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Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 28425

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Special Issue Editor

Dr. Arianna Scuteri

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Guest Editor

Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
Interests: mesenchymal stem cell neuroprotection; neurotoxicity; neuroprotective molecular mechanisms; peripheral neuropathies; pancreatic islet transplantation for diabetes treatment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

So far mesenchymal stem cells (MSCs) have been used in a huge number of studies, with very promising results in the largest part of experimental models. In particular, MSCs have displayed a protective action, being able both to support the survival of different kinds of cells and to protect them against different toxic stimuli. Many researchers have contributed to shed light on such a unique effect, by proposing new and different mechanisms of action for MSCs as well as by developing new experimental models to test them. In this way, the field of MSC application is rapidly expanding, and a clear understanding of the molecular mechanisms underlying their protective action represents a very important goal, with a potential great impact on different diseases. The aim of this open-access Special Issue is to update the knowledge about MSC mechanisms of action, thus also providing new inspiration to seek new and unexplored ideas.

Authors are invited to submit original research and review articles which address the study of MSC protective molecular mechanisms.

Topics include, but are not limited to:

Cell-to-cell contact;
Tunneling nanotubes;
Trophic factors;
Extracellular vesicles;
Exosome release;
Immune-modulatory action;
Apoptosis

Prof. Arianna Scuteri
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

Apoptosis
Exosomes
Cellular contact
Paracrine effect
Tunneling nanotubes

Published Papers (7 papers)

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Research

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15 pages, 2580 KiB

Open AccessArticle

Characterization of Extracellular Vesicles from Preconditioned Human Adipose-Derived Stromal/Stem Cells

by Alec Geßner, Benjamin Koch, Kevin Klann, Dominik C. Fuhrmann, Samira Farmand, Ralf Schubert, Christian Münch, Helmut Geiger and Patrick C. Baer

Int. J. Mol. Sci. 2021, 22(6), 2873; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062873 - 12 Mar 2021

Cited by 11 | Viewed by 2189

Abstract

Cell-free therapy using extracellular vesicles (EVs) from adipose-derived mesenchymal stromal/stem cells (ASCs) seems to be a safe and effective therapeutic option to support tissue and organ regeneration. The application of EVs requires particles with a maximum regenerative capability and hypoxic culture conditions as an in vitro preconditioning regimen has been shown to alter the molecular composition of released EVs. Nevertheless, the EV cargo after hypoxic preconditioning has not yet been comprehensively examined. The aim of the present study was the characterization of EVs from hypoxic preconditioned ASCs. We investigated the EV proteome and their effects on renal tubular epithelial cells in vitro. While no effect of hypoxia was observed on the number of released EVs and their protein content, the cargo of the proteins was altered. Proteomic analysis showed 41 increased or decreased proteins, 11 in a statistically significant manner. Furthermore, the uptake of EVs in epithelial cells and a positive effect on oxidative stress in vitro were observed. In conclusion, culture of ASCs under hypoxic conditions was demonstrated to be a promising in vitro preconditioning regimen, which alters the protein cargo and increases the anti-oxidative potential of EVs. These properties may provide new potential therapeutic options for regenerative medicine. Full article

(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action)

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20 pages, 3393 KiB

Open AccessArticle

HGF and TSG-6 Released by Mesenchymal Stem Cells Attenuate Colon Radiation-Induced Fibrosis

by Benoît Usunier, Clément Brossard, Bruno L’Homme, Christine Linard, Marc Benderitter, Fabien Milliat and Alain Chapel

Int. J. Mol. Sci. 2021, 22(4), 1790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041790 - 11 Feb 2021

Cited by 15 | Viewed by 3324

Abstract

Fibrosis is a leading cause of death in occidental states. The increasing number of patients with fibrosis requires innovative approaches. Despite the proven beneficial effects of mesenchymal stem cell (MSC) therapy on fibrosis, there is little evidence of their anti-fibrotic effects in colorectal fibrosis. The ability of MSCs to reduce radiation-induced colorectal fibrosis has been studied in vivo in Sprague–Dawley rats. After local radiation exposure, rats were injected with MSCs before an initiation of fibrosis. MSCs mediated a downregulation of fibrogenesis by a control of extra cellular matrix (ECM) turnover. For a better understanding of the mechanisms, we used an in vitro model of irradiated cocultured colorectal fibrosis in the presence of human MSCs. Pro-fibrotic cells in the colon are mainly intestinal fibroblasts and smooth muscle cells. Intestinal fibroblasts and smooth muscle cells were irradiated and cocultured in the presence of unirradiated MSCs. MSCs mediated a decrease in profibrotic gene expression and proteins secretion. Silencing hepatocyte growth factor (HGF) and tumor necrosis factor-stimulated gene 6 (TSG-6) in MSCs confirmed the complementary effects of these two genes. HGF and TSG-6 limited the progression of fibrosis by reducing activation of the smooth muscle cells and myofibroblast. To settle in vivo the contribution of HGF and TSG-6 in MSC-antifibrotic effects, rats were treated with MSCs silenced for HGF or TSG-6. HGF and TSG-6 silencing in transplanted MSCs resulted in a significant increase in ECM deposition in colon. These results emphasize the potential of MSCs to influence the pathophysiology of fibrosis-related diseases, which represent a challenging area for innovative treatments. Full article

(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action)

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13 pages, 2265 KiB

Open AccessArticle

Umbilical Cord-Derived CD362⁺ Mesenchymal Stromal Cells Attenuate Polymicrobial Sepsis Induced by Caecal Ligation and Puncture

by Hector Gonzalez, Colm Keane, Claire H. Masterson, Shahd Horie, Stephen J. Elliman, Brendan D. Higgins, Michael Scully, John G. Laffey and Daniel O’Toole

Int. J. Mol. Sci. 2020, 21(21), 8270; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218270 - 04 Nov 2020

Cited by 10 | Viewed by 1872

Abstract

Mesenchymal stromal cells (MSCs) have a multimodal, immunomodulatory mechanism of action and are now in clinical trials for single organ and systemic sepsis. However, a number of practicalities around source, homogeneity and therapeutic window remain to be determined. Here, we utilised conditioned medium from CD362⁺-sorted umbilical cord-human MSCs (UC-hMSCs) for a series of in vitro anti-inflammatory assays and the cryopreserved MSCs themselves in a severe (Series 1) or moderate (Series 2+3) caecal ligation and puncture (CLP) rodent model. Surviving animals were assessed at 48 h post injury induction. MSCs improved human lung, colonic and kidney epithelial cell survival following cytokine activation. In severe systemic sepsis, MSCs administered at 30 min enhanced survival (Series 1), and reduced organ bacterial load. In moderate systemic sepsis (Series 2), MSCs were ineffective when delivered immediately or 24 h later. Of importance, MSCs delivered 4 h post induction of moderate sepsis (Series 3) were effective, improving serum lactate, enhancing bacterial clearance from tissues, reducing pro-inflammatory cytokine concentrations and increasing antimicrobial peptides in serum. While demonstrating benefit and immunomodulation in systemic sepsis, therapeutic efficacy may be limited to a specific point of disease onset, and repeat dosing, MSC enhancement or other contingencies may be necessary. Full article

(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action)

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17 pages, 1801 KiB

Open AccessArticle

Anti-Tumor Effects of Exosomes Derived from Drug-Incubated Permanently Growing Human MSC

by Catharina Melzer, Juliane von der Ohe and Ralf Hass

Int. J. Mol. Sci. 2020, 21(19), 7311; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197311 - 03 Oct 2020

Cited by 30 | Viewed by 2979

Abstract

Similar to growth-limited human primary cultures of mesenchymal stroma/stem-like cells (MSC), the continuously proliferating human MSC544 cell line produced extracellular vesicles as characterized by expression of the tetraspanin molecules CD9, CD63, and CD81. Release of these particles was predominantly detectable during continuous cell growth of MSC544 in contrast to confluency-mediated transient growth arrest. For therapeutic use, these particles were isolated from proliferating MSC544 after taxol treatment and applied to different cancer cell cultures. A pronounced cytotoxicity of lung, ovarian, and breast cancer cells was observed primarily with taxol-loaded exosomes, similar to the effects displayed by application of taxol substance. While these findings suggested pronounced cancer cell targeting of MSC544 exosomes, a tumor therapeutic approach was performed using a mouse in vivo breast cancer model. Thus, intravenous injection of taxol-loaded MSC544 exosomes displayed superior tumor-reducing capabilities as compared to application of taxol exosomes by oral gavage. To broaden this therapeutic spectrum, epirubicin was applied to MSC544, and the derived exosomes likewise exhibited significant cytotoxic effects in different cancer cell cultures. These findings suggest an unlimited source for large-scale exosome production with reproducible quality to enable variable drug targeting of tumors or other diseases. Full article

(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action)

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Review

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15 pages, 1328 KiB

Open AccessReview

Neural Stem Cell-Based Therapies and Glioblastoma Management: Current Evidence and Clinical Challenges

by Amira Yasmine Benmelouka, Malak Munir, Ahmed Sayed, Mohamed Salah Attia, Mohamad M. Ali, Ahmed Negida, Badrah S. Alghamdi, Mohammad Amjad Kamal, George E. Barreto, Ghulam Md Ashraf, Mostafa Meshref and Eshak I. Bahbah

Int. J. Mol. Sci. 2021, 22(5), 2258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052258 - 24 Feb 2021

Cited by 17 | Viewed by 6372

Abstract

Gliomas, which account for nearly a quarter of all primary CNS tumors, present significant contemporary therapeutic challenges, particularly the highest-grade variant (glioblastoma multiforme), which has an especially poor prognosis. These difficulties are due to the tumor’s aggressiveness and the adverse effects of radio/chemotherapy on the brain. Stem cell therapy is an exciting area of research being explored for several medical issues. Neural stem cells, normally present in the subventricular zone and the hippocampus, preferentially migrate to tumor masses. Thus, they have two main advantages: They can minimize the side effects associated with systemic radio/chemotherapy while simultaneously maximizing drug delivery to the tumor site. Another feature of stem cell therapy is the variety of treatment approaches it allows. Stem cells can be genetically engineered into expressing a wide variety of immunomodulatory substances that can inhibit tumor growth. They can also be used as delivery vehicles for oncolytic viral vectors, which can then be used to combat the tumorous mass. An alternative approach would be to combine stem cells with prodrugs, which can subsequently convert them into the active form upon migration to the tumor mass. As with any therapeutic modality still in its infancy, much of the research regarding their use is primarily based upon knowledge gained from animal studies, and a number of ongoing clinical trials are currently investigating their effectiveness in humans. The aim of this review is to highlight the current state of stem cell therapy in the treatment of gliomas, exploring the different mechanistic approaches, clinical applicability, and the existing limitations. Full article

(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action)

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20 pages, 2098 KiB

Open AccessReview

Therapeutic Properties of Mesenchymal Stromal/Stem Cells: The Need of Cell Priming for Cell-Free Therapies in Regenerative Medicine

by Vitale Miceli, Matteo Bulati, Gioacchin Iannolo, Giovanni Zito, Alessia Gallo and Pier Giulio Conaldi

Int. J. Mol. Sci. 2021, 22(2), 763; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020763 - 14 Jan 2021

Cited by 79 | Viewed by 6114

Abstract

Mesenchymal stromal/stem cells (MSCs) are multipotent adult stem cells that support homeostasis during tissue regeneration. In the last decade, cell therapies based on the use of MSCs have emerged as a promising strategy in the field of regenerative medicine. Although these cells possess robust therapeutic properties that can be applied in the treatment of different diseases, variables in preclinical and clinical trials lead to inconsistent outcomes. MSC therapeutic effects result from the secretion of bioactive molecules affected by either local microenvironment or MSC culture conditions. Hence, MSC paracrine action is currently being explored in several clinical settings either using a conditioned medium (CM) or MSC-derived exosomes (EXOs), where these products modulate tissue responses in different types of injuries. In this scenario, MSC paracrine mechanisms provide a promising framework for enhancing MSC therapeutic benefits, where the composition of secretome can be modulated by priming of the MSCs. In this review, we examine the literature on the priming of MSCs as a tool to enhance their therapeutic properties applicable to the main processes involved in tissue regeneration, including the reduction of fibrosis, the immunomodulation, the stimulation of angiogenesis, and the stimulation of resident progenitor cells, thereby providing new insights for the therapeutic use of MSCs-derived products. Full article

(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action)

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35 pages, 589 KiB

Open AccessReview

Mesenchymal Stem Cells in Multiple Sclerosis: Recent Evidence from Pre-Clinical to Clinical Studies

by Agnese Gugliandolo, Placido Bramanti and Emanuela Mazzon

Int. J. Mol. Sci. 2020, 21(22), 8662; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228662 - 17 Nov 2020

Cited by 39 | Viewed by 4976

Abstract

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Nowadays, available therapies for MS can help to manage MS course and symptoms, but new therapeutic approaches are required. Stem cell therapy using mesenchymal stem cells (MSCs) appeared promising in different neurodegenerative conditions, thanks to their beneficial capacities, including the immunomodulation ability, and to their secretome. The secretome is represented by growth factors, cytokines, and extracellular vesicles (EVs) released by MSCs. In this review, we focused on studies performed on in vivo MS models involving the administration of MSCs and on clinical trials evaluating MSCs administration. Experimental models of MS evidenced that MSCs were able to reduce inflammatory cell infiltration and disease score. Moreover, MSCs engineered to express different genes, preconditioned with different compounds, differentiated or in combination with other compounds also exerted beneficial actions in MS models, in some cases also superior to native MSCs. Secretome, both conditioned medium and EVs, also showed protective effects in MS models and appeared promising to develop new approaches. Clinical trials highlighted the safety and feasibility of MSC administration and reported some improvements, but other trials using larger cohorts of patients are needed. Full article

(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Mesenchymal Stem Cells Protective Action)

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