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Cells
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Immunomodulation by Mesenchymal Stem Cells 2020
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Immunomodulation by Mesenchymal Stem Cells 2020

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (10 April 2021) | Viewed by 32028

Special Issue Editor

Prof. Dr. Guenther Eissner

E-Mail Website
Guest Editor
Systems Biology Ireland, University College Dublin, Dublin, Ireland
Interests: endothelial cells; mesenchymal stromal cells; transplantation; immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mesenchymal stromal or stem cells (MSC) are fibroblast-like multipotent  cells that can differentiate into various cell types of mesenchymal origin. Because of their immune properties and differentiation potential, MSC are discussed and tested for the use in tissue regeneration and tolerance induction in transplant medicine. However, the precise mechanisms of action (MOAs) and whether whole MSC or MSC-derived products are needed for the clinical efficacy remain enigmatic. This Special Issue of Cells should provide a state-of-the-art look into the various immunomodulatory properties of MSC, elaborate differences among different sources of MSC, and elucidate MOAs where possible. Current reports about the Good Manufacturing Practice-compliant processing of MSC are also welcome. This should help to optimize personalized cellular therapies with MSC in the future.

Prof. Guenther Eissner
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Mesenchymal stem cells (MSC)
  • immunomodulation
  • mechanism of action
  • MSC-derived products
  • Good Manufacturing Practice (GMP) processing

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Related Special Issue

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

2 pages, 176 KiB  
Editorial
Mesenchymal Stromal Cells “Think” Globally, but Act Locally
by Günther Eissner
Cells 2023, 12(3), 509; https://doi.org/10.3390/cells12030509 - 3 Feb 2023
Cited by 1 | Viewed by 1413
Abstract
In this Special Issue of Cells, entitled “Immunomodulation by Mesenchymal Stem Cells 2020”, you can find five excellent papers on the role of mesenchymal stem/stromal cells (MSCs) in immunomodulation, which also includes regenerative processes, such as wound healing [...] Full article
(This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells 2020)

Research

Jump to: Editorial, Review

15 pages, 13283 KiB  
Article
Humoral Immunity to Allogeneic Immunoproteasome-Expressing Mesenchymal Stromal Cells Requires Efferocytosis by Endogenous Phagocytes
by Jean-Pierre Bikorimana, Jamilah Abusarah, Natasha Salame, Nehme El-Hachem, Riam Shammaa and Moutih Rafei
Cells 2022, 11(4), 596; https://doi.org/10.3390/cells11040596 - 9 Feb 2022
Cited by 4 | Viewed by 2559
Abstract
The extensive use of mesenchymal stromal cells (MSCs) over the last decade has revolutionized modern medicine. From the delivery of pharmacological proteins to regenerative medicine and immune modulation, these cells have proven to be highly pleiotropic and responsive to their surrounding environment. Nevertheless, [...] Read more.
The extensive use of mesenchymal stromal cells (MSCs) over the last decade has revolutionized modern medicine. From the delivery of pharmacological proteins to regenerative medicine and immune modulation, these cells have proven to be highly pleiotropic and responsive to their surrounding environment. Nevertheless, their role in promoting inflammation has been fairly limited by the questionable use of interferon-gamma, as this approach has also been proven to enhance the cells’ immune-suppressive abilities. Alternatively, we have previously shown that de novo expression of the immunoproteasome (IPr) complex instills potent antigen cross-presentation capabilities in MSCs. Interestingly, these cells were found to express the major histocompatibility class (MHC) II protein, which prompted us to investigate their ability to stimulate humoral immunity. Using a series of in vivo studies, we found that administration of allogeneic ovalbumin (OVA)-pulsed MSC-IPr cells elicits a moderate antibody titer, which was further enhanced by the combined use of pro-inflammatory cytokines. The generated antibodies were functional as they blocked CD4 T-cell activation following their co-culture with OVA-pulsed MSC-IPr and mitigated E.G7 tumor growth in vivo. The therapeutic potency of MSC-IPr was, however, dependent on efferocytosis, as phagocyte depletion prior to vaccination abrogated MSC-IPr-induced humoral responses while promoting their survival in the host. In contrast, antibody-mediated neutralization of CD47, a potent “do not eat me signal”, enhanced antibody titer levels. These observations highlight the major role played by myeloid cells in supporting antibody production by MSC-IPr and suggest that the immune outcome is dictated by a net balance between efferocytosis-stimulating and -inhibiting signals. Full article
(This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells 2020)
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15 pages, 1740 KiB  
Article
Modulatory Impact of Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients on T Helper Cell Differentiation
by Ewa Kuca-Warnawin, Iwona Janicka, Krzysztof Bonek and Ewa Kontny
Cells 2021, 10(2), 280; https://doi.org/10.3390/cells10020280 - 30 Jan 2021
Cited by 14 | Viewed by 2670
Abstract
The domination of pro-inflammatory Th subsets (Th1, Th17) is characteristic of ankylosing spondylitis (AS). Mesenchymal stem cells (MSC) were reported to normalize Th imbalance, but whether MSCs from AS adipose tissue (AS/ASCs) possess such properties is unknown. We examined AS/ASCs’ impact on Th-cell [...] Read more.
The domination of pro-inflammatory Th subsets (Th1, Th17) is characteristic of ankylosing spondylitis (AS). Mesenchymal stem cells (MSC) were reported to normalize Th imbalance, but whether MSCs from AS adipose tissue (AS/ASCs) possess such properties is unknown. We examined AS/ASCs’ impact on Th-cell differentiation, using healthy donors ASCs (HD/ASCs) as a control. The assessment of the expression of transcription factors defining Th1 (T-bet), Th2 (GATA3), Th17 (RORc), and Treg (FoxP3) subsets by quantitative RT-PCR, the concentrations of subset-specific cytokines by ELISA, and Treg (CD4+CD25highFoxP3+) formation by flow cytometry, were performed in the co-cultures of ASCs with activated CD4+ T cells or peripheral blood mononuclear cells (PBMCs). AS/ASCs and HD/ASCs exerted similar immunomodulatory effects. Acting directly on CD4+ T cells, ASCs decreased the T-bet/GATA3 and RORc/FoxP3 ratios, diminished Treg formation, but increase IFNγ and IL-17AF production, while ASCs co-cultured with PBMCs enhanced Treg generation and reduced IFNγ release. ASCs failed to up-regulate the anti-inflammatory IL-10 and TGFβ. AS/ASCs’ impact on allogeneic and autologous PBMCs was similar. In conclusion, to shift Th differentiation to a functional anti-inflammatory direction, ASCs require accessory cell support, whereas their direct effect may be pro-inflammatory. Because ASCs neither inhibit IL-17AF nor up-regulate anti-inflammatory cytokines, their usefulness for AS patients’ treatment remains uncertain. Full article
(This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells 2020)
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19 pages, 2614 KiB  
Article
Human Adipose Tissue-Derived Mesenchymal Stromal Cells Inhibit CD4+ T Cell Proliferation and Induce Regulatory T Cells as Well as CD127 Expression on CD4+CD25+ T Cells
by Agnese Fiori, Stefanie Uhlig, Harald Klüter and Karen Bieback
Cells 2021, 10(1), 58; https://doi.org/10.3390/cells10010058 - 1 Jan 2021
Cited by 23 | Viewed by 4064
Abstract
Mesenchymal stromal cells (MSC) exert their immunomodulatory potential on several cell types of the immune system, affecting and influencing the immune response. MSC efficiently inhibit T cell proliferation, reduce the secretion of pro-inflammatory cytokines, limit the differentiation of pro-inflammatory Th subtypes and promote [...] Read more.
Mesenchymal stromal cells (MSC) exert their immunomodulatory potential on several cell types of the immune system, affecting and influencing the immune response. MSC efficiently inhibit T cell proliferation, reduce the secretion of pro-inflammatory cytokines, limit the differentiation of pro-inflammatory Th subtypes and promote the induction of regulatory T cells (Treg). In this study, we analyzed the immunomodulatory potential of human adipose tissue-derived MSC (ASC), on CD4+ T cells, addressing potential cell-contact dependency in relation to T cell receptor stimulation of whole human peripheral blood mononuclear cells (PBMC). ASC were cultured with not stimulated or anti-CD3/CD28-stimulated PBMC in direct and transwell cocultures; PBMC alone were used as controls. After 7 days, cocultures were harvested and we analyzed: (1) the inhibitory potential of ASC on CD4+ cell proliferation and (2) phenotypic changes in CD4+ cells in respect of Treg marker (CD25, CD127 and FoxP3) expression. We confirmed the inhibitory potential of ASC on CD4+ cell proliferation, which occurs upon PBMC stimulation and is mediated by indoleamine 2,3-dioxygenase. Importantly, ASC reduce both pro- and anti-inflammatory cytokine secretion, without indications on specific Th differentiation. We found that stimulation induces CD25 expression on CD4+ cells and that, despite inhibiting overall CD4+ cell proliferation, ASC can specifically induce the proliferation of CD4+CD25+ cells. We observed that ASC induce Treg (CD4+CD25+CD127−FoxP3+) only in not stimulated cocultures and that ASC increase the ratio of CD4+CD25+CD127+FoxP3− cells at the expense of CD4+CD25+CD127−FoxP3− cells. Our study provides new insights on the interplay between ASC and CD4+ T cells, proposing that ASC-dependent induction of Treg depends on PBMC activation which affects the balance between the different subpopulations of CD4+CD25+ cells expressing CD127 and/or FoxP3. Full article
(This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells 2020)
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21 pages, 1730 KiB  
Article
Human Adipose Tissue-Derived Stromal Cells Suppress Human, but Not Murine Lymphocyte Proliferation, via Indoleamine 2,3-Dioxygenase Activity
by Adriana Torres Crigna, Stefanie Uhlig, Susanne Elvers-Hornung, Harald Klüter and Karen Bieback
Cells 2020, 9(11), 2419; https://doi.org/10.3390/cells9112419 - 5 Nov 2020
Cited by 34 | Viewed by 3186
Abstract
Over recent years, mesenchymal stromal cells (MSC) have gained immense attraction in immunotherapy, regenerative medicine and tissue engineering. MSC microenvironment modulation occurs through synergy of direct cell–cell contact, and secreted soluble factors and extracellular vesicles (EV). MSC-derived EV have been suggested as cell-free [...] Read more.
Over recent years, mesenchymal stromal cells (MSC) have gained immense attraction in immunotherapy, regenerative medicine and tissue engineering. MSC microenvironment modulation occurs through synergy of direct cell–cell contact, and secreted soluble factors and extracellular vesicles (EV). MSC-derived EV have been suggested as cell-free immunomodulatory alternative to MSC; however, previous findings have challenged this. Furthermore, recent data suggest that evaluating the mechanism of action of human MSC (hMSC) in animal models might promote adverse immune reactions or lack of functionality due to xeno-incompatibilities. In this study, we first assessed the immunomodulatory strength of different human MSC sources on in vitro stimulated T cells and compared this to interferon-gamma (IFNγ) primed MSC conditioned medium (CM) and EV. Second, we addressed the main molecular mechanisms, and third, we assessed the MSC in vitro immunosuppressive effect across interspecies barriers. We identified human adipose tissue-derived stromal cells (ASC) with strongest immunomodulatory strength, followed by bone marrow (BM) and cord blood-derived MSC (CB). Whilst CM from primed ASC managed to exert analogous effects as their cellular counterpart, EV derived thereof did not, reproducing previous findings. IFNγ-induced indoleamine 2,3-dioxygenase (IDO) activity was identified as key mechanism to suppress human lymphocyte proliferation, as in the presence of the IDO inhibitor epacadostat (Epac) a stimulation of proliferation was seen. In addition, we revealed MSC immunosuppressive effects to be species-specific, because human cells failed to suppress murine lymphocyte proliferation. In summary, ASC were the strongest immunomodulators with the IDO-kynurenine pathway being key within the human system. Importantly, the in vitro lack of interspecies immunomodulatory strength suggests that preclinical data need to be carefully interpreted especially when considering a possible translation to clinical field. Full article
(This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells 2020)
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Review

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15 pages, 13867 KiB  
Review
The Role of MSC in Wound Healing, Scarring and Regeneration
by Raquel Guillamat-Prats
Cells 2021, 10(7), 1729; https://doi.org/10.3390/cells10071729 - 8 Jul 2021
Cited by 196 | Viewed by 17252
Abstract
Tissue repair and regeneration after damage is not completely understood, and current therapies to support this process are limited. The wound healing process is associated with cell migration and proliferation, extracellular matrix remodeling, angiogenesis and re-epithelialization. In normal conditions, a wound will lead [...] Read more.
Tissue repair and regeneration after damage is not completely understood, and current therapies to support this process are limited. The wound healing process is associated with cell migration and proliferation, extracellular matrix remodeling, angiogenesis and re-epithelialization. In normal conditions, a wound will lead to healing, resulting in reparation of the tissue. Several risk factors, chronic inflammation, and some diseases lead to a deficient wound closure, producing a scar that can finish with a pathological fibrosis. Mesenchymal stem/stromal cells (MSCs) are widely used for their regenerative capacity and their possible therapeutically potential. Derived products of MSCs, such as exosomes or extravesicles, have shown a therapeutic potential similar to MSCs, and these cell-free products may be interesting in clinics. MSCs or their derivative products have shown paracrine beneficial effects, regulating inflammation, modifying the fibroblast activation and production of collagen and promoting neovascularization and re-epithelialization. This review describes the effects of MSCs and their derived products in each step of the wound repair process. As well, it reviews the pre-clinical and clinical use of MSCs to benefit in skin wound healing in diabetic associated wounds and in pathophysiological fibrosis. Full article
(This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells 2020)
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