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Mesenchymal Stem Cells: Immunobiology and Role in Immunomodulation and Tissue Regeneration

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 20082

Special Issue Editor

Dr. Katia Mareschi

E-Mail Website
Guest Editor
1. Department of Public Health and Paediatrics, The University of Turin, Piazza Polonia 94, 10126 Torino, Italy
2. Stem Cell Transplantation and Cellular Therapy Laboratory, Paediatric Onco-Haematology Division, Regina Margherita Children’s Hospital, City of Health and Science of Turin, 10126 Torino, Italy
Interests: mesenchymal stem cells; GMP production; cell therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mesenchymal stromal/stem cells (MSCs) are excellent candidates for the development of cell-based therapies in the treatment of various conditions, with over 900 clinical trials worldwide currently using MSCs to treat, among other conditions, bone/cartilage damage, diabetes, cardiovascular diseases, immune-related disorders, and neurological disorders (www.clinicaltrials.gov).

MSCs can be used to repair injured tissue by migrating them into injured sites and engrafting them to function as end-stage cells. The role of homing within MSC-based therapies, however, remains unclear, although increasing evidence suggests that their therapeutic role is actually due to immunomodulation rather than to their capacity for differentiation. It has, in fact, been shown that MSCs exert immunomodulatory and anti-inflammatory effects by regulating multiple immune cell types of both the innate and adaptive immune systems. This means that MSCs can promote neovascularization, increase angiogenesis, enhance cell viability and/or proliferation, inhibit cell death, and modulate immune responses via paracrine and cell–cell contact effects as well as through extracellular vesicles. Interestingly, despite some encouraging results from animal studies, some clinical trials have shown that MSCs have no therapeutic efficacy. Therefore, understanding the biology of MSCs and their role in treatment will be critical to determining their potential in therapeutic applications.

We invite you to contribute to this Special Issue with original research articles describing recent developments in MSC-based therapy. We are particularly interested in studies that illustrate the mechanisms underlying the protective effects of MSCs and demonstrate their role in immunomodulation and tissue regeneration.

Dr. Katia Mareschi
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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • Immunomodulation
  • tissue regeration
  • anti-inflammatory effects

Related Special Issue

Published Papers (7 papers)

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Research

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16 pages, 2934 KiB  
Article
A New Human Platelet Lysate for Mesenchymal Stem Cell Production Compliant with Good Manufacturing Practice Conditions Preserves the Chemical Characteristics and Biological Activity of Lyo-Secretome Isolated by Ultrafiltration
by Katia Mareschi, Alessia Giovanna Santa Banche Niclot, Elena Marini, Elia Bari, Luciana Labanca, Graziella Lucania, Ivana Ferrero, Sara Perteghella, Maria Luisa Torre and Franca Fagioli
Int. J. Mol. Sci. 2022, 23(8), 4318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084318 - 13 Apr 2022
Cited by 4 | Viewed by 1813
Abstract
Recently, we proposed a Good Manufacturing Practice (GMP)-compliant production process for freeze-dried mesenchymal stem cell (MSC)-secretome (lyo-secretome): after serum starvation, the cell supernatant was collected, and the secretome was concentrated by ultrafiltration and freeze-dried, obtaining a standardized ready-to-use and stable powder. In this [...] Read more.
Recently, we proposed a Good Manufacturing Practice (GMP)-compliant production process for freeze-dried mesenchymal stem cell (MSC)-secretome (lyo-secretome): after serum starvation, the cell supernatant was collected, and the secretome was concentrated by ultrafiltration and freeze-dried, obtaining a standardized ready-to-use and stable powder. In this work, we modified the type of human platelet lysate (HPL) used as an MSC culture supplement during the lyo-secretome production process: the aim was to verify whether this change had an impact on product quality and also whether this new procedure could be validated according to GMP, proving the process robustness. MSCs were cultured with two HPLs: the standard previously validated one (HPL-E) and the new one (HPL-S). From the same pool of platelets, two batches of HPL were obtained: HPL-E (by repeated freezing and thawing cycles) and HPL-S (by adding Ca-gluconate to form a clot and its subsequent mechanical wringing). Bone marrow MSCs from three donors were separately cultured with the two HPLs until the third passage and then employed to produce lyo-secretome. The following indicators were selected to evaluate the process performance: (i) the lyo-secretome quantitative composition (in lipids and proteins), (ii) the EVs size distribution, and (iii) anti-elastase and (iv) immunomodulant activity as potency tests. The new HPL supplementation for MSCs culture induced only a few minimal changes in protein/lipid content and EVs size distribution; despite this, it did not significantly influence biological activity. The donor intrinsic MSCs variability in secretome secretion instead strongly affected the quality of the finished product and could be mitigated by concentrating the final product to reach a determined protein (and lipid) concentration. In conclusion, the modification of the type of HPL in the MSCs culture during lyo-secretome production induces only minimal changes in the composition but not in the potency, and therefore, the new procedure can be validated according to GMP. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Immunobiology and Role in Immunomodulation and Tissue Regeneration)
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16 pages, 18783 KiB  
Article
A New Human Platelet Lysate for Mesenchymal Stem Cell Production Compliant with Good Manufacturing Practice Conditions
by Katia Mareschi, Elena Marini, Alessia Giovanna Santa Banche Niclot, Marta Barone, Giuseppe Pinnetta, Aloe Adamini, Manuela Spadea, Luciana Labanca, Graziella Lucania, Ivana Ferrero and Franca Fagioli
Int. J. Mol. Sci. 2022, 23(6), 3234; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063234 - 17 Mar 2022
Cited by 5 | Viewed by 2281
Abstract
Mesenchymal stem cells (MSCs) are classified as advanced therapy medicinal products, a new category of GMP (good manufacturing practice)-compliant medicines for clinical use. We isolated MSCs from 5 bone marrow (BM) samples using human platelet lysate (HPL) instead of foetal bovine serum (FBS). [...] Read more.
Mesenchymal stem cells (MSCs) are classified as advanced therapy medicinal products, a new category of GMP (good manufacturing practice)-compliant medicines for clinical use. We isolated MSCs from 5 bone marrow (BM) samples using human platelet lysate (HPL) instead of foetal bovine serum (FBS). We used a new method of HPL production consisting of treating platelet (PLTs) pools with Ca-Gluconate to form a gel clot, then mechanically squeezing to release growth factors. We compared the new HPL (HPL-S) with the standard (HPL-E) obtained by freezing/thawing cycles and by adding heparin. HPL-S had not PLTs and fibrinogen but the quantity of proteins and growth factors was comparable to HPL-E. Therefore, HPL-S needed fewer production steps to be in compliance with GMP conditions. The number of colonies forming unit-fibroblasts (CFU-F) and the maintenance of stem markers showed no significant differences between MSCs with HPL-E and HPL-S. The cumulative population doubling was higher in MSCs with HPL-E in the earlier passages, but we observed an inverted trend of cell growth at the fourth passage. Immunophenotypic analysis showed a significant lower expression of HLA-DR in the MSCs with HPL-S (1.30%) than HPL-E (14.10%). In conclusion, we demonstrated that HPL-S is an effective alternative for MSC production under GMP conditions. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Immunobiology and Role in Immunomodulation and Tissue Regeneration)
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15 pages, 1691 KiB  
Article
Mesenchymal Stem Cells Can Both Enhance and Inhibit the Cellular Response to DNA Immunization by Genes of Nonstructural Proteins of the Hepatitis C Virus
by Olga V. Masalova, Ekaterina I. Lesnova, Regina R. Klimova, Alexander V. Ivanov and Alla A. Kushch
Int. J. Mol. Sci. 2021, 22(15), 8121; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158121 - 29 Jul 2021
Cited by 3 | Viewed by 1775
Abstract
Despite extensive research, there is still no vaccine against the hepatitis C virus (HCV). The aim of this study was to investigate whether MSCs can exhibit adjuvant properties during DNA vaccination against hepatitis C. We used the pcNS3-NS5B plasmid encoding five nonstructural HCV [...] Read more.
Despite extensive research, there is still no vaccine against the hepatitis C virus (HCV). The aim of this study was to investigate whether MSCs can exhibit adjuvant properties during DNA vaccination against hepatitis C. We used the pcNS3-NS5B plasmid encoding five nonstructural HCV proteins and MSCs derived from mice bone marrow. Five groups of DBA mice were immunized with the plasmid and/or MSCs in a different order. Group 1 was injected with the plasmid twice at intervals of 3 weeks; Group 2 with the plasmid, and after 24 h with MSCs; Group 3 with MSCs followed by the plasmid the next day; Group 4 with only MSCs; and Group 5 with saline. When the MSCs were injected prior to DNA immunization, the cell immune response to HCV proteins assessed by the level of IFN-γ synthesis was markedly increased compared to DNA alone. In contrast, MSCs injected after DNA suppressed the immune response. Apparently, the high level of proinflammatory cytokines detected after DNA injection promotes the conversion of MSCs introduced later into the immunosuppressive MSC2. The low level of cytokines in mice before MSC administration promotes the high immunostimulatory activity of MSC1 in response to a DNA vaccine. Thus, when administered before DNA, MSCs are capable of exhibiting promising adjuvant properties. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Immunobiology and Role in Immunomodulation and Tissue Regeneration)
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20 pages, 16703 KiB  
Article
Jaw Periosteum-Derived Mesenchymal Stem Cells Regulate THP-1-Derived Macrophage Polarization
by Fang He, Felix Umrath, Siegmar Reinert and Dorothea Alexander
Int. J. Mol. Sci. 2021, 22(9), 4310; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094310 - 21 Apr 2021
Cited by 10 | Viewed by 6302
Abstract
Mesenchymal stem cells from bone marrow have powerful immunomodulatory capabilities. The interactions between jaw periosteal cells (JPCs) and macrophages are not only relevant for the application of JPCs in regenerative medicine, but this understanding could also help treating diseases like osteonecrosis of the [...] Read more.
Mesenchymal stem cells from bone marrow have powerful immunomodulatory capabilities. The interactions between jaw periosteal cells (JPCs) and macrophages are not only relevant for the application of JPCs in regenerative medicine, but this understanding could also help treating diseases like osteonecrosis of the jaw. In previous studies, we analyzed, for the first time, immunomodulatory features of 2D- and 3D-cultured JPCs. In the present work, the effects of JPCs on the polarization state of macrophages in contact coculture were analyzed. To improve the macrophage polarization study, different concentrations of PMA (5 nM, 25 nM, and 150 nM) or different medium supplementations (10% FBS, 10% hPL and 5% hPL) were compared. Further, in order to analyze the effects of JPCs on macrophage polarization, JPCs and PMA-stimulated THP-1 cells were cocultured under LPS/IFN-γ or IL-4/IL-13 stimulatory conditions. Surface marker expression of M1 and M2 macrophages were analyzed under the different culture supplementations in order to investigate the immunomodulatory properties of JPCs. Our results showed that 5 nM PMA can conduct an effective macrophage polarization. The analyses of morphological parameters and surface marker expression showed more distinct M1/M2 phenotypes over FBS supplementation when using 5% hPL during macrophage polarization. In the coculture, immunomodulatory properties of JPCs improved significantly under 5% hPL supplementation compared to other supplementations. We concluded that, under the culture condition with 5% hPL, JPCs were able to effectively induce THP-1-derived macrophage polarization. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Immunobiology and Role in Immunomodulation and Tissue Regeneration)
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Review

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24 pages, 421 KiB  
Review
Mesenchymal Stromal Cells Preconditioning: A New Strategy to Improve Neuroprotective Properties
by Giovanni Schepici, Agnese Gugliandolo and Emanuela Mazzon
Int. J. Mol. Sci. 2022, 23(4), 2088; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042088 - 14 Feb 2022
Cited by 6 | Viewed by 2036
Abstract
Neurological diseases represent one of the main causes of disability in human life. Consequently, investigating new strategies capable of improving the quality of life in neurological patients is necessary. For decades, researchers have been working to improve the efficacy and safety of mesenchymal [...] Read more.
Neurological diseases represent one of the main causes of disability in human life. Consequently, investigating new strategies capable of improving the quality of life in neurological patients is necessary. For decades, researchers have been working to improve the efficacy and safety of mesenchymal stromal cells (MSCs) therapy based on MSCs’ regenerative and immunomodulatory properties and multilinear differentiation potential. Therefore, strategies such as MSCs preconditioning are useful to improve their application to restore damaged neuronal circuits following neurological insults. This review is focused on preconditioning MSCs therapy as a potential application to major neurological diseases. The aim of our work is to summarize both the in vitro and in vivo studies that demonstrate the efficacy of MSC preconditioning on neuronal regeneration and cell survival as a possible application to neurological damage. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Immunobiology and Role in Immunomodulation and Tissue Regeneration)
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14 pages, 316 KiB  
Review
A Review on the Role of Stem Cells against SARS-CoV-2 in Children and Pregnant Women
by Fatemeh Sanie-Jahromi, Yaser NejatyJahromy and Rahim Raoofi Jahromi
Int. J. Mol. Sci. 2021, 22(21), 11787; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111787 - 30 Oct 2021
Cited by 1 | Viewed by 2293
Abstract
Since the COVID-19 outbreak was acknowledged by the WHO on 30 January 2020, much research has been conducted to unveil various features of the responsible SARS-CoV-2 virus. Different rates of contagion in adults, children, and pregnant women may guide us to understand the [...] Read more.
Since the COVID-19 outbreak was acknowledged by the WHO on 30 January 2020, much research has been conducted to unveil various features of the responsible SARS-CoV-2 virus. Different rates of contagion in adults, children, and pregnant women may guide us to understand the underlying infection conditions of COVID-19. In this study, we first provide a review of recent reports of COVID-19 clinical outcomes in children and pregnant women. We then suggest a mechanism that explains the curious case of COVID-19 in children/pregnant women. The unique stem cell molecular signature, as well as the very low expression of angiotensin-converting enzyme 2 and the lower ACE/ACE2 ratio in stem cells of children/pregnant women compared to adults might be the cause of milder symptoms of COVID-19 in them. This study provides the main molecular keys on how stem cells can function properly and exert their immunomodulatory and regenerative effects in COVID-19-infected children/pregnant women, while failing to replicate their role in adults. This can lay the groundwork for both predicting the pattern of spread and severity of the symptoms in a population and designing novel stem cell-based treatment and prevention strategies for COVID-19. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Immunobiology and Role in Immunomodulation and Tissue Regeneration)
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Other

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24 pages, 4240 KiB  
Brief Report
Transcriptional Profile of Cytokines, Regulatory Mediators and TLR in Mesenchymal Stromal Cells after Inflammatory Signaling and Cell-Passaging
by Makram Merimi, Karolien Buyl, Dhouha Daassi, Robim M. Rodrigues, Rahma Melki, Philippe Lewalle, Tamara Vanhaecke, Hassan Fahmi, Vera Rogiers, Laurence Lagneaux, Joery De Kock and Mehdi Najar
Int. J. Mol. Sci. 2021, 22(14), 7309; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147309 - 07 Jul 2021
Cited by 8 | Viewed by 2370
Abstract
Adult human subcutaneous adipose tissue (AT) harbors a rich population of mesenchymal stromal cells (MSCs) that are of interest for tissue repair. For this purpose, it is of utmost importance to determine the response of AT-MSCs to proliferative and inflammatory signals within the [...] Read more.
Adult human subcutaneous adipose tissue (AT) harbors a rich population of mesenchymal stromal cells (MSCs) that are of interest for tissue repair. For this purpose, it is of utmost importance to determine the response of AT-MSCs to proliferative and inflammatory signals within the damaged tissue. We have characterized the transcriptional profile of cytokines, regulatory mediators and Toll-like receptors (TLR) relevant to the response of MSCs. AT-MSCs constitutively present a distinct profile for each gene and differentially responded to inflammation and cell-passaging. Inflammation leads to an upregulation of IL-6, IL-8, IL-1β, TNFα and CCL5 cytokine expression. Inflammation and cell-passaging increased the expression of HGF, IDO1, PTGS1, PTGS2 and TGFβ. The expression of the TLR pattern was differentially modulated with TLR 1, 2, 3, 4, 9 and 10 being increased, whereas TLR 5 and 6 downregulated. Functional enrichment analysis demonstrated a complex interplay between cytokines, TLR and regulatory mediators central for tissue repair. This profiling highlights that following a combination of inflammatory and proliferative signals, the sensitivity and responsive capacity of AT-MSCs may be significantly modified. Understanding these transcriptional changes may help the development of novel therapeutic approaches. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Immunobiology and Role in Immunomodulation and Tissue Regeneration)
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