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Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 4.0
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Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 4.0

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: 30 June 2025 | Viewed by 7196

Special Issue Editors

Dr. Alessandra Pelagalli

E-Mail Website
Guest Editor
Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137 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. 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

Special Issue Information

Dear Colleagues,

Developments in our understanding of mesenchymal stem cell (MSC) biology, gene regulation and intercellular interactions hold promise for the evolution of therapeutic approaches in tissue regeneration both in humans and in animals. Due to 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 on 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 into the genetic manipulation, reprogramming and/or gene editing of MSCs, also addressing the physical, biological and biochemical properties of MSCs in order to boost their regenerative capabilities and tissue repair. Last but not least, studies concerning MSC extracellular vesicles and MSC secretome for tissue regeneration and immune modulation will enrich the knowledge on MSC functions, opening new possibilities for stem-cell-free advanced strategies. Accordingly, we invite investigators to contribute 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)

Dr. Alessandra Pelagalli
Prof. Dr. Heba Abdelrazik
Guest Editors

Manuscript Submission Information

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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
  • MSC vesicles
  • MSC secretome
  • MSCs as genetic vectors

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Related Special Issue

Published Papers (5 papers)

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Research

14 pages, 4795 KiB  
Article
O-GlcNAcylation in Gli1+ Mesenchymal Stem Cells Is Indispensable for Bone Formation and Fracture Healing
by Moyu Liu, Yujie Hu, Chengjia You, Ding Xiong, Ling Ye and Yu Shi
Int. J. Mol. Sci. 2025, 26(6), 2712; https://doi.org/10.3390/ijms26062712 - 18 Mar 2025
Viewed by 379
Abstract
Adult mesenchymal stem cells (MSCs) play a crucial role in maintaining bone health and promoting regeneration. In our previous research, we identified Gli1+ MSCs as key contributors to the formation of most trabecular bone in adulthood and as essential for healing bicortical [...] Read more.
Adult mesenchymal stem cells (MSCs) play a crucial role in maintaining bone health and promoting regeneration. In our previous research, we identified Gli1+ MSCs as key contributors to the formation of most trabecular bone in adulthood and as essential for healing bicortical fractures. However, the mechanisms behind the maintenance and differentiation of Gli1+ MSCs are still not fully understood. O-linked N-acetylglucosamine modification (O-GlcNAcylation), mediated by O-GlcNAc glycosyltransferase (OGT), is involved in various biological processes and diseases. Our earlier work also demonstrated that O-GlcNAcylation is necessary for Wnt-stimulated bone formation. Nonetheless, the specific functions of O-GlcNAcylation in MSCs have not been completely elucidated. In this study, we found that the absence of OGT in Gli1+ MSCs led to a decrease in O-GlcNAcylation, which impaired both the bone formation and regeneration following fractures. Mechanistically, the Hedgehog signaling pathway induced O-GlcNAcylation through the insulin-like growth factor (Igf)-mTORC2 axis. This process stabilized the Gli2 protein at a specific site Ser355 and promoted osteogenesis in MSCs in vitro. Our findings reveal a significant mechanism by which O-GlcNAcylation regulates bone development and repair in mammals. Full article
(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 4.0)
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15 pages, 8460 KiB  
Article
Targeting Lung Damage: Amniotic Mesenchymal Stem Cells Mitigate Lipopolysaccharide-Induced Acute Lung Injury via Multiple Signaling Pathways
by Xinhui Niu, Lina Zhang, Shaoliang Xing, Jinrui Liu, Deming Li, Yating Wang, Yi Wang and Manman Su
Int. J. Mol. Sci. 2025, 26(5), 2314; https://doi.org/10.3390/ijms26052314 - 5 Mar 2025
Viewed by 700
Abstract
Acute lung injury (ALI) is a life-threatening condition triggered by pneumonia, viral infections, or physical trauma. It manifests clinically as progressive respiratory failure and refractory hypoxemia. Using a lipopolysaccharide (LPS)-induced acute lung injury mouse model, we demonstrated that amniotic mesenchymal stem cells (AMSCs) [...] Read more.
Acute lung injury (ALI) is a life-threatening condition triggered by pneumonia, viral infections, or physical trauma. It manifests clinically as progressive respiratory failure and refractory hypoxemia. Using a lipopolysaccharide (LPS)-induced acute lung injury mouse model, we demonstrated that amniotic mesenchymal stem cells (AMSCs) exhibit robust reparative and anti-inflammatory properties. Our analysis encompassed inflammatory mediators; histological damage; tight junction integrity; epithelial–mesenchymal transition (EMT); and the TGF-β/Smad, TLR4/NF-κB/MAPK, pyroptosis, and apoptosis signaling pathways. Our key results demonstrated that in ALI-afflicted mice, AMSCs exhibited targeted pulmonary tropism, homing in on injured alveolar regions, where they restored the morphology and functionality of damaged tissues and organelles, re-established lung barrier function, and attenuated the aberrantly activated TLR4/NF-κB/MAPK and TGF-β/Smad pathways associated with inflammation. These coordinated mechanisms contributed to pyroptosis, apoptosis, and fibrosis suppression. In conclusion, AMSCs mitigated the inflammatory injury process in ALI mice through multiple mechanisms, thereby supporting the potential development of MSC-based therapeutic strategies. Full article
(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 4.0)
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15 pages, 2851 KiB  
Article
Human Placenta MSC-Derived DNA Fragments Exert Therapeutic Effects in a Skin Wound Model via the A2A Receptor
by Hankyu Lee, Hyun-Jung Lee, Hyeon-Jun Jang, Hyeri Park and Gi Jin Kim
Int. J. Mol. Sci. 2025, 26(4), 1769; https://doi.org/10.3390/ijms26041769 - 19 Feb 2025
Viewed by 1002
Abstract
PDRN, polydeoxyribonucleotide, which is used as a tissue-regeneration material, is present in human cells under physiological conditions and stimulates regeneration and metabolic activity. PDRN can be used as a biomaterial for several types of regeneration, including wound healing, to promote cell growth and [...] Read more.
PDRN, polydeoxyribonucleotide, which is used as a tissue-regeneration material, is present in human cells under physiological conditions and stimulates regeneration and metabolic activity. PDRN can be used as a biomaterial for several types of regeneration, including wound healing, to promote cell growth and growth-factor production. The aims of this study were to determine the effect of PDRN derived from human placenta-derived mesenchymal stem cells (hPD-MSCs) on cellular regeneration through A2A receptor signaling and to investigate its therapeutic effects in a mouse model of wound healing. Human PDRN (UNIPlax) was extracted from hPD-MSCs fragmented via a sonication system and evaluated for its effect on the migration of HaCaT cells in an in vitro system and in a wound-healing mouse model in vivo. Compared with the sham treatment, UNIPlax treatment significantly increased the migration of injured HaCaT cells (p < 0.05). Additionally, the tube formation of human umbilical vein endothelial cells (HUVECs) was greater than that of the sham group (p < 0.05), and the effects of this treatment were mediated through the A2A receptor. Furthermore, UNIPlax treatment led to a decrease in wound size; in addition, the area of granulation and the rate of collagen formation at the wound site were significantly greater than those in the sham group in the wound-healing mouse model (p < 0.001). We also confirmed that UNIPlax promoted tissue regeneration and the expression of VEGF through the A2A receptor. Taken together, these findings indicate that UNIPlax has potential for regeneration of damaged tissues, including during wound healing. Full article
(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 4.0)
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12 pages, 1589 KiB  
Article
Partial Reprogramming Exerts a Rejuvenating Effect on Human Mesenchymal Stem Cells That Underwent Replicative Senescence in Culture
by Julia Ivanova, Mariia Shorokhova, Natalia Pugovkina, Irina Kozhukharova, Larisa Alekseenko, Nikita Guriev, Ivan Kuneev, Alisa Domnina, Tatiana Grinchuk, Victoria Zemelko and Olga Lyublinskaya
Int. J. Mol. Sci. 2024, 25(23), 12533; https://doi.org/10.3390/ijms252312533 - 22 Nov 2024
Viewed by 2322
Abstract
Mesenchymal stem/stromal cells (MSCs) are becoming increasingly important for biomedical applications, such as cell therapy, disease modeling, and drug screening. At the same time, long-term cultivation, which is necessary to prepare a sufficient amount of cellular material for therapeutic and research purposes, is [...] Read more.
Mesenchymal stem/stromal cells (MSCs) are becoming increasingly important for biomedical applications, such as cell therapy, disease modeling, and drug screening. At the same time, long-term cultivation, which is necessary to prepare a sufficient amount of cellular material for therapeutic and research purposes, is accompanied by the development of replicative senescence. Partial reprogramming emerged as a novel method that shows promising results in the rejuvenation of cells in vitro and in vivo; however, it has not yet been applied for human MSCs that have undergone replicative senescence in culture. In the present study, we subjected senescent human endometrial MSCs to partial reprogramming using Sendai virus vectors containing genes encoding Yamanaka transcription factors Oct4, Sox2, Klf4, and c-Myc. Characterization of the MSCs 5 days after transduction showed the loss of key markers of senescence: the youthful morphology was restored, the expression of senescent-associated β-galactosidase and the number of double-strand DNA breaks decreased, proliferation was activated, and the DNA damage response was enhanced. Further, using an in vitro wound-healing assay, we demonstrated that conditioned medium from partially reprogrammed MSCs showed higher therapeutic activity than that from senescent cells. However, a biosafety test revealed the presence of viral components in conditioned medium, which caused the agglutination of erythrocytes. Collectively, our data suggest that partial reprogramming is a potentially effective strategy for the rejuvenation of cultured MSCs in late passages but requires the use of virus-free protocols, such as chemical reprogramming. Full article
(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 4.0)
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12 pages, 1780 KiB  
Article
Long-Term Cryopreservation May Cause Genomic Instability and the Premature Senescence of Cells
by Mariia Shorokhova, Natalia Pugovkina, Victoria Zemelko, Olga Lyublinskaya and Tatiana Grinchuk
Int. J. Mol. Sci. 2024, 25(3), 1467; https://doi.org/10.3390/ijms25031467 - 25 Jan 2024
Cited by 1 | Viewed by 2073
Abstract
Cryopreservation is an essential step for utilizing various cell types for biological research and medical purposes. At the same time, there is a lack of data on the effect of cryopreservation, especially when prolonged, on the karyotype of cells. In the present work, [...] Read more.
Cryopreservation is an essential step for utilizing various cell types for biological research and medical purposes. At the same time, there is a lack of data on the effect of cryopreservation, especially when prolonged, on the karyotype of cells. In the present work, we analyzed the genetic stability of cells subjected to a cryopreservation procedure. The objects were immortalized Chinese hamster lung fibroblasts (CHL V-79 RJK line) and human endometrial mesenchymal stem/stromal cells (eMSCs). We showed that short-term cryopreservation in liquid nitrogen for up to 6 months did not affect the karyotype stability of CHL V-79 RJK and eMSCs. On the contrary, karyotyping of G-banded metaphase chromosomes in cells underwent 10-year cryopreservation, which revealed genomic instability in both cell lines associated with the variability of chromosome number in cells, random chromosomal rearrangements, and condensation disorder in homologs. In addition, we found out that long-term cryopreservation of eMSCs does not affect the expression of their typical surface markers and morphology, but results in a significant reduction in proliferative potential and early manifestation of cellular senescence features upon eMSCs culturing. Thus, we concluded that the long-term cryopreservation of cells of different types and biological origin can lead to irreversible changes of their karyotype and acceleration of cellular senescence. Full article
(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 4.0)
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