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Special Issue "Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editors

Prof. Dr. Heba Abdelrazik
E-Mail Website
Guest Editor
1. Department of Clinical Pathology, Immunology and Cell Therapy Unit, Cairo University, Cairo, Egypt
2. Department of Immunology and Translation Medicine, University of Genoa and San Martino Hospital, Genova, Italy
Interests: MSCs for immune-modulation and regenerative medicine; reprogramming, gene editing and target gene therapy; neural lineage differentiation; intercellular communication and drug interactions
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Elena De Falco
E-Mail Website
Guest Editor
Faculty of Pharmacy and Medicine, Department of Medico-Surgical Sciences and Biotechnologies, University of Rome Sapienza, C.so della Repubblica 79, 04100 Latina, Italy
Interests: cardiac-transdifferentiation of MSCs; MSC-based cell therapies in cardiovascular diseases and regenerative medicine; cell plasticity of MSCs; platelet lysate and MSCs
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandra Pelagalli
E-Mail Website
Guest Editor
1. Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137 Naples, Italy
2. Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), 80131 Naples, Italy
Interests: MSCs from domestic animal species; MSCs physiology and behavior for translational regenerative medicine; migration and proliferation of MSCs and role of Aquaporin (AQPs); MSCs, conditioned medium and microenvironment in physiological condition
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Sara Perteghella
E-Mail Website
Guest Editor
Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
Interests: mesenchymal stem cells (MSCs); MSC-extracellular vesicles; MSC-secretome; tissue engineering; cell encapsulation; silk-based scaffolds; drug delivery systems; alginate; silk fibroin; silk sericin; silk-based nanoparticles; silk-based microparticles

Special Issue Information

Dear Colleagues,

The development in understanding mesenchymal stem cell (MSC) biology, gene regulation and intercellular interactions is holding promise for the evolution of therapeutic approaches in tissue regeneration both in humans and in animals. For their exclusive capacity to self renew and commitment towards defined cell lineages, MSCs offer novel perspectives and tools for clinical application in a safe and effective manner. Recent knowledge in the crosstalk between MSCs and the microenvironment has highlighted that key soluble modulators, specific signaling pathways and/or the employment of biomaterials are able to foster a wide array of MSC properties including migration, behavior and also gene expression and cell fate. This provides new insights for the genetic manipulation, reprogramming and/or gene editing of MSCs addressing also physical, biological and biochemical properties of MSCs in order to boost their regenerative capabilities and tissue repair. Last but not least, studies concerning MSCs extracellular vesicles and MSCs secretome for tissue regeneration and immune modulation will allow enrich the knowledge on MSC functions opening new possibilities for stem cell free advanced strategies. Accordingly, we invite investigators to contribute with their novel findings in the field of MSCs helping to bridge the gap between biology and applied regenerative medicine to encourage the progression of MSC-based translational research.

Gruppo Italiano Staminali Mesenchimali (GISM)

Prof. Dr. Heba Abdelrazik
Prof. Dr. Elena De Falco
Dr. Alessandra Pelagalli
Dr. Dr. Sara Perteghella
Guest Editors

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 papers will be 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.

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Keywords

  • Mesenchymal stem cells (MSCs)
  • Regenerative medicine
  • Tissue Engineering
  • Tissue repair
  • Cell differentiation
  • Cell behaviour and cell fate
  • Traslational medicine
  • Animal sources
  • MSCs vesicles
  • MSCs secretome
  • MSCs as genetic vectors

Published Papers (8 papers)

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Research

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Article
Freeze-Dried Secretome (Lyosecretome) from Mesenchymal Stem/Stromal Cells Promotes the Osteoinductive and Osteoconductive Properties of Titanium Cages
Int. J. Mol. Sci. 2021, 22(16), 8445; https://doi.org/10.3390/ijms22168445 - 06 Aug 2021
Viewed by 520
Abstract
Titanium is one of the most frequently used materials in bone regeneration due to its good biocompatibility, excellent mechanical properties, and great osteogenic performance. However, osseointegration with host tissue is often not definite, which may cause implant failure at times. The present study [...] Read more.
Titanium is one of the most frequently used materials in bone regeneration due to its good biocompatibility, excellent mechanical properties, and great osteogenic performance. However, osseointegration with host tissue is often not definite, which may cause implant failure at times. The present study investigates the capacity of the mesenchymal stem cell (MSC)-secretome, formulated as a ready-to-use and freeze-dried medicinal product (the Lyosecretome), to promote the osteoinductive and osteoconductive properties of titanium cages. In vitro tests were conducted using adipose tissue-derived MSCs seeded on titanium cages with or without Lyosecretome. After 14 days, in the presence of Lyosecretome, significant cell proliferation improvement was observed. Scanning electron microscopy revealed the cytocompatibility of titanium cages: the seeded MSCs showed a spread morphology and an initial formation of filopodia. After 7 days, in the presence of Lyosecretome, more frequent and complex cellular processes forming bridges across the porous surface of the scaffold were revealed. Also, after 14 and 28 days of culturing in osteogenic medium, the amount of mineralized matrix detected by alizarin red was significantly higher when Lyosecretome was used. Finally, improved osteogenesis with Lyosecretome was confirmed by confocal analysis after 28 and 56 days of treatment, and demonstrating the production by osteoblast-differentiated MSCs of osteocalcin, a specific bone matrix protein. Full article
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Article
In Vitro Osteoinductivity Assay of Hydroxylapatite Scaffolds, Obtained with Biomorphic Transformation Processes, Assessed Using Human Adipose Stem Cell Cultures
Int. J. Mol. Sci. 2021, 22(13), 7092; https://doi.org/10.3390/ijms22137092 - 30 Jun 2021
Viewed by 688
Abstract
In this study, the in vitro biocompatibility and osteoinductive ability of a recently developed biomorphic hydroxylapatite ceramic scaffold (B-HA) derived from transformation of wood structures were analyzed using human adipose stem cells (hASCs). Cell viability and metabolic activity were evaluated in hASCs, parental [...] Read more.
In this study, the in vitro biocompatibility and osteoinductive ability of a recently developed biomorphic hydroxylapatite ceramic scaffold (B-HA) derived from transformation of wood structures were analyzed using human adipose stem cells (hASCs). Cell viability and metabolic activity were evaluated in hASCs, parental cells and in recombinant genetically engineered hASC-eGFP cells expressing the green fluorescence protein. B-HA osteoinductivity properties, such as differentially expressed genes (DEG) involved in the skeletal development pathway, osteocalcin (OCN) protein expression and mineral matrix deposition in hASCs, were evaluated. In vitro induction of osteoblastic genes, such as Alkaline phosphatase (ALPL), Bone gamma-carboxyglutamate (gla) protein (BGLAP), SMAD family member 3 (SMAD3), Sp7 transcription factor (SP7) and Transforming growth factor, beta 3 (TGFB3) and Tumor necrosis factor (ligand) superfamily, member 11 (TNFSF11)/Receptor activator of NF-κB (RANK) ligand (RANKL), involved in osteoclast differentiation, was undertaken in cells grown on B-HA. Chondrogenic transcription factor SRY (sex determining region Y)-box 9 (SOX9), tested up-regulated in hASCs grown on the B-HA scaffold. Gene expression enhancement in the skeletal development pathway was detected in hASCs using B-HA compared to sintered hydroxylapatite (S-HA). OCN protein expression and calcium deposition were increased in hASCs grown on B-HA in comparison with the control. This study demonstrates the biocompatibility of the novel biomorphic B-HA scaffold and its potential use in osteogenic differentiation for hASCs. Our data highlight the relevance of B-HA for bone regeneration purposes. Full article
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Article
Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids
Int. J. Mol. Sci. 2021, 22(12), 6431; https://doi.org/10.3390/ijms22126431 - 16 Jun 2021
Viewed by 733
Abstract
Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory [...] Read more.
Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress. Full article
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Review

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Review
Mesenchymal Stem Cell-Derived Extracellular Vesicle: A Promising Alternative Therapy for Osteoporosis
Int. J. Mol. Sci. 2021, 22(23), 12750; https://doi.org/10.3390/ijms222312750 - 25 Nov 2021
Viewed by 200
Abstract
Osteoporosis is the chronic metabolic bone disease caused by the disturbance of bone remodeling due to the imbalance of osteogenesis and osteoclastogenesis. A large population suffers from osteoporosis, and most of them are postmenopausal women or older people. To date, bisphosphonates are the [...] Read more.
Osteoporosis is the chronic metabolic bone disease caused by the disturbance of bone remodeling due to the imbalance of osteogenesis and osteoclastogenesis. A large population suffers from osteoporosis, and most of them are postmenopausal women or older people. To date, bisphosphonates are the main therapeutic agents in the treatment of osteoporosis. However, limited therapeutic effects with diverse side effects caused by bisphosphonates hindered the therapeutic applications and decreased the quality of life. Therefore, an alternative therapy for osteoporosis is still needed. Stem cells, especially mesenchymal stem cells, have been shown as a promising medication for numerous human diseases including many refractory diseases. Recently, researchers found that the extracellular vesicles derived from these stem cells possessed the similar therapeutic potential to that of parental cells. To date, a number of studies demonstrated the therapeutic applications of exogenous MSC-EVs for the treatment of osteoporosis. In this article, we reviewed the basic back ground of EVs, the cargo and therapeutic potential of MSC-EVs, and strategies of engineering of MSC-EVs for osteoporosis treatment. Full article
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Review
Immunomodulation and Regenerative Capacity of MSCs for Long-COVID
Int. J. Mol. Sci. 2021, 22(22), 12421; https://doi.org/10.3390/ijms222212421 - 17 Nov 2021
Viewed by 419
Abstract
The rapid mutation of the SARS-CoV-2 virus is now a major concern with no effective drugs and treatments. The severity of the disease is linked to the induction of a cytokine storm that promotes extensive inflammation in the lung, leading to many acute [...] Read more.
The rapid mutation of the SARS-CoV-2 virus is now a major concern with no effective drugs and treatments. The severity of the disease is linked to the induction of a cytokine storm that promotes extensive inflammation in the lung, leading to many acute lung injuries, pulmonary edema, and eventually death. Mesenchymal stem cells (MSCs) might prove to be a treatment option as they have immunomodulation and regenerative properties. Clinical trials utilizing MSCs in treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) have provided a basis in treating post-COVID-19 patients. In this review, we discussed the effects of MSCs as an immunomodulator to reduce the severity and death in patients with COVID-19, including the usage of MSCs as an alternative regenerative therapy in post-COVID-19 patients. This review also includes the current clinical trials in utilizing MSCs and their potential future utilization for long-COVID treatments. Full article
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Review
Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment
Int. J. Mol. Sci. 2021, 22(20), 11187; https://doi.org/10.3390/ijms222011187 - 17 Oct 2021
Viewed by 447
Abstract
Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem [...] Read more.
Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem cells (MSCs) can cross biological barriers, migrate to sites of injuries to exert many healing effects, and be engineered to incorporate different types of cargo, making them an ideal vehicle to transport anti-tumor agents to the central nervous system. Extracellular vesicles (EVs) produced by MSCs (MSC-EVs) have valuable innate properties from parent cells, and are being exploited as cell-free treatments for many neurological diseases. Compared to using MSCs, targeted delivery via MSC-EVs has a better pharmacokinetic profile, yet avoids many critical issues of cell-based systems. As the field of MSC therapeutic applications is quickly expanding, this article aims to give an overall picture for one direction of EV-based targeting of brain tumors, with updates on available techniques, outcomes of experimental models, and critical challenges of this concept. Full article
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Review
Mesenchymal Stem Cell Transplantation for the Treatment of Age-Related Musculoskeletal Frailty
Int. J. Mol. Sci. 2021, 22(19), 10542; https://doi.org/10.3390/ijms221910542 - 29 Sep 2021
Viewed by 608
Abstract
Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies leading to rapid growth of geriatric population. Thus, age-associated diseases especially in the musculoskeletal system are becoming more common. Loss of bone (osteoporosis) and muscle (sarcopenia) mass [...] Read more.
Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies leading to rapid growth of geriatric population. Thus, age-associated diseases especially in the musculoskeletal system are becoming more common. Loss of bone (osteoporosis) and muscle (sarcopenia) mass are conditions whose prevalence is increasing because of the change in population distribution in the world towards an older mean age. The deterioration in the bone and muscle functions can cause severe disability and seriously affects the patients’ quality of life. Currently, there is no treatment to prevent and reverse age-related musculoskeletal frailty. Existing interventions are mainly to slow down and control the signs and symptoms. Mesenchymal stem cell (MSC) transplantation is a promising approach to attenuate age-related musculoskeletal frailty. This review compiles the present knowledge of the causes and changes of the musculoskeletal frailty and the potential of MSC transplantation as a regenerative therapy for age-related musculoskeletal frailty. Full article
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Review
TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles
Int. J. Mol. Sci. 2021, 22(17), 9531; https://doi.org/10.3390/ijms22179531 - 02 Sep 2021
Cited by 2 | Viewed by 517
Abstract
Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of [...] Read more.
Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of MSC immunoregulatory mechanisms. In addition, the importance of cell–cell contact for MSCs to efficiently modulate the immune response has recently been highlighted. Because these interactions would be difficult to achieve in the physiological context, the release of extracellular vesicles (EVs) and their participation as intermediaries of communication between MSCs and immune cells becomes relevant. Therefore, this article focuses on analyzing immunoregulatory mechanisms mediated by cell contact, highlighting the importance of intercellular adhesion molecule-1 (ICAM-1) and the participation of EVs. Moreover, the effects of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), the main cytokines involved in MSC activation, are examined. These cytokines, when used at the appropriate concentrations and times, would promote increases in the expression of immunoregulatory molecules in the cell and allow the acquisition of EVs enriched with these molecules. The establishment of certain in vitro activation guidelines will facilitate the design of conditioning protocols to obtain functional MSCs or EVs in different pathophysiological conditions. Full article
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