleman, Hassan Fahmi, Vera Rogiers, Laurence Lagneaux, Joery De Kock and Mehdi Najar
J. Clin. Med. 2020, 9(3), 696; https://doi.org/10.3390/jcm9030696 - 4 Mar 2020
Cited by 13 | Viewed by 3000
Abstract
Background: As a cell-based therapeutic, AT-MSCs need to create an immuno-reparative environment appropriate for tissue repair. In the presence of injury, MSCs may have to proliferate and face inflammation. Clinical application requires repeated administrations of a high number of cells with a well-established [...] Read more.
Background: As a cell-based therapeutic, AT-MSCs need to create an immuno-reparative environment appropriate for tissue repair. In the presence of injury, MSCs may have to proliferate and face inflammation. Clinical application requires repeated administrations of a high number of cells with a well-established immune profile. Methods: We have established an immuno-comparative screening by determining the expression of 28 molecules implicated in immune regulation. This screening was performed during cell-expansion and inflammatory priming of AT-MSCs. Results: Our study confirms that AT-MSCs are highly expandable and sensitive to inflammation. Both conditions have substantially modulated the expression of a panel of immunological marker. Specifically, CD34 expression was substantially decreased upon cell-passaging. HLA-ABC, CD40 CD54, CD106, CD274 and CD112 were significantly increased by inflammation. In vitro cell-expansion also significantly altered the expression profile of HLA-DR, CD40, CD62L, CD106, CD166, HLA-G, CD200, HO-1, CD155 and ULBP-3. Conclusion: This study points out the response and characteristics of MSCs following expansion and inflammatory priming. It will strength our knowledge about the molecular mechanisms that may improve or hamper the therapeutic potential of MSCs. These immunological changes need to be further characterized to guarantee a safe cellular product with consistent quality and high therapeutic efficacy. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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19 pages, 3549 KiB  
Article
Are the Immune Properties of Mesenchymal Stem Cells from Wharton’s Jelly Maintained during Chondrogenic Differentiation?
by Charlotte Voisin, Ghislaine Cauchois, Loïc Reppel, Caroline Laroye, Laetitia Louarn, Chantal Schenowitz, Paulin Sonon, Isabelle Poras, Valentine Wang, Edgardo D. Carosella, Nadia Benkirane-Jessel, Philippe Moreau, Nathalie Rouas-Freiss, Danièle Bensoussan and Céline Huselstein
J. Clin. Med. 2020, 9(2), 423; https://doi.org/10.3390/jcm9020423 - 4 Feb 2020
Cited by 12 | Viewed by 3038
Abstract
Background: Umbilical mesenchymal stem/stromal cells (MSCs), and especially those derived from Wharton’s jelly (WJ), are a promising engineering tool for tissue repair in an allogeneic context. This is due to their differentiation capacity and immunological properties, like their immunomodulatory potential and paracrine activity. [...] Read more.
Background: Umbilical mesenchymal stem/stromal cells (MSCs), and especially those derived from Wharton’s jelly (WJ), are a promising engineering tool for tissue repair in an allogeneic context. This is due to their differentiation capacity and immunological properties, like their immunomodulatory potential and paracrine activity. Hence, these cells may be considered an Advanced Therapy Medicinal Product (ATMP). The purpose of this work was to differentiate MSCs from WJ (WJ-MSCs) into chondrocytes using a scaffold and to evaluate, in vitro, the immunomodulatory capacities of WJ-MSCs in an allogeneic and inflammatory context, mimicked by IFN-γ and TNF-α priming during the chondrogenic differentiation. Methods: Scaffolds were made from hydrogel composed by alginate enriched in hyaluronic acid (Alg/HA). Chondrogenic differentiation, immunological function, phenotype expression, but also secreted soluble factors were the different parameters followed during 28 days of culture. Results: During chondrocyte differentiation, even in an allogeneic context, WJ-MSCs remained unable to establish the immunological synapse or to induce T cell alloproliferation. Moreover, interestingly, paracrine activity and functional immunomodulation were maintained during cell differentiation. Conclusion: These results show that WJ-MSCs remained hypoimmunogenic and retained immunomodulatory properties even when they had undergone chondrocyte differentiation. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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17 pages, 3338 KiB  
Article
HCMV Infection in a Mesenchymal Stem Cell Niche: Differential Impact on the Development of NK Cells versus ILC3
by Ricarda Ising, Sandra Weinhold, Sabrina Bianca Bennstein, Albert Zimmermann, Özer Degistirici, Gesine Kögler, Roland Meisel, Hartmut Hengel, Jörg Timm and Markus Uhrberg
J. Clin. Med. 2020, 9(1), 10; https://doi.org/10.3390/jcm9010010 - 19 Dec 2019
Cited by 8 | Viewed by 3945
Abstract
Human cytomegalovirus (HCMV) is highly prevalent in most populations worldwide and has a major influence on shaping the human immune system. Natural killer (NK) cells are important antiviral effectors that adapt to HCMV infection by expansion of virus-specific effector/memory cells. The impact of [...] Read more.
Human cytomegalovirus (HCMV) is highly prevalent in most populations worldwide and has a major influence on shaping the human immune system. Natural killer (NK) cells are important antiviral effectors that adapt to HCMV infection by expansion of virus-specific effector/memory cells. The impact of HCMV infection on the development of NK cells and innate lymphoid cells (ILC) in general is less well understood. In this context, we have recently established a novel in vitro platform to study human NK cell development in a stem cell niche based on human bone marrow-derived mesenchymal stem cells (MSC). Here, the system was modified by infecting MSC with HCMV to study the influence of virus infection on NK/ILC development. We show that cord blood-derived hematopoietic progenitor cells are successfully differentiated into mature CD56+CD94+NKG2A+ NK cells on HCMV-infected MSC with significant higher anti-viral cytokine production compared to NK cells developing on non-infected MSC. Furthermore, the generation of ILC3, characterized by expression of the signature transcription factor RAR-related orphan receptor gamma (RORγt) and the production of IL-22, was strongly impaired by HCMV infection. These observations are clinically relevant, given that ILC3 are associated with protection from graft-versus-host disease (GvHD) following stem cell transplantation and HCMV reactivation in turn is associated with increased incidence of GvHD. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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18 pages, 2620 KiB  
Article
1,25(OH)2D3 Differently Affects Immunomodulatory Activities of Mesenchymal Stem Cells Depending on the Presence of TNF-α, IL-1β and IFN-γ
by Christian Behm, Alice Blufstein, Johannes Gahn, Barbara Kubin, Michael Nemec, Andreas Moritz, Xiaohui Rausch-Fan and Oleh Andrukhov
J. Clin. Med. 2019, 8(12), 2211; https://doi.org/10.3390/jcm8122211 - 14 Dec 2019
Cited by 14 | Viewed by 3944
Abstract
Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D3 has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)2D3 [...] Read more.
Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D3 has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)2D3 on the immunomodulatory activities of hPDLSCs in the presence of different cytokines. In the present study, the effects of hPDLSCs treated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or interferon (IFN)-γ in the presence of 1,25(OH)2D3 on the proliferation of allogenic CD4+ T lymphocyte or on the functional status of primary CD68+ macrophages were analyzed in coculture models. Additionally, the effects of 1,25(OH)2D3 on TNF-α-, IL-1β-, and IFN-γ-induced gene expression of some immunomodulatory factors in hPDLSCs were compared. Under coculture conditions, 1,25(OH)2D3 increased or decreased CD4+ T lymphocyte proliferation via hPDLSCs, depending on the cytokine. hPDLSCs primed with 1,25(OH)2D3 and different cytokines affected pro- and anti-inflammatory cytokine expression in macrophages variably, depending on the priming cytokine. With one exception, 1,25(OH)2D3 significantly reduced TNF-α-, IL-1β-, and IFN-γ-induced expression of all the investigated immunomediators in hPDLSCs, albeit to different extents. These results suggest that 1,25(OH)2D3 influences the immunomodulatory activities of hPDLSCs depending qualitatively and quantitatively on the presence of certain inflammatory cytokines. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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13 pages, 2111 KiB  
Article
Mesenchymal Stem/Stromal Cell Production Compliant with Good Manufacturing Practice: Comparison between Bone Marrow, the Gold Standard Adult Source, and Wharton’s Jelly, an Extraembryonic Source
by Caroline Laroye, Mélanie Gauthier, Hélène Antonot, Véronique Decot, Loïc Reppel and Danièle Bensoussan
J. Clin. Med. 2019, 8(12), 2207; https://doi.org/10.3390/jcm8122207 - 14 Dec 2019
Cited by 19 | Viewed by 4943
Abstract
Many clinical trials report mesenchymal stem/stromal cells (MSCs) efficacy in various indications. Therefore, standardization of MSC production becomes necessary. MSC properties are impacted by tissue origin, especially if they are from extraembryonic tissue or adult sources. For this reason, we evaluated the impact [...] Read more.
Many clinical trials report mesenchymal stem/stromal cells (MSCs) efficacy in various indications. Therefore, standardization of MSC production becomes necessary. MSC properties are impacted by tissue origin, especially if they are from extraembryonic tissue or adult sources. For this reason, we evaluated the impact of MSC tissue origin on production. Methods: Three productions of MSC from Wharton’s Jelly (WJ) or from bone marrow (BM) were performed according to good manufacturing practice. The identity (phenotype, differentiation, and clonogenic capacities), safety (karyotype, telomerase activity, sterility, and donor qualification), and functionality (viability, mixed lymphocyte reaction) of each cell batch were analyzed. Results: Slight differences between MSC sources were observed for phenotype, telomerase activity, and clonogenic capacities. Conclusion: Both sources have made it possible to quickly and easily obtain clinical grade MSC. However, as availability of the source is thought to be essential, WJ seems more advantageous than BM. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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20 pages, 2104 KiB  
Article
Short and Long Term Clinical and Immunologic Follow up after Bone Marrow Mesenchymal Stromal Cell Therapy in Progressive Multiple Sclerosis—A Phase I Study
by Ellen Iacobaeus, Nadir Kadri, Katia Lefsihane, Erik Boberg, Caroline Gavin, Anton Törnqvist Andrén, Anders Lilja, Lou Brundin and Katarina Le Blanc
J. Clin. Med. 2019, 8(12), 2102; https://doi.org/10.3390/jcm8122102 - 2 Dec 2019
Cited by 23 | Viewed by 3921
Abstract
Bone marrow derived mesenchymal stromal cells (BM-MSCs) have emerged as a possible new therapy for Multiple Sclerosis (MS), however studies regarding efficacy and in vivo immune response have been limited and inconclusive. We conducted a phase I clinical study assessing safety and clinical [...] Read more.
Bone marrow derived mesenchymal stromal cells (BM-MSCs) have emerged as a possible new therapy for Multiple Sclerosis (MS), however studies regarding efficacy and in vivo immune response have been limited and inconclusive. We conducted a phase I clinical study assessing safety and clinical and peripheral immune responses after MSC therapy in MS. Seven patients with progressive MS were intravenously infused with a single dose of autologous MSC (1–2 × 106 MSCs/kg body weight). The infusions were safe and well tolerated when given during clinical remission. Five out of seven patients completed the follow up of 48 weeks post-infusion. Brain magnetic resonance imaging (MRI) showed the absence of new T2 lesions at 12 weeks in 5/6 patients, while 3/5 had accumulated new T2 lesions at 48 weeks. Patient expanded disability status scales (EDSS) were stable in 6/6 at 12 weeks but declined in 3/5 patients at 48 weeks. Early changes of circulating microRNA levels (2 h) and increased proportion of FOXP3+ Tregs were detected at 7 days post-infusion compared to baseline levels. In conclusion, MSC therapy was safe and well tolerated and is associated with possible transient beneficial clinical and peripheral immunotolerogenic effects. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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17 pages, 2228 KiB  
Article
Adipose-Derived Stem Cells from Systemic Sclerosis Patients Maintain Pro-Angiogenic and Antifibrotic Paracrine Effects In Vitro
by Mélanie VELIER, Stéphanie SIMONCINI, Maxime ABELLAN, Pauline FRANCOIS, Sandy EAP, Anaïs LAGRANGE, Baptiste BERTRAND, Aurélie DAUMAS, Brigitte GRANEL, Bruno DELORME, Françoise DIGNAT GEORGE, Jérémy MAGALON and Florence SABATIER
J. Clin. Med. 2019, 8(11), 1979; https://doi.org/10.3390/jcm8111979 - 14 Nov 2019
Cited by 15 | Viewed by 2949
Abstract
Innovative therapies based on autologous adipose-derived stem/stromal cells (ASC) are currently being evaluated for treatment of systemic sclerosis (SSc). Although paracrine angiogenic and antifibrotic effects are considered the predominant mechanisms of ASC therapeutic potential, the impact of SSc on ASC paracrine functions remains [...] Read more.
Innovative therapies based on autologous adipose-derived stem/stromal cells (ASC) are currently being evaluated for treatment of systemic sclerosis (SSc). Although paracrine angiogenic and antifibrotic effects are considered the predominant mechanisms of ASC therapeutic potential, the impact of SSc on ASC paracrine functions remains controversial. In this study, phenotype, senescence, differentiation potential, and molecular profile were determined in ASC from SSc patients (SSc-ASC) (n = 7) and healthy donors (HD-ASC) (n = 7). ASC were co-cultured in indirect models with dermal fibroblasts (DF) from SSc patients or endothelial cells to assess their pro-angiogenic and antifibrotic paracrine effects. The angiogenic activity of endothelial cells was measured in vitro using tube formation and spheroid assays. DF collagen and alpha smooth muscle actin (αSMA) content were quantified after five days of co-culture with ASC. Differentiation capacity, senescence, and mRNA profiles did not differ significantly between SSc-ASC and HD-ASC. SSc-ASC retained the ability to stimulate angiogenesis through paracrine mechanisms; however, functional assays revealed reduced potential compared to HD-ASC. DF fibrosis markers were significantly decreased after co-culture with SSc-ASC. Together, these results indicate that SSc effects do not significantly compromise the angiogenic and the antifibrotic paracrine properties of ASC, thereby supporting further development of ASC-based autologous therapies for SSc treatment. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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18 pages, 4727 KiB  
Article
Parathyroid Hormone-Related Protein (PTHrP) Accelerates Soluble RANKL Signals for Downregulation of Osteogenesis of Bone Mesenchymal Stem Cells
by Jeevithan Elango, Saeed Ur Rahman, Yves Henrotin, José Eduardo Maté Sánchez de Val, Bin Bao, Shujun Wang, Bailin Li and Wenhui Wu
J. Clin. Med. 2019, 8(6), 836; https://doi.org/10.3390/jcm8060836 - 12 Jun 2019
Cited by 9 | Viewed by 3132
Abstract
A recent study reported the expression of receptor activator of nuclear factor-κB (RANK) in mesenchymal stem cells (MSCs) surface that negatively regulates osteogenesis of MSCs. Empirical evidence from the previous study confirmed the role of parathyroid hormone-related protein (PTHrP) in osteoblastogenesis. However, it [...] Read more.
A recent study reported the expression of receptor activator of nuclear factor-κB (RANK) in mesenchymal stem cells (MSCs) surface that negatively regulates osteogenesis of MSCs. Empirical evidence from the previous study confirmed the role of parathyroid hormone-related protein (PTHrP) in osteoblastogenesis. However, it is necessary to understand the paracrine role of PTHrP and RANKL for osteogenesis in order to explore the hidden secrets in bone biology. Considering the above concept, paracrine cues of soluble-receptor activator of nuclear factor-κB ligand (sRANKL) and PTHrP in osteogenic differentiation of MSCs were investigated. Our results confirmed that sRANKL increased the expression of surface-RANK in MSCs at the earlier stage of osteogenesis, which was downregulated later in differentiated MSCs. In contrast, RANKL expression was low at the earlier stage of MSCs proliferation and high at the differentiation stage of MSCs, which may play a fundamental role in osteoclast formation. sRANKL downregulated osteogenesis of MSCs by decreasing progressive ankylosis (ANK) protein expression while PTHrP upregulated the osteogenic exploitive effect of sRANKL. Interestingly, when they were co-cultured with MSCs, T-lymphocytes expressed high membrane-RANKL levels that contribute to osteogenesis inhibition during MSC differentiation. Thus, our results disclose that sRANKL treatment downregulates osteogenesis of MSCs by increasing RANK expression at the earlier stage of differentiation and by inhibiting ANK. Further, we demonstrated that PTHrP accelerated the downregulating osteogenic effect of sRANKL. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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11 pages, 2326 KiB  
Article
T-Regulatory Cells Confer Increased Myelination and Stem Cell Activity after Stroke-Induced White Matter Injury
by Sydney Zarriello, Elliot G. Neal, Yuji Kaneko and Cesario V. Borlongan
J. Clin. Med. 2019, 8(4), 537; https://doi.org/10.3390/jcm8040537 - 19 Apr 2019
Cited by 19 | Viewed by 4059
Abstract
Stroke-induced hypoxia causes oligodendrocyte death due to inflammation, lack of oxygen and exacerbation of cell death. Bone marrow-derived stem cells (BMSCs) possess an endogenous population of T-regulatory cells (Tregs) which reduce secretion of pro-inflammatory cytokines that lead to secondary cell death. [...] Read more.
Stroke-induced hypoxia causes oligodendrocyte death due to inflammation, lack of oxygen and exacerbation of cell death. Bone marrow-derived stem cells (BMSCs) possess an endogenous population of T-regulatory cells (Tregs) which reduce secretion of pro-inflammatory cytokines that lead to secondary cell death. Here, we hypothesize that oligodendrocyte progenitor cells (OPCs) cultured with BMSCs containing their native Treg population show greater cell viability, less pro-inflammatory cytokine secretion and greater myelin production after exposure to oxygen-glucose deprivation and reoxygenation (OGD/R) than OPCs cultured without Tregs. OPCs were cultured and then exposed to OGD/R. BMSCs with or without Tregs were added to the co-culture immediately after ischemia. The Tregs were depleted by running the BMSCs through a column containing a magnetic substrate. Fibroblast growth factor beta (FGF-β) and interleukin 6 (IL-6) ELISAs determined BMSC activity levels. Immunohistochemistry assessed OPC differentiation. OPCs cultured with BMSCs containing their endogenous Tregs showed increased myelin production compared to the BMSCs with depleted Tregs. IL-6 and FGF-β were increased in the group cultured with Tregs. Collectively, these results suggest that BMSCs containing Tregs are more therapeutically active, and that Tregs have beneficial effects on OPCs subjected to ischemia. Tregs play an important role in stem cell therapy and can potentially treat white matter injury post-stroke. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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Review

Jump to: Editorial, Research

14 pages, 815 KiB  
Review
The Role of Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles (MSC-EVs) in Normal and Abnormal Hematopoiesis and Their Therapeutic Potential
by Aristea K. Batsali, Anthie Georgopoulou, Irene Mavroudi, Angelos Matheakakis, Charalampos G. Pontikoglou and Helen A. Papadaki
J. Clin. Med. 2020, 9(3), 856; https://doi.org/10.3390/jcm9030856 - 20 Mar 2020
Cited by 56 | Viewed by 8157
Abstract
Mesenchymal stem cells (MSCs) represent a heterogeneous cellular population responsible for the support, maintenance, and regulation of normal hematopoietic stem cells (HSCs). In many hematological malignancies, however, MSCs are deregulated and may create an inhibitory microenvironment able to induce the disease initiation and/or [...] Read more.
Mesenchymal stem cells (MSCs) represent a heterogeneous cellular population responsible for the support, maintenance, and regulation of normal hematopoietic stem cells (HSCs). In many hematological malignancies, however, MSCs are deregulated and may create an inhibitory microenvironment able to induce the disease initiation and/or progression. MSCs secrete soluble factors including extracellular vesicles (EVs), which may influence the bone marrow (BM) microenvironment via paracrine mechanisms. MSC-derived EVs (MSC-EVs) may even mimic the effects of MSCs from which they originate. Therefore, MSC-EVs contribute to the BM homeostasis but may also display multiple roles in the induction and maintenance of abnormal hematopoiesis. Compared to MSCs, MSC-EVs have been considered a more promising tool for therapeutic purposes including the prevention and treatment of Graft Versus Host Disease (GVHD) following allogenic HSC transplantation (HSCT). There are, however, still unanswered questions such as the molecular and cellular mechanisms associated with the supportive effect of MSC-EVs, the impact of the isolation, purification, large-scale production, storage conditions, MSC source, and donor characteristics on MSC-EV biological effects as well as the optimal dose and safety for clinical usage. This review summarizes the role of MSC-EVs in normal and malignant hematopoiesis and their potential contribution in treating GVHD. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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45 pages, 730 KiB  
Review
MSC Based Therapies—New Perspectives for the Injured Lung
by Judith Behnke, Sarah Kremer, Tayyab Shahzad, Cho-Ming Chao, Eva Böttcher-Friebertshäuser, Rory E. Morty, Saverio Bellusci and Harald Ehrhardt
J. Clin. Med. 2020, 9(3), 682; https://doi.org/10.3390/jcm9030682 - 3 Mar 2020
Cited by 120 | Viewed by 7936
Abstract
Chronic lung diseases pose a tremendous global burden. At least one in four people suffer from severe pulmonary sequelae over the course of a lifetime. Despite substantial improvements in therapeutic interventions, persistent alleviation of clinical symptoms cannot be offered to most patients affected [...] Read more.
Chronic lung diseases pose a tremendous global burden. At least one in four people suffer from severe pulmonary sequelae over the course of a lifetime. Despite substantial improvements in therapeutic interventions, persistent alleviation of clinical symptoms cannot be offered to most patients affected to date. Despite broad discrepancies in origins and pathomechanisms, the important disease entities all have in common the pulmonary inflammatory response which is central to lung injury and structural abnormalities. Mesenchymal stem cells (MSC) attract particular attention due to their broadly acting anti-inflammatory and regenerative properties. Plenty of preclinical studies provided congruent and convincing evidence that MSC have the therapeutic potential to alleviate lung injuries across ages. These include the disease entities bronchopulmonary dysplasia, asthma and the different forms of acute lung injury and chronic pulmonary diseases in adulthood. While clinical trials are so far restricted to pioneering trials on safety and feasibility, preclinical results point out possibilities to boost the therapeutic efficacy of MSC application and to take advantage of the MSC secretome. The presented review summarizes the most recent advances and highlights joint mechanisms of MSC action across disease entities which provide the basis to timely tackle this global disease burden. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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13 pages, 1783 KiB  
Review
Eph/ephrin Signaling and Biology of Mesenchymal Stromal/Stem Cells
by David Alfaro, Mariano R. Rodríguez-Sosa and Agustín G. Zapata
J. Clin. Med. 2020, 9(2), 310; https://doi.org/10.3390/jcm9020310 - 22 Jan 2020
Cited by 7 | Viewed by 3968
Abstract
Mesenchymal stromal/stem cells (MSCs) have emerged as important therapeutic agents, owing to their easy isolation and culture, and their remarkable immunomodulatory and anti-inflammatory properties. However, MSCs constitute a heterogeneous cell population which does not express specific cell markers and has important problems for [...] Read more.
Mesenchymal stromal/stem cells (MSCs) have emerged as important therapeutic agents, owing to their easy isolation and culture, and their remarkable immunomodulatory and anti-inflammatory properties. However, MSCs constitute a heterogeneous cell population which does not express specific cell markers and has important problems for in vivo homing, and factors regulating their survival, proliferation, and differentiation are largely unknown. Accordingly, in the present article, we review the current evidence on the relationships between Eph kinase receptors, their ephrin ligands, and MSCs. These molecules are involved in the adult homeostasis of numerous tissues, and we and other authors have demonstrated their expression in human and murine MSCs derived from both bone marrow and adipose tissue, as well as their involvement in the MSC biology. We extend these studies providing new results on the effects of Eph/ephrins in the differentiation and immunomodulatory properties of MSCs. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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18 pages, 374 KiB  
Review
Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy
by Ruxandra I. Sava, Carl J. Pepine and Keith L. March
J. Clin. Med. 2020, 9(1), 241; https://doi.org/10.3390/jcm9010241 - 16 Jan 2020
Cited by 10 | Viewed by 6242
Abstract
Over 26 million people worldwide suffer from heart failure, a disease associated with a 1 year mortality rate of 22%. Half of these patients present heart failure with preserved ejection fraction (HFpEF), for which there is no available therapy to improve prognosis. HFpEF [...] Read more.
Over 26 million people worldwide suffer from heart failure, a disease associated with a 1 year mortality rate of 22%. Half of these patients present heart failure with preserved ejection fraction (HFpEF), for which there is no available therapy to improve prognosis. HFpEF is strongly associated with aging, inflammation, and comorbid burden, which are thought to play causal roles in disease development. Mesenchymal stromal/stem cells (MSCs) have potent immunomodulatory actions and promote tissue healing, thus representing an attractive therapeutic option in HFpEF. In this review, we summarize recent data suggesting that a two-hit model of immune dysregulation lies at the heart of the HFpEF. A first hit is represented by genetic mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), which skew immune cells toward a pro-inflammatory phenotype, are associated with HFpEF development in animal models, and with immune dysregulation and risk of HF hospitalization in patients. A second hit is induced by cardiovascular risk factors, which cause subclinical cardiac dysfunction and production of danger signals. In mice, these attract proinflammatory macrophages, Th1 and Th17 cells into the myocardium, where they are required for the development of HFpEF. MSCs have been shown to reduce the pro-inflammatory activity of immune cell types involved in murine HFpEF in vitro, and to reduce myocardial fibrosis and improve diastolic function in vivo, thus they may efficiently target immune dysregulation in HFpEF and stop disease progression. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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23 pages, 2556 KiB  
Review
Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders
by Stefania Crippa, Ludovica Santi, Roberto Bosotti, Giulia Porro and Maria Ester Bernardo
J. Clin. Med. 2020, 9(1), 2; https://doi.org/10.3390/jcm9010002 - 18 Dec 2019
Cited by 29 | Viewed by 7401
Abstract
Mesenchymal stromal cells (MSCs) are crucial elements in the bone marrow (BM) niche where they provide physical support and secrete soluble factors to control and maintain hematopoietic stem progenitor cells (HSPCs). Given their role in the BM niche and HSPC support, MSCs have [...] Read more.
Mesenchymal stromal cells (MSCs) are crucial elements in the bone marrow (BM) niche where they provide physical support and secrete soluble factors to control and maintain hematopoietic stem progenitor cells (HSPCs). Given their role in the BM niche and HSPC support, MSCs have been employed in the clinical setting to expand ex-vivo HSPCs, as well as to facilitate HSPC engraftment in vivo. Specific alterations in the mesenchymal compartment have been described in hematological malignancies, as well as in rare genetic disorders, diseases that are amenable to allogeneic hematopoietic stem cell transplantation (HSCT), and ex-vivo HSPC-gene therapy (HSC-GT). Dissecting the in vivo function of human MSCs and studying their biological and functional properties in these diseases is a critical requirement to optimize transplantation outcomes. In this review, the role of MSCs in the orchestration of the BM niche will be revised, and alterations in the mesenchymal compartment in specific disorders will be discussed, focusing on the need to correct and restore a proper microenvironment to ameliorate transplantation procedures, and more in general disease outcomes. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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17 pages, 598 KiB  
Review
The Immunomodulatory Functions of Mesenchymal Stromal/Stem Cells Mediated via Paracrine Activity
by Yueyuan Zhou, Yusuke Yamamoto, Zhongdang Xiao and Takahiro Ochiya
J. Clin. Med. 2019, 8(7), 1025; https://doi.org/10.3390/jcm8071025 - 12 Jul 2019
Cited by 203 | Viewed by 9940
Abstract
Mesenchymal stromal/stem cells (MSCs) exist in almost all tissues, possessing the potential to differentiate into specialized cell types and exert immunomodulatory functions. Thus, they have attracted much attention as a promising therapeutic candidate. Recent studies have demonstrated that paracrine signaling is mainly responsible [...] Read more.
Mesenchymal stromal/stem cells (MSCs) exist in almost all tissues, possessing the potential to differentiate into specialized cell types and exert immunomodulatory functions. Thus, they have attracted much attention as a promising therapeutic candidate. Recent studies have demonstrated that paracrine signaling is mainly responsible for the involvement of MSCs in the modulation of immune responses and the progression of diseases. Through release of secretome consisting of a diverse range of cytokines, chemokines, and extracellular vesicles (EVs), MSCs convey regulatory messages to recipient immune cells in the microenvironment. In this review, we focus on the recent advances in how MSCs contribute to immunomodulation through the secretion of paracrine factors. The further improved understanding of the molecular mechanism underlying the interactions between MSCs and immune cells highlights the paracrine biology of MSCs in the modulation of the immune microenvironment and promotes the clinical application of MSCs in regenerative medicine and immune diseases. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cells in Immunity and Disease)
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