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Therapeutic Modulation of Mesenchymal Stem Cells for Effective Regenerative Medicine
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Therapeutic Modulation of Mesenchymal Stem Cells for Effective Regenerative Medicine

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

Deadline for manuscript submissions: closed (30 December 2020) | Viewed by 20136

Special Issue Editor

Prof. Azza B. El-Remessy

E-Mail Website
Guest Editor
Department of Pharmacy, Doctors Hospital, Augusta, GA 30909, USA
Interests: obesity; diabetes; retinopathy; ischemic vascular disease; diabetic microvascular complications
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mesenchymal stem cells (MSCs), multipotent stem cells that could be isolated from various tissue sources, have been shown to regenerate various tissues of mesodermal origin. The therapeutic effect of MSCs is largely mediated via paracrine effects and the secretion of extensive bioactive molecules, known as the “secretome”. The regenerative benefit of the secretome has been attributed to MSC-derived extracellular vesicles, as well as the release of trophic factors and cytokines that play neuroprotective, angiogenic, anti-inflammatory, and immune-modulatory roles.

The advancement of autologous MSC therapy or its secretome can be hindered when introduced back to a hostile/disease environment. Impaired endogenous MSC function, limited viability of cells post-transplantation, and altered immunomodulatory efficiency of MSC are a few examples. Thus, restoring the functional capabilities of these impaired MSCs prior to transplantation or utilizing secretome is an effective strategy for ultimate success as repair mediators.

This Special Issue welcomes submissions of research, commentary, and review articles that address the following: (1) preclinical studies testing the impact of therapeutic modulators on MSCs efficacy in animal models; (2) the molecular mechanisms of their therapeutic modulation; and (3) translational application of MSCs or its secretome in endocrine/metabolic disorders.

Prof. Azza B. El-Remessy
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 (MSCs)
  • Regenerative medicine
  • Bioactive materials
  • Cell differentiation/cell fate
  • Survival/anti-apoptotic
  • Angiogenesis/ Repair
  • Neuroprotection
  • Immune-modulation
  • Inflammation
  • Clinical translation
  • Animal models

Related Special Issue

Published Papers (6 papers)

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Research

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18 pages, 6879 KiB  
Article
Modulation of p75NTR on Mesenchymal Stem Cells Increases Their Vascular Protection in Retinal Ischemia-Reperfusion Mouse Model
by Sally L. Elshaer, Hang-soo Park, Laura Pearson, William D. Hill, Frank M. Longo and Azza B. El-Remessy
Int. J. Mol. Sci. 2021, 22(2), 829; https://doi.org/10.3390/ijms22020829 - 15 Jan 2021
Cited by 7 | Viewed by 2546
Abstract
Mesenchymal stem cells (MSCs) are a promising therapy to improve vascular repair, yet their role in ischemic retinopathy is not fully understood. The aim of this study is to investigate the impact of modulating the neurotrophin receptor; p75NTR on the vascular protection [...] Read more.
Mesenchymal stem cells (MSCs) are a promising therapy to improve vascular repair, yet their role in ischemic retinopathy is not fully understood. The aim of this study is to investigate the impact of modulating the neurotrophin receptor; p75NTR on the vascular protection of MSCs in an acute model of retinal ischemia/reperfusion (I/R). Wild type (WT) and p75NTR-/- mice were subjected to I/R injury by increasing intra-ocular pressure to 120 mmHg for 45 min, followed by perfusion. Murine GFP-labeled MSCs (100,000 cells/eye) were injected intravitreally 2 days post-I/R and vascular homing was assessed 1 week later. Acellular capillaries were counted using trypsin digest 10-days post-I/R. In vitro, MSC-p75NTR was modulated either genetically using siRNA or pharmacologically using the p75NTR modulator; LM11A-31, and conditioned media were co-cultured with human retinal endothelial cells (HREs) to examine the angiogenic response. Finally, visual function in mice undergoing retinal I/R and receiving LM11A-31 was assessed by visual-clue water-maze test. I/R significantly increased the number of acellular capillaries (3.2-Fold) in WT retinas, which was partially ameliorated in p75NTR-/- retinas. GFP-MSCs were successfully incorporated and engrafted into retinal vasculature 1 week post injection and normalized the number of acellular capillaries in p75NTR-/- retinas, yet ischemic WT retinas maintained a 2-Fold increase. Silencing p75NTR on GFP-MSCs coincided with a higher number of cells homing to the ischemic WT retinal vasculature and normalized the number of acellular capillaries when compared to ischemic WT retinas receiving scrambled-GFP-MSCs. In vitro, silencing p75NTR-MSCs enhanced their secretome, as evidenced by significant increases in SDF-1, VEGF and NGF release in MSCs conditioned medium; improved paracrine angiogenic response in HREs, where HREs showed enhanced migration (1.4-Fold) and tube formation (2-Fold) compared to controls. In parallel, modulating MSCs-p75NTR using LM11A-31 resulted in a similar improvement in MSCs secretome and the enhanced paracrine angiogenic potential of HREs. Further, intervention with LM11A-31 significantly mitigated the decline in visual acuity post retinal I/R injury. In conclusion, p75NTR modulation can potentiate the therapeutic potential of MSCs to harness vascular repair in ischemic retinopathy diseases. Full article
(This article belongs to the Special Issue Therapeutic Modulation of Mesenchymal Stem Cells for Effective Regenerative Medicine)
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20 pages, 12292 KiB  
Article
Aging-Affected MSC Functions and Severity of Periodontal Tissue Destruction in a Ligature-Induced Mouse Periodontitis Model
by Kyaw Thu Aung, Kentaro Akiyama, Masayoshi Kunitomo, Aung Ye Mun, Ikue Tosa, Ha Thi Thu Nguyen, Jiewen Zhang, Teisaku Kohno, Mitsuaki Ono, Emilio Satoshi Hara and Takuo Kuboki
Int. J. Mol. Sci. 2020, 21(21), 8103; https://doi.org/10.3390/ijms21218103 - 30 Oct 2020
Cited by 23 | Viewed by 3866
Abstract
Mesenchymal stem cells (MSCs) are known to play important roles in the repair of lost or damaged tissues and immunotolerance. On the other hand, aging is known to impair MSC function. However, little is currently known about how aged MSCs affect the host [...] Read more.
Mesenchymal stem cells (MSCs) are known to play important roles in the repair of lost or damaged tissues and immunotolerance. On the other hand, aging is known to impair MSC function. However, little is currently known about how aged MSCs affect the host response to the local inflammatory condition and tissue deterioration in periodontitis, which is a progressive destructive disease of the periodontal tissue potentially leading to multiple tooth loss. In this study, we examined the relationship between aging-induced impairment of MSC function and the severity of periodontal tissue destruction associated with the decrease in host immunomodulatory response using a ligature-induced periodontitis model in young and aged mice. The results of micro computerized tomography (micro-CT) and histological analysis revealed a more severe bone loss associated with increased osteoclast activity in aged (50-week-old) mice compared to young (5-week-old) mice. Immunostaining analysis revealed that, in aged mice, the accumulation of inflammatory T and B cells was higher, whereas the percentage of platelet-derived growth factor receptor α (PDGFRα)+ MSCs, which are known to modulate the apoptosis of T cells, was significantly lower than in young mice. In vitro analysis of MSC function showed that the expression of surface antigen markers for MSCs (Sca-1, CD90, CD146), colony formation, migration, and osteogenic differentiation of aged MSCs were significantly declined compared to those of young MSCs. Moreover, a significantly higher proportion of aged MSCs were positive for the senescence-associated β galactosidase activity. Importantly, aged MSCs presented a decreased expression of FAS-L, which was associated with a lower immunomodulatory property of aged MSCs to induce T cell apoptosis in co-cultures compared with young MSCs. In summary, this is the first study showing that aging-induced impairment of MSC function, including immunomodulatory response, is potentially correlated with progressive periodontal tissue deterioration. Full article
(This article belongs to the Special Issue Therapeutic Modulation of Mesenchymal Stem Cells for Effective Regenerative Medicine)
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18 pages, 2758 KiB  
Article
Encapsulation of Adipose-Derived Mesenchymal Stem Cells in Calcium Alginate Maintains Clonogenicity and Enhances their Secretory Profile
by Lucille Capin, Nacira Abbassi, Maëlle Lachat, Marie Calteau, Cynthia Barratier, Ali Mojallal, Sandrine Bourgeois and Céline Auxenfans
Int. J. Mol. Sci. 2020, 21(17), 6316; https://doi.org/10.3390/ijms21176316 - 31 Aug 2020
Cited by 8 | Viewed by 3186
Abstract
Adipose-derived mesenchymal stem cells (ASCs) are well known for their secretory potential, which confers them useful properties in cell therapy. Nevertheless, this therapeutic potential is reduced after transplantation due to their short survival in the human body and their migration property. This study [...] Read more.
Adipose-derived mesenchymal stem cells (ASCs) are well known for their secretory potential, which confers them useful properties in cell therapy. Nevertheless, this therapeutic potential is reduced after transplantation due to their short survival in the human body and their migration property. This study proposes a method to protect cells during and after injection by encapsulation in microparticles of calcium alginate. Besides, the consequences of encapsulation on ASC proliferation, pluripotential, and secretome were studied. Spherical particles with a mean diameter of 500 µm could be obtained in a reproducible manner with a viability of 70% after 16 days in vitro. Moreover, encapsulation did not alter the proliferative properties of ASCs upon return to culture nor their differentiation potential in adipocytes, chondrocytes, and osteocytes. Concerning their secretome, encapsulated ASCs consistently produced greater amounts of interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) compared to monolayer cultures. Encapsulation therefore appears to enrich the secretome with transforming growth factor β1 (TGF-β1) and macrophage inflammatory protein-1β (MIP-1β) not detectable in monolayer cultures. Alginate microparticles seem sufficiently porous to allow diffusion of the cytokines of interest. With all these cytokines playing an important role in wound healing, it appears relevant to investigate the impact of using encapsulated ASCs on the wound healing process. Full article
(This article belongs to the Special Issue Therapeutic Modulation of Mesenchymal Stem Cells for Effective Regenerative Medicine)
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14 pages, 3286 KiB  
Article
HLA-G Expression in Human Mesenchymal Stem Cells (MSCs) Is Related to Unique Methylation Pattern in the Proximal Promoter as well as Gene Body DNA
by B. Linju Yen, Hsiao-Lin Hwa, Pei-Ju Hsu, Pei-Min Chen, Li-Tzu Wang, Shih-Sheng Jiang, Ko-Jiunn Liu, Huey-Kang Sytwu and Men-Luh Yen
Int. J. Mol. Sci. 2020, 21(14), 5075; https://doi.org/10.3390/ijms21145075 - 18 Jul 2020
Cited by 11 | Viewed by 2839
Abstract
Multipotent human mesenchymal stem cells (MSCs) harbor clinically relevant immunomodulation, and HLA-G, a non-classical MHC class I molecule with highly restricted tissue expression, is one important molecule involved in these processes. Understanding of the natural regulatory mechanisms involved in expression of this elusive [...] Read more.
Multipotent human mesenchymal stem cells (MSCs) harbor clinically relevant immunomodulation, and HLA-G, a non-classical MHC class I molecule with highly restricted tissue expression, is one important molecule involved in these processes. Understanding of the natural regulatory mechanisms involved in expression of this elusive molecule has been difficult, with near exclusive reliance on cancer cell lines. We therefore studied the transcriptional control of HLA-G in primary isolated human bone marrow- (BM), human embryonic stem cell-derived (hE-), as well as placenta-derived MSCs (P-MSCs), and found that all 3 types of MSCs express 3 of the 7 HLA-G isoforms at the gene level; however, fibroblasts did not express HLA-G. Protein validation using BM- and P-MSCs demonstrated expression of 2 isoforms including a larger HLA-G-like protein. Interferon-γ (IFN-γ) stimulation upregulated both gene and protein expression in MSCs but not the constitutively expressing JEG-3 cell line. Most interestingly in human MSCs and placental tissue, hypomethylation of CpG islands not only occurs on the HLA-G proximal promoter but also on the gene body as well, a pattern not seen in either of the 2 commonly used choriocarcinoma cell lines which may contribute to the unique HLA-G expression patterns and IFN-γ-responsiveness in MSCs. Our study implicates the importance of using normal cells and tissues for physiologic understanding of tissue-specific transcriptional regulation, and highlight the utility of human MSCs in unraveling the transcriptional regulation of HLA-G for better therapeutic application. Full article
(This article belongs to the Special Issue Therapeutic Modulation of Mesenchymal Stem Cells for Effective Regenerative Medicine)
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Review

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17 pages, 1140 KiB  
Review
Regulation of Limbal Epithelial Stem Cells: Importance of the Niche
by Sarah Y. T. Robertson, JoAnn S. Roberts and Sophie X. Deng
Int. J. Mol. Sci. 2021, 22(21), 11975; https://doi.org/10.3390/ijms222111975 - 5 Nov 2021
Cited by 17 | Viewed by 3143
Abstract
Limbal epithelial stem/progenitor cells (LSCs) reside in a niche that contains finely tuned balances of various signaling pathways including Wnt, Notch, BMP, Shh, YAP, and TGFβ. The activation or inhibition of these pathways is frequently dependent on the interactions of LSCs with various [...] Read more.
Limbal epithelial stem/progenitor cells (LSCs) reside in a niche that contains finely tuned balances of various signaling pathways including Wnt, Notch, BMP, Shh, YAP, and TGFβ. The activation or inhibition of these pathways is frequently dependent on the interactions of LSCs with various niche cell types and extracellular substrates. In addition to receiving molecular signals from growth factors, cytokines, and other soluble molecules, LSCs also respond to their surrounding physical structure via mechanotransduction, interaction with the ECM, and interactions with other cell types. Damage to LSCs or their niche leads to limbal stem cell deficiency (LSCD). The field of LSCD treatment would greatly benefit from an understanding of the molecular regulation of LSCs in vitro and in vivo. This review synthesizes current literature around the niche factors and signaling pathways that influence LSC function. Future development of LSCD therapies should consider all these niche factors to achieve improved long-term restoration of the LSC population. Full article
(This article belongs to the Special Issue Therapeutic Modulation of Mesenchymal Stem Cells for Effective Regenerative Medicine)
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13 pages, 554 KiB  
Review
The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging
by Jordan Marcano Anaya, Wendy B. Bollag, Mark W. Hamrick and Carlos M. Isales
Int. J. Mol. Sci. 2020, 21(18), 6670; https://doi.org/10.3390/ijms21186670 - 11 Sep 2020
Cited by 21 | Viewed by 3977
Abstract
Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for [...] Read more.
Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress. Full article
(This article belongs to the Special Issue Therapeutic Modulation of Mesenchymal Stem Cells for Effective Regenerative Medicine)
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