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Wei H, Liu Y, Huang C, Wang C, Jiang H, Wang L, Wang Y, Wang Z. Ginsenoside Rg1 targets TLR2 to inhibit the NF-κB signaling pathway and ameliorate hematopoietic support of mesenchymal stromal cells. JOURNAL OF ETHNOPHARMACOLOGY 2025; 349:119917. [PMID: 40348305 DOI: 10.1016/j.jep.2025.119917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/19/2025] [Accepted: 05/01/2025] [Indexed: 05/14/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ginsenoside Rg1 is a key bioactive compound in ginseng, a traditional herbal medicine known for tonifying qi and nourishing blood, traditionally used to replenish "qi" by regulating hematopoietic function. But its underlying mechanism remains to be elucidated. AIM OF THE STUDY This study aims to delve into the role of Rg1 on senescent hematopoiesis and its mechanisms. MATERIALS AND METHODS A model of D-galactose-induced hematopoietic injury was established with ginsenoside Rg1. The hematopoietic supportive effect of Rg1 was assessed by quantifying the levels of hematopoietic supportive factors VCAM1, CXCL12 and SCF, CFU-Mix formation and cellular senescence; and the levels of inflammatory factors and oxidative stress were measured by ELISA in the serum and cellular supernatant of mice. Co-culture technique was used to examine the ability of Rg1 to restore impaired hematopoiesis by improving the inflammatory hematopoietic microenvironment. For mechanism exploration, RNA-Seq was used to detect differential genes in Rg1-treated MSCs, GO- and KEGG-based enrichment analyses were used to screen the key pathways in which Rg1 exerts its effects, and molecular docking was used to demonstrate the feasibility of molecular interconnections between Rg1 and TLR2. To further explore the mechanism, pathway activators were further used and the expression levels of target proteins downstream of the TLR2 pathway were quantified using Western blotting. RESULTS Rg1 decreased the levels of inflammatory factors IL-1β, IL-6 and TNFα, while enhancing the expression of hematopoietic support factors in senescent MSCs, thereby improving the self-renewal and differentiation of aged HSPCs. Additionally, Rg1 also delayed HSPC senescence and reduced the level of oxidative stress. KEGG and GO were enriched for the Toll/NF-κB signaling pathway, based on differential genes obtained by transcriptional sequencing. Rg1 could inhibit the elevated levels of MyD88, NF-κB-p65 and IκBα proteins, and their phosphorylation levels by binding to TLR2 protein and inhibiting them. In conclusion, Rg1 ameliorates the inflammatory hematopoietic microenvironment induced by MSCs senescence via the TLR2/NF-κB-p65 signaling pathway, alleviating HSPCs senescence. CONCLUSIONS Our results reveal the mechanism by which Rg1 regulates HSPCs function and represent a potential therapeutic strategy for hematopoietic dysfunction, highlighting the potential value of traditional Chinese medicine extracts in clinical applications.
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Affiliation(s)
- Han Wei
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Yonggang Liu
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Caihong Huang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Cheng Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Honghui Jiang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Lu Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Yaping Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China.
| | - Ziling Wang
- Department of Pathology, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, PR China.
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Riazuelo L, Planat-Bénard V, Vinel A, Laurencin S, Casteilla L, Kémoun P, Marty M, Monsarrat P. Acceptability of Allogeneic Mesenchymal Stromal Cell-Based Tissue Engineering for the Treatment of Periodontitis: A Qualitative Study in France. Int Dent J 2025; 75:840-848. [PMID: 39245621 PMCID: PMC11976543 DOI: 10.1016/j.identj.2024.07.1208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/15/2024] [Accepted: 07/20/2024] [Indexed: 09/10/2024] Open
Abstract
INTRODUCTION AND AIMS Periodontitis, the main cause of tooth loss in adults, is a public health concern; its incidence increases with age, and its prevalence increases with increasing life expectancy of the population. Innovative therapies such as cell therapy represent promising future solutions for guided tissue regeneration. However, these therapies may be associated with fears and mistrust from the general public. The aim of this study was to estimate the acceptability of an advanced therapy medicinal product combining allogeneic mesenchymal stromal cells from adipose tissue with a natural fibrin hydrogel in the treatment of periodontitis. METHODS The methodology was based on a qualitative study conducted through semi-structured interviews with patients followed for periodontitis in the Oral Medicine Department of the Toulouse University Hospital, Toulouse, France. Qualitative studies are essential methodologies to understand the patterns of health behaviours, describe illness experiences, and design health interventions in a humanistic and person-centred way of discovering. RESULTS Eleven interviews (with 4 men and 7 women) were required to reach thematic saturation. Analysis allowed 4 main themes to emerge: (1) perception of new treatments, science, and caregivers; (2) conditions that the treatment must meet; (3) patient perception of the disease; and (4) factors related to the content of the treatment. CONCLUSIONS Patients find cell therapy for periodontitis to be acceptable. If they express a need to be informed about the benefit/risk ratio, they are not particularly worried about side effects of the treatment, for either allogeneic or blood-derived products. Periodontitis is a prototypical model of chronic inflammatory pathology and is multitissular, with hard- and soft-tissue lesions. In a patient-centred approach, the success of cell therapy will require a bilateral, informed decision, taking into account potential therapeutic effectiveness and patient expectations for regeneration.
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Affiliation(s)
- Lucas Riazuelo
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France
| | - Valérie Planat-Bénard
- RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Alexia Vinel
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; I2MC, INSERM UMR 1297, University of Toulouse III, Toulouse, France
| | - Sara Laurencin
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; Center for Epidemiology and Research in POPulation Health (CERPOP), UMR 1295, Paul Sabatier University, Toulouse, France
| | - Louis Casteilla
- RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Philippe Kémoun
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Mathieu Marty
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; LIRDEF, Faculty of Educational Sciences, Paul Valery University, Montpellier, France
| | - Paul Monsarrat
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France; Artificial and Natural Intelligence Toulouse Institute ANITI, Toulouse, France.
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Hu M, Liu R, Chen X, Yan S, Gao J, Zhang Y, Wu D, Sun L, Jia Z, Sun G, Liu D. Metabolomics Dysfunction in Replicative Senescence of Periodontal Ligament Stem Cells Regulated by AMPK Signaling Pathway. Stem Cells Dev 2024; 33:607-615. [PMID: 39302052 DOI: 10.1089/scd.2024.0112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2024] Open
Abstract
Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for stem cell-based regenerative medicine in dentistry, but they inevitably acquire a senescent phenotype after prolonged in vitro expansion. The key regulators of PDLSCs during replicative senescence remain unclear. Here, we sought to elucidate the role of metabolomic changes in determining the cellular senescence of PDLSCs. PDLSCs were cultured to passages 4, 10, and 20. The senescent phenotypes of PDLSCs were detected, and metabolomics analysis was performed. We found that PDLSCs manifested senescence phenotype during passaging. Metabolomics analysis showed that the metabolism of replicative senescence in PDLSCs varied significantly. The AMP-activated protein kinase (AMPK) signaling pathway was closely related to adenosine monophosphate (AMP) levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK, FOXO1 and FOXO3a decreased with senescence. We treated PDLSCs with an activator of the AMPK pathway (AICAR) and observed that the phosphorylated AMPK level at P20 PDLSCs was partially restored. These data delineate that the metabolic process of PDLSCs is active in the early stage of senescence and attenuated in the later stages of senescence; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism.
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Affiliation(s)
- Meilin Hu
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
| | - Ruiqi Liu
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
| | - Xiaoyu Chen
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
| | - Shen Yan
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
| | - Jian Gao
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
| | - Yao Zhang
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
| | - Di Wu
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Lu Sun
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
| | - Zhi Jia
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
| | - Guangyunhao Sun
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
| | - Dayong Liu
- Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, China
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Košuthová H, Fecskeová LK, Matejová J, Slovinská L, Morávek M, Bártová Z, Harvanová D. Effects of Replicative Senescence of Human Chorionic MSCs on their EV-miRNA Profile. Stem Cell Rev Rep 2024; 20:2318-2335. [PMID: 39305404 PMCID: PMC11554840 DOI: 10.1007/s12015-024-10790-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2024] [Indexed: 11/12/2024]
Abstract
Chorionic mesenchymal stromal cells (CHO-MSCs) and their extracellular vesicles (EVs) are becoming increasingly popular, since chorion is ethically harmless and an easily accessible source of MSCs. However, until now there is only a limited number of studies with a thorough characterization of CHO-MSCs derived EVs and their miRNA profile. In this study, we monitored changes in the EV-miRNA profile between early and late passage of human CHO-MSCs. First, senescence of CHO-MSCs was induced by serial passaging and confirmed by morphological changes, shortened telomeres and changes in the expression of selected genes. The expression of MSCs-specific surface markers CD73, CD90, CD105 did not change with increasing passages. Next, EVs and their miRNA profiles were compared between early vs late passage cells. Number of EVs and their size were not significantly changed. Seven of the top 10 most expressed EV-miRNAs were common to both early and late passages. A differential expression study between early and late passages identified 37 significantly differentially expressed EV-miRNAs, out of which 23 were found to be associated with pathways of cellular senescence based on KEGG pathway analysis. A set of 9 miRNAs were identified as the most frequently associated with senescence and/or with the most altered expression between early and late passages, out of which miR-145-5p, miR-335-5p and miR-199b-3p were the most significant downregulated miRNAs in late passages. The most upregulated EV-miRNAs were miR-1307-3p, miR-3615 and miR320b. Targeting these miRNAs in future experiments may prolong the therapeutic potential of CHO-MSCs and their EVs.
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Affiliation(s)
- Hedviga Košuthová
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
| | - Lívia K Fecskeová
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia.
| | - Jana Matejová
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
| | - Lucia Slovinská
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
| | - Marko Morávek
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
| | - Zuzana Bártová
- Institute of Geotechnics of the Slovak Academy of Sciences, Watsonova 45, 040 01, Kosice, Slovakia
| | - Denisa Harvanová
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
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Zhang H, Jin C, Hua J, Chen Z, Gao W, Xu W, Zhou L, Shan L. Roles of Microenvironment on Mesenchymal Stem Cells Therapy for Osteoarthritis. J Inflamm Res 2024; 17:7069-7079. [PMID: 39377043 PMCID: PMC11457791 DOI: 10.2147/jir.s475617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 09/21/2024] [Indexed: 10/09/2024] Open
Abstract
Osteoarthritis (OA) induced microenvironmental alterations are a common and unavoidable phenomenon that greatly exacerbate the pathologic process of OA. Imbalances in the synthesis and degradation of cartilage extracellular matrix (ECM) have been reported to be associated with an adverse microenvironment. Stem cell therapy is a promising treatment for OA, and mesenchymal stem cells (MSCs) are the main cell sources for this therapy. With multispectral differentiation and immunomodulation, MSCs can effectively regulate the microenvironment of articular cartilage, ameliorate inflammation, promote regeneration of damaged cartilage, and ultimately alleviate OA symptoms. However, the efficacy of MSCs in the treatment of OA is greatly influenced by articular cavity microenvironments. This article reviews the five microenvironments of OA articular cavity, including inflammatory microenvironment, senescence microenvironment, hypoxic microenvironment, high glucose microenvironment and high lipid environment, focus on the positive and negative effects of OA microenvironments on the fate of MSCs. In this regard, we emphasize the mechanisms of the current use of MSCs in OA treatment, as well as its limitations and challenges.
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Affiliation(s)
- Haiyan Zhang
- The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chaoying Jin
- School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Jiaqing Hua
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Zuxiang Chen
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Wenxin Gao
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Wenting Xu
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Li Zhou
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Letian Shan
- The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
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Shan Y, Zhang M, Tao E, Wang J, Wei N, Lu Y, Liu Q, Hao K, Zhou F, Wang G. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther 2024; 9:242. [PMID: 39271680 PMCID: PMC11399464 DOI: 10.1038/s41392-024-01936-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/04/2024] [Accepted: 07/23/2024] [Indexed: 09/15/2024] Open
Abstract
Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.
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Affiliation(s)
- Yunlong Shan
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Mengying Zhang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Enxiang Tao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jing Wang
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Ning Wei
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Yi Lu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qing Liu
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Kun Hao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Fang Zhou
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
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Aghazadeh S, Peng Q, Dardmeh F, Hjortdal JØ, Zachar V, Alipour H. Immunophenotypical Characterization of Limbal Mesenchymal Stromal Cell Subsets during In Vitro Expansion. Int J Mol Sci 2024; 25:8684. [PMID: 39201371 PMCID: PMC11354999 DOI: 10.3390/ijms25168684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Limbal mesenchymal stromal cells (LMSCs) reside in the limbal niche, supporting corneal integrity and facilitating regeneration. While mesenchymal stem/stromal cells (MSCs) are used in regenerative therapies, there is limited knowledge about LMSC subpopulations and their characteristics. This study characterized human LMSC subpopulations through the flow cytometric assessment of fifteen cell surface markers, including MSC, wound healing, immune regulation, ASC, endothelial, and differentiation markers. Primary LMSCs were established from remnant human corneal transplant specimens and passaged eight times to observe changes during subculture. The results showed the consistent expression of typical MSC markers and distinct subpopulations with the passage-dependent expression of wound healing, immune regulation, and differentiation markers. High CD166 and CD248 expressions indicated a crucial role in ocular surface repair. CD29 expression suggested an immunoregulatory role. Comparable pigment-epithelial-derived factor (PEDF) expression supported anti-inflammatory and anti-angiogenic roles. Sustained CD201 expression indicated maintained differentiation capability, while VEGFR2 expression suggested potential endothelial differentiation. LMSCs showed higher VEGF expression than fibroblasts and endothelial cells, suggesting a potential contribution to ocular surface regeneration through the modulation of angiogenesis and inflammation. These findings highlight the heterogeneity and multipotent potential of LMSC subpopulations during in vitro expansion, informing the development of standardized protocols for regenerative therapies and improving treatments for ocular surface disorders.
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Affiliation(s)
- Sara Aghazadeh
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
| | - Qiuyue Peng
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
| | - Fereshteh Dardmeh
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
| | | | - Vladimir Zachar
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
| | - Hiva Alipour
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
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Surowiecka A, Korzeniowski T, Korulczyk P, Budzyńska J, Leśniewska M, Kozioł I, Górecka Z, Łączyk M, Wilhelm G, Staśkiewicz M, Torres K, Strużyna J. The correlation of BMI and insulin resistance in moderately burned patients. POLISH JOURNAL OF SURGERY 2024; 96:39-46. [PMID: 39635748 DOI: 10.5604/01.3001.0054.6748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
<b>Introduction:</b> Obesity is strongly related to serious comorbidities that might affect the healing process. Elevated Body Mass Index (BMI) and insulin resistance have a significant impact on the development of the metabolic syndrome often leading to lethal cardiovascular complications.<b>Aim:</b> The aim of the study was to verify the correlation of BMI and insulin resistance with clinical parameters of moderately burned patients.<b>Materials and methods:</b> There were 149 patients enrolled in the study and their clinical data was retrospectively analyzed. The laboratory tests, insulin demand, BMI, and surgical procedures were evaluated on admission and discharge.<b>Results:</b> Burned patients who required insulin were characterized by worse laboratory results on admission to the burn unit, they had lower hemoglobin (HGB) levels (P = 0.0001), higher creatinine levels by 0.323 units (P = 0.009), higher C-reactive protein (CRP) by approximately 94 units (P = 0.0001), as higher procalcitonin (PCT) by approximately 0.5 units (P = 0.001) as compared to non-insulin-treated patients. Moreover, burned patients who required insulin stayed in the hospital for an average of 10 days longer. All patients from the insulin-demand subgroup had elevated triglycerides (Tg) levels on admission with increased indexes of insulin resistance.<b>Discussion:</b> Our study suggests that the protective effect of a higher BMI in burned patients, known as the 'obesity paradox' may be compromised by insulin resistance.<b>Conclusions and significance of the study:</b> The results show that elevated Tg on admission to the burn unit coexisting with a BMI over 25 kg/m<sup>2</sup> may be used as an important prognostic factor and may help with prediction of insulin demand and worse outcome in moderately burned patients.
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Affiliation(s)
- Agnieszka Surowiecka
- East Center of Burns Treatment and Reconstructive Surgery, Medical University of Lublin, Leczna, Poland, Chair and Department of Didactics and Medical Simulation, Medical University of Lublin, Poland, Department of Plastic and Reconstructive Surgery and Microsurgery, Medical University of Lublin, Poland
| | - Tomasz Korzeniowski
- East Center of Burns Treatment and Reconstructive Surgery, Medical University of Lublin, Leczna, Poland, Department of Plastic Surgery, Reconstructive Surgery and Burn Treatment, Medical University of Lublin, Polish Students' Scientific Association of Medical Simulation, Poland
| | - Patrycja Korulczyk
- Chair and Department of Didactics and Medical Simulation, Medical University of Lublin, Poland
| | - Julia Budzyńska
- Department of Didactics and Medical Simulation, Medical University of Lublin, Poland
| | - Magdalena Leśniewska
- Department of Didactics and Medical Simulation, Medical University of Lublin, Poland
| | - Ilona Kozioł
- Department of Didactics and Medical Simulation, Medical University of Lublin, Poland
| | - Zofia Górecka
- East Center of Burns Treatment and Reconstructive Surgery, Medical University of Lublin, Leczna, Poland
| | - Maciej Łączyk
- East Center of Burns Treatment and Reconstructive Surgery, Medical University of Lublin, Leczna, Poland
| | - Grzegorz Wilhelm
- Department of Plastic and Reconstructive Surgery and Microsurgery, Medical University of Lublin, Poland
| | | | - Kamil Torres
- Chair and Department of Didactics and Medical Simulation, Medical University of Lublin, Poland, Department of Plastic and Reconstructive Surgery and Microsurgery, Medical University of Lublin, Poland
| | - Jerzy Strużyna
- East Center of Burns Treatment and Reconstructive Surgery, Medical University of Lublin, Leczna, Poland, Department of Plastic Surgery, Reconstructive Surgery and Burn Treatment, Medical University of Lublin, Polish Students' Scientific Association of Medical Simulation, Poland
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Park JM, Rahmati M, Lee SC, Shin JI, Kim YW. Effects of mesenchymal stem cell on dopaminergic neurons, motor and memory functions in animal models of Parkinson's disease: a systematic review and meta-analysis. Neural Regen Res 2024; 19:1584-1592. [PMID: 38051903 PMCID: PMC10883506 DOI: 10.4103/1673-5374.387976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 10/09/2023] [Indexed: 12/07/2023] Open
Abstract
ABSTRACT Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and although restoring striatal dopamine levels may improve symptoms, no treatment can cure or reverse the disease itself. Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson's disease. Mesenchymal stem cells are considered a promising option due to fewer ethical concerns, a lower risk of immune rejection, and a lower risk of teratogenicity. We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function, memory, and preservation of dopaminergic neurons in a Parkinson's disease animal model. We searched bibliographic databases (PubMed/MEDLINE, Embase, CENTRAL, Scopus, and Web of Science) to identify articles and included only peer-reviewed in vivo interventional animal studies published in any language through June 28, 2023. The study utilized the random-effect model to estimate the 95% confidence intervals (CI) of the standard mean differences (SMD) between the treatment and control groups. We use the systematic review center for laboratory animal experimentation's risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment. A total of 33 studies with data from 840 Parkinson's disease model animals were included in the meta-analysis. Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test. Among the stem cell types, the bone marrow MSCs with neurotrophic factor group showed largest effect size (SMD [95% CI] = -6.21 [-9.50 to -2.93], P = 0.0001, I2 = 0.0 %). The stem cell treatment group had significantly more tyrosine hydroxylase positive dopaminergic neurons in the striatum ([95% CI] = 1.04 [0.59 to 1.49], P = 0.0001, I2 = 65.1 %) and substantia nigra (SMD [95% CI] = 1.38 [0.89 to 1.87], P = 0.0001, I2 = 75.3 %), indicating a protective effect on dopaminergic neurons. Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route (SMD [95% CI] = -2.59 [-3.25 to -1.94], P = 0.0001, I2 = 74.4 %). The memory test showed significant improvement only in the intravenous route (SMD [95% CI] = 4.80 [1.84 to 7.76], P = 0.027, I2 = 79.6 %). Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson's disease. Further research is required to determine the optimal stem cell types, modifications, transplanted cell numbers, and delivery methods for these protocols.
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Affiliation(s)
- Jong Mi Park
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Masoud Rahmati
- Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khoramabad, Iran
| | - Sang Chul Lee
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, South Korea
| | - Yong Wook Kim
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, South Korea
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10
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Massidda MW, Demkov A, Sices A, Lee M, Lee J, Paull TT, Kim J, Baker AB. Mechanical Rejuvenation of Mesenchymal Stem Cells from Aged Patients. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.06.597781. [PMID: 38895474 PMCID: PMC11185588 DOI: 10.1101/2024.06.06.597781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Mesenchymal stem cells (MSC) are an appealing therapeutic cell type for many diseases. However, patients with poor health or advanced age often have MSCs with poor regenerative properties. A major limiter of MSC therapies is cellular senescence, which is marked by limited proliferation capability, diminished multipotency, and reduced regenerative properties. In this work, we explored the ability of applied mechanical forces to reduce cellular senescence in MSCs. Our studies revealed that mechanical conditioning caused a lasting enhancement in proliferation, overall cell culture expansion potential, multipotency, and a reduction of senescence in MSCs from aged donors. Mechanistic studies suggested that these functional enhancements were mediated by oxidative stress and DNA damage repair signaling with mechanical load altering the expression of proteins of the sirtuin pathway, the DNA damage repair protein ATM, and antioxidant proteins. In addition, our results suggest a biophysical mechanism in which mechanical stretch leads to improved recognition of damaged DNA in the nucleus. Analysis of the cells through RNA-seq and ATAC-seq, demonstrated that mechanical loading alters the cell's genetic landscape to cause broad shifts in transcriptomic patterns that related to senescence. Overall, our results demonstrate that mechanical conditioning can rejuvenate mesenchymal stem cells derived from aged patients and improve their potential as a therapeutic cell type. GRAPHICAL ABSTRACT
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11
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Boulestreau J, Maumus M, Bertolino GM, Toupet K, Jorgensen C, Noël D. Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis. J Nanobiotechnology 2024; 22:255. [PMID: 38755672 PMCID: PMC11097483 DOI: 10.1186/s12951-024-02509-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/29/2024] [Indexed: 05/18/2024] Open
Abstract
Age is the most important risk factor in degenerative diseases such as osteoarthritis (OA), which is associated with the accumulation of senescent cells in the joints. Here, we aimed to assess the impact of senescence on the therapeutic properties of extracellular vesicles (EVs) from human fat mesenchymal stromal cells (ASCs) in OA. We generated a model of DNA damage-induced senescence in ASCs using etoposide and characterized EVs isolated from their conditioned medium (CM). Senescent ASCs (S-ASCs) produced 3-fold more EVs (S-EVs) with a slightly bigger size and that contain 2-fold less total RNA. Coculture experiments showed that S-ASCs were as efficient as healthy ASCs (H-ASCs) in improving the phenotype of OA chondrocytes cultured in resting conditions but were defective when chondrocytes were proliferating. S-EVs were also impaired in their capacity to polarize synovial macrophages towards an anti-inflammatory phenotype. A differential protein cargo mainly related to inflammation and senescence was detected in S-EVs and H-EVs. Using the collagenase-induced OA model, we found that contrary to H-EVs, S-EVs could not protect mice from cartilage damage and joint calcifications, and were less efficient in protecting subchondral bone degradation. In addition, S-EVs induced a pro-catabolic and pro-inflammatory gene signature in the joints of mice shortly after injection, while H-EVs decreased hypertrophic, catabolic and inflammatory pathways. In conclusion, S-EVs are functionally impaired and cannot protect mice from developing OA.
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Affiliation(s)
- Jérémy Boulestreau
- IRMB, University of Montpellier, INSERM U1183, Hôpital Saint-Eloi, 80 Avenue Augustin Fliche, Montpellier Cedex 5, 34295, France
| | - Marie Maumus
- IRMB, University of Montpellier, INSERM U1183, Hôpital Saint-Eloi, 80 Avenue Augustin Fliche, Montpellier Cedex 5, 34295, France
| | - Giuliana M Bertolino
- IRMB, University of Montpellier, INSERM U1183, Hôpital Saint-Eloi, 80 Avenue Augustin Fliche, Montpellier Cedex 5, 34295, France
| | - Karine Toupet
- IRMB, University of Montpellier, INSERM U1183, Hôpital Saint-Eloi, 80 Avenue Augustin Fliche, Montpellier Cedex 5, 34295, France
| | - Christian Jorgensen
- IRMB, University of Montpellier, INSERM U1183, Hôpital Saint-Eloi, 80 Avenue Augustin Fliche, Montpellier Cedex 5, 34295, France
- Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU Montpellier, Montpellier, France
| | - Daniéle Noël
- IRMB, University of Montpellier, INSERM U1183, Hôpital Saint-Eloi, 80 Avenue Augustin Fliche, Montpellier Cedex 5, 34295, France.
- Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU Montpellier, Montpellier, France.
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12
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Krishnan I, Chan AML, Law JX, Ng MH, Jayapalan JJ, Lokanathan Y. Proteomic Analysis of Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review. Int J Mol Sci 2024; 25:5340. [PMID: 38791378 PMCID: PMC11121203 DOI: 10.3390/ijms25105340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/29/2024] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
Numerous challenges remain within conventional cell-based therapy despite the growing trend of stem cells used to treat various life-debilitating diseases. These limitations include batch-to-batch heterogeneity, induced alloreactivity, cell survival and integration, poor scalability, and high cost of treatment, thus hindering successful translation from lab to bedside. However, recent pioneering technology has enabled the isolation and enrichment of small extracellular vesicles (EVs), canonically known as exosomes. EVs are described as a membrane-enclosed cargo of functional biomolecules not limited to lipids, nucleic acid, and proteins. Interestingly, studies have correlated the biological role of MSC-EVs to the paracrine activity of MSCs. This key evidence has led to rigorous studies on MSC-EVs as an acellular alternative. Using EVs as a therapy was proposed as a model leading to improvements through increased safety; enhanced bioavailability due to size and permeability; reduced heterogeneity by selective and quantifiable properties; and prolonged shelf-life via long-term freezing or lyophilization. Yet, the identity and potency of EVs are still relatively unknown due to various methods of preparation and to qualify the final product. This is reflected by the absence of regulatory strategies overseeing manufacturing, quality control, clinical implementation, and product registration. In this review, the authors review the various production processes and the proteomic profile of MSC-EVs.
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Affiliation(s)
- Illayaraja Krishnan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Alvin Man Lung Chan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Min Hwei Ng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | | | - Yogeswaran Lokanathan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
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13
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Zhang S, Lee Y, Liu Y, Yu Y, Han I. Stem Cell and Regenerative Therapies for the Treatment of Osteoporotic Vertebral Compression Fractures. Int J Mol Sci 2024; 25:4979. [PMID: 38732198 PMCID: PMC11084822 DOI: 10.3390/ijms25094979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 04/28/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
Osteoporotic vertebral compression fractures (OVCFs) significantly increase morbidity and mortality, presenting a formidable challenge in healthcare. Traditional interventions such as vertebroplasty and kyphoplasty, despite their widespread use, are limited in addressing the secondary effects of vertebral fractures in adjacent areas and do not facilitate bone regeneration. This review paper explores the emerging domain of regenerative therapies, spotlighting stem cell therapy's transformative potential in OVCF treatment. It thoroughly describes the therapeutic possibilities and mechanisms of action of mesenchymal stem cells against OVCFs, relying on recent clinical trials and preclinical studies for efficacy assessment. Our findings reveal that stem cell therapy, particularly in combination with scaffolding materials, holds substantial promise for bone regeneration, spinal stability improvement, and pain mitigation. This integration of stem cell-based methods with conventional treatments may herald a new era in OVCF management, potentially improving patient outcomes. This review advocates for accelerated research and collaborative efforts to translate laboratory breakthroughs into clinical practice, emphasizing the revolutionary impact of regenerative therapies on OVCF management. In summary, this paper positions stem cell therapy at the forefront of innovation for OVCF treatment, stressing the importance of ongoing research and cross-disciplinary collaboration to unlock its full clinical potential.
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Affiliation(s)
- Songzi Zhang
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (S.Z.); (Y.L.); (Y.Y.)
| | - Yunhwan Lee
- Department of Medicine, School of Medicine, CHA University, Seongnam-si 13496, Republic of Korea;
| | - Yanting Liu
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (S.Z.); (Y.L.); (Y.Y.)
| | - Yerin Yu
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (S.Z.); (Y.L.); (Y.Y.)
| | - Inbo Han
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (S.Z.); (Y.L.); (Y.Y.)
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14
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Asgari R, Mehran YZ, Weber HM, Weber M, Golestanha SA, Hosseini Kazerouni SM, Panahi F, Mohammadi P, Mansouri K. Management of oxidative stress for cell therapy through combinational approaches of stem cells, antioxidants, and photobiomodulation. Eur J Pharm Sci 2024; 196:106715. [PMID: 38301971 DOI: 10.1016/j.ejps.2024.106715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 01/05/2024] [Accepted: 01/29/2024] [Indexed: 02/03/2024]
Abstract
Over the recent decades, stem cell-based therapies have been considered as a beneficial approach for the treatment of various diseases. In these types of therapies, the stem cells and their products are used as treating agents. Despite the helpful efficacy of stem cell-based therapies, there may be challenges. Oxidative stress (OS) is one of these challenges that can affect the therapeutic properties of stem cells. Therefore, it seems that employing strategies for the reduction of OS in combination with stem cell therapy can lead to better results of these therapies. Based on the available evidence, antioxidant therapy and photobiomodulation (PBM) are strategies that can regulate the OS in the cells. Antioxidant therapy is a method in which various antioxidants are used in the therapeutic processes. PBM is also the clinical application of light that gained importance in medicine. Antioxidants and PBM can regulate OS by the effect on mitochondria as an important source of OS in the cells. Considering the importance of OS in pathologic pathways and its effect on the treatment outcomes of stem cells, in the present review first the stem cell therapy and effects of OS on this type of therapy are summarized. Then, antioxidant therapy and PBM as approaches for reducing OS with a focus on mitochondrial function are discussed. Also, a novel combination treatment with the hope of achieving better and more stable outcomes in the treatment process of diseases is proposed.
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Affiliation(s)
- Rezvan Asgari
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Yasaman Zandi Mehran
- Department of Biomedical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Hans Michael Weber
- International Society of Medical Laser Applications, Lauenfoerde, Germany
| | | | | | | | - Farzad Panahi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Pantea Mohammadi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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15
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Zhang X, Kuang Q, Xu J, Lin Q, Chi H, Yu D. MSC-Based Cell Therapy in Neurological Diseases: A Concise Review of the Literature in Pre-Clinical and Clinical Research. Biomolecules 2024; 14:538. [PMID: 38785945 PMCID: PMC11117494 DOI: 10.3390/biom14050538] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to self-renew and multi-directional differentiation potential. Exogenously administered MSCs can migrate to damaged tissue sites and participate in the repair of damaged tissues. A large number of pre-clinical studies and clinical trials have demonstrated that MSCs have the potential to treat the abnormalities of congenital nervous system and neurodegenerative diseases. Therefore, MSCs hold great promise in the treatment of neurological diseases. Here, we summarize and highlight current progress in the understanding of the underlying mechanisms and strategies of MSC application in neurological diseases.
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Affiliation(s)
- Xiaorui Zhang
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Qihong Kuang
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Jianguang Xu
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Qing Lin
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Haoming Chi
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Daojin Yu
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
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16
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Norte-Muñoz M, García-Bernal D, García-Ayuso D, Vidal-Sanz M, Agudo-Barriuso M. Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina. Neural Regen Res 2024; 19:542-547. [PMID: 37721282 PMCID: PMC10581591 DOI: 10.4103/1673-5374.380876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/25/2023] [Accepted: 05/11/2023] [Indexed: 09/19/2023] Open
Abstract
Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models. Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration, namely trophic factor deprivation and neuroinflammation. Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement. However, little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system. Here, we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system, focusing on recent work in the retina and the importance of the type of transplantation.
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Affiliation(s)
- María Norte-Muñoz
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - David García-Bernal
- Grupo de Investigación Trasplante Hematopoyético y Terapia celular, Departamento de Bioquímica e Inmunología. Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Diego García-Ayuso
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Manuel Vidal-Sanz
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Marta Agudo-Barriuso
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
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17
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Escarrer-Garau G, Martín-Medina A, Truyols-Vives J, Gómez-Bellvert C, Elowsson L, Westergren-Thorsson G, Molina-Molina M, Mercader-Barceló J, Sala-Llinàs E. In Vivo and In Vitro Pro-Fibrotic Response of Lung-Resident Mesenchymal Stem Cells from Patients with Idiopathic Pulmonary Fibrosis. Cells 2024; 13:160. [PMID: 38247851 PMCID: PMC10814068 DOI: 10.3390/cells13020160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
Lung-resident mesenchymal stem cells (LR-MSC) are thought to participate in idiopathic pulmonary fibrosis (IPF) by differentiating into myofibroblasts. On the other hand, LR-MSC in IPF patients present senescence-related features. It is unclear how they respond to a profibrotic environment. Here, we investigated the profibrotic response of LR-MSC isolated from IPF and control (CON) patients. LR-MSC were inoculated in mice 48 h after bleomycin (BLM) instillation to analyze their contribution to lung damage. In vitro, LR-MSC were exposed to TGFβ. Mice inoculated with IPF LR-MSC exhibited worse maintenance of their body weight. The instillation of either IPF or CON LR-MSC sustained BLM-induced histological lung damage, bronchoalveolar lavage fluid cell count, and the expression of the myofibroblast marker, extracellular matrix (ECM) proteins, and proinflammatory cytokines in the lungs. In vitro, IPF LR-MSC displayed higher basal protein levels of aSMA and fibronectin than CON LR-MSC. However, the TGFβ response in the expression of TGFβ, aSMA, and ECM genes was attenuated in IPF LR-MSC. In conclusion, IPF LR-MSC have acquired myofibroblastic features, but their capacity to further respond to profibrotic stimuli seems to be attenuated. In an advanced stage of the disease, LR-MSC may participate in disease progression owing to their limited ability to repair epithelial damage.
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Affiliation(s)
| | - Aina Martín-Medina
- iRESPIRE Research Group, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain
| | - Joan Truyols-Vives
- MolONE Research Group, University of the Balearic Islands (UIB), 07122 Palma, Spain
| | | | - Linda Elowsson
- Lung Biology, Department of Experimental Medical Science, Lund University, 08908 Lund, Sweden
| | | | - Maria Molina-Molina
- ILD Unit, Respiratory Department, University Hospital of Bellvitge-Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain
- Centre of Biomedical Research Network in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - Josep Mercader-Barceló
- MolONE Research Group, University of the Balearic Islands (UIB), 07122 Palma, Spain
- iRESPIRE Research Group, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain
- Centre of Biomedical Research Network in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - Ernest Sala-Llinàs
- iRESPIRE Research Group, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain
- Centre of Biomedical Research Network in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
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18
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Soria B, Escacena N, Gonzaga A, Soria-Juan B, Andreu E, Hmadcha A, Gutierrez-Vilchez AM, Cahuana G, Tejedo JR, De la Cuesta A, Miralles M, García-Gómez S, Hernández-Blasco L. Cell Therapy of Vascular and Neuropathic Complications of Diabetes: Can We Avoid Limb Amputation? Int J Mol Sci 2023; 24:17512. [PMID: 38139339 PMCID: PMC10743405 DOI: 10.3390/ijms242417512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/07/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023] Open
Abstract
Globally, a leg is amputated approximately every 30 seconds, with an estimated 85 percent of these amputations being attributed to complications arising from diabetic foot ulcers (DFU), as stated by the American Diabetes Association. Peripheral arterial disease (PAD) is a risk factor resulting in DFU and can, either independently or in conjunction with diabetes, lead to recurring, slow-healing ulcers and amputations. According to guidelines amputation is the recommended treatment for patients with no-option critical ischemia of the limb (CTLI). In this article we propose cell therapy as an alternative strategy for those patients. We also suggest the optimal time-frame for an effective therapy, such as implanting autologous mononuclear cells (MNCs), autologous and allogeneic mesenchymal stromal cells (MSC) as these treatments induce neuropathy relief, regeneration of the blood vessels and tissues, with accelerated ulcer healing, with no serious side effects, proving that advanced therapy medicinal product (ATMPs) application is safe and effective and, hence, can significantly prevent limb amputation.
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Affiliation(s)
- Bernat Soria
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
- CIBERDEM Network Research Center for Diabetes and Associated Metabolic Diseases, Carlos III Health Institute, 28029 Madrid, Spain
| | - Natalia Escacena
- Fresci Consultants, Human Health Innovation, 08025 Barcelona, Spain
| | - Aitor Gonzaga
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
| | - Barbara Soria-Juan
- Reseaux Hôpitalieres Neuchatelois et du Jura, 2000 Neuchâtel, Switzerland
| | - Etelvina Andreu
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Department of Applied Physics, University Miguel Hernández Elche, 03202 Elche, Spain
| | - Abdelkrim Hmadcha
- Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), 46002 Valencia, Spain
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | - Ana Maria Gutierrez-Vilchez
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
- Department of Pharmacology, Pediatrics and Organic Chemistry, University Miguel Hernández, 03202 Elche, Spain
| | - Gladys Cahuana
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | - Juan R. Tejedo
- CIBERDEM Network Research Center for Diabetes and Associated Metabolic Diseases, Carlos III Health Institute, 28029 Madrid, Spain
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | | | - Manuel Miralles
- University and Polytechnic Hospital La Fe, 46026 Valencia, Spain
| | | | - Luis Hernández-Blasco
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
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19
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Zheng L, Gong H, Zhang J, Guo L, Zhai Z, Xia S, Hu Z, Chang J, Jiang Y, Huang X, Ge J, Zhang B, Yan M. Strategies to improve the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease. Front Bioeng Biotechnol 2023; 11:1322514. [PMID: 38155924 PMCID: PMC10753838 DOI: 10.3389/fbioe.2023.1322514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/29/2023] [Indexed: 12/30/2023] Open
Abstract
Liver disease has emerged as a significant worldwide health challenge due to its diverse causative factors and therapeutic complexities. The majority of liver diseases ultimately progress to end-stage liver disease and liver transplantation remains the only effective therapy with the limitations of donor organ shortage, lifelong immunosuppressants and expensive treatment costs. Numerous pre-clinical studies have revealed that extracellular vesicles released by mesenchymal stem cells (MSC-EV) exhibited considerable potential in treating liver diseases. Although natural MSC-EV has many potential advantages, some characteristics of MSC-EV, such as heterogeneity, uneven therapeutic effect, and rapid clearance in vivo constrain its clinical translation. In recent years, researchers have explored plenty of ways to improve the therapeutic efficacy and rotation rate of MSC-EV in the treatment of liver disease. In this review, we summarized current strategies to enhance the therapeutic potency of MSC-EV, mainly including optimization culture conditions in MSC or modifications of MSC-EV, aiming to facilitate the development and clinical application of MSC-EV in treating liver disease.
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Affiliation(s)
- Lijuan Zheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Jing Zhang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Linna Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Zhuofan Zhai
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Zhiyu Hu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Jing Chang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yizhu Jiang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Xinran Huang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Jingyi Ge
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
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20
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Bertolino GM, Maumus M, Jorgensen C, Noël D. Therapeutic potential in rheumatic diseases of extracellular vesicles derived from mesenchymal stromal cells. Nat Rev Rheumatol 2023; 19:682-694. [PMID: 37666995 DOI: 10.1038/s41584-023-01010-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2023] [Indexed: 09/06/2023]
Abstract
The incidence of rheumatic diseases such as rheumatoid arthritis and osteoarthritis and injuries to articular cartilage that lead to osteochondral defects is predicted to rise as a result of population ageing and the increase in high-intensity physical activities among young and middle-aged people. Current treatments focus on the management of pain and joint functionality to improve the patient's quality of life, but curative strategies are greatly desired. In the past two decades, the therapeutic value of mesenchymal stromal cells (MSCs) has been evaluated because of their regenerative potential, which is mainly attributed to the secretion of paracrine factors. Many of these factors are enclosed in extracellular vesicles (EVs) that reproduce the main functions of parental cells. MSC-derived EVs have anti-inflammatory, anti-apoptotic as well as pro-regenerative activities. Research on EVs has gained considerable attention as they are a potential cell-free therapy with lower immunogenicity and easier management than whole cells. MSC-derived EVs can rescue the pathogenetic phenotypes of chondrocytes and exert a protective effect in animal models of rheumatic disease. To facilitate the therapeutic use of EVs, appropriate cell sources for the production of EVs with the desired biological effects in each disease should be identified. Production and isolation of EVs should be optimized, and pre-isolation and post-isolation modifications should be considered to maximize the disease-modifying potential of the EVs.
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Affiliation(s)
| | - Marie Maumus
- IRMB, University of Montpellier, INSERM, 34295, Montpellier, France
| | - Christian Jorgensen
- IRMB, University of Montpellier, INSERM, 34295, Montpellier, France.
- Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU Montpellier, 34095, Montpellier, France.
| | - Danièle Noël
- IRMB, University of Montpellier, INSERM, 34295, Montpellier, France.
- Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU Montpellier, 34095, Montpellier, France.
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21
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Grun LK, Maurmann RM, Scholl JN, Fogaça ME, Schmitz CRR, Dias CK, Gasparotto J, Padoin AV, Mottin CC, Klamt F, Figueiró F, Jones MH, Filippi-Chiela EC, Guma FCR, Barbé-Tuana FM. Obesity drives adipose-derived stem cells into a senescent and dysfunctional phenotype associated with P38MAPK/NF-KB axis. Immun Ageing 2023; 20:51. [PMID: 37821967 PMCID: PMC10566105 DOI: 10.1186/s12979-023-00378-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 09/19/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND Adipose-derived stem cells (ADSC) are multipotent cells implicated in tissue homeostasis. Obesity represents a chronic inflammatory disease associated with metabolic dysfunction and age-related mechanisms, with progressive accumulation of senescent cells and compromised ADSC function. In this study, we aimed to explore mechanisms associated with the inflammatory environment present in obesity in modulating ADSC to a senescent phenotype. We evaluated phenotypic and functional alterations through 18 days of treatment. ADSC were cultivated with a conditioned medium supplemented with a pool of plasma from eutrophic individuals (PE, n = 15) or with obesity (PO, n = 14), and compared to the control. RESULTS Our results showed that PO-treated ADSC exhibited decreased proliferative capacity with G2/M cycle arrest and CDKN1A (p21WAF1/Cip1) up-regulation. We also observed increased senescence-associated β-galactosidase (SA-β-gal) activity, which was positively correlated with TRF1 protein expression. After 18 days, ADSC treated with PO showed augmented CDKN2A (p16INK4A) expression, which was accompanied by a cumulative nuclear enlargement. After 10 days, ADSC treated with PO showed an increase in NF-κB phosphorylation, while PE and PO showed an increase in p38MAPK activation. PE and PO treatment also induced an increase in senescence-associated secretory phenotype (SASP) cytokines IL-6 and IL-8. PO-treated cells exhibited decreased metabolic activity, reduced oxygen consumption related to basal respiration, increased mitochondrial depolarization and biomass, and mitochondrial network remodeling, with no superoxide overproduction. Finally, we observed an accumulation of lipid droplets in PO-treated ADSC, implying an adaptive cellular mechanism induced by the obesogenic stimuli. CONCLUSIONS Taken together, our data suggest that the inflammatory environment observed in obesity induces a senescent phenotype associated with p38MAPK/NF-κB axis, which stimulates and amplifies the SASP and is associated with impaired mitochondrial homeostasis.
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Affiliation(s)
- L K Grun
- Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
- Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
| | - R M Maurmann
- Graduate Program in Cellular and Molecular Biology, School of Health, Sciences, and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
- Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - J N Scholl
- Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - M E Fogaça
- Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - C R R Schmitz
- Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
- Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - C K Dias
- Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - J Gasparotto
- Institute of Biomedical Sciences, Federal University at Alfenas, Alfenas, Brazil
| | - A V Padoin
- Graduate Program in Medicine and Health Sciences, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - C C Mottin
- Graduate Program in Medicine and Health Sciences, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - F Klamt
- Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - F Figueiró
- Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - M H Jones
- Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - E C Filippi-Chiela
- Institute of Basic Health Sciences, Department of Morphological Sciences, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Center for Biotechnology, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - F C R Guma
- Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - F M Barbé-Tuana
- Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
- Graduate Program in Cellular and Molecular Biology, School of Health, Sciences, and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
- Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
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22
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Huang X, Liu B, Liang Y, Mai C, Shen Y, Huang X, Chen J, Liang X, Hu B, Li W, Li X, Zhang Y. TRAF3IP2 drives mesenchymal stem cell senescence via regulation of NAMPT-mediated NAD biosynthesis. Heliyon 2023; 9:e19505. [PMID: 37809895 PMCID: PMC10558736 DOI: 10.1016/j.heliyon.2023.e19505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 08/21/2023] [Accepted: 08/24/2023] [Indexed: 10/10/2023] Open
Abstract
The cellular senescence of mesenchymal stem cells (MSCs) limits their application in regenerative medicine. This study aimed to clarify the role of TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a pro-inflammatory cytoplasmic adaptor protein, in regulating MSC senescence and to explore the potential mechanisms. Methods: MSC senescence was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The expression of TRAF3IP2 and senescence-related proteins was detected by Western blotting. The nicotinamide adenine dinucleotide (NAD+) level and nicotinamide phosphoribosyl transferase (NAMPT) expression in MSCs was measured. Results: Compared with that in MSCs isolated from young donors (YMSCs), the expression of TRAF3IP2 was greatly increased in MSCs derived from aged donors (AMSCs). Overexpression of TRAF3IP2 accelerated YMSC senescence whereas downregulation significantly rescued cellular senescence. The protein level of NAMPT and the level of NAD+ were significantly decreased in AMSCs compared with YMSCs. Mechanistically, TRAF3IP2 induced MSC senescence via downregulation of NAMPT expression and NAD + level by inhibiting the AMPK signaling pathway. These effects were partially reversed by treatment with an AMPK or NAMPT activator. Conclusion: We revealed that TRAF3IP2 accelerated MSC senescence via downregulation of NAMPT-mediated NAD biosynthesis by mediation of the AMPK pathway, highlighting a novel means to rejuvenate senescent MSCs.
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Affiliation(s)
- Xiaoran Huang
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Baojuan Liu
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Yaowen Liang
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Medical College, Shantou University, Shantou, Guangdong, China
| | - Cong Mai
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Ying Shen
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Xinran Huang
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaqi Chen
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoting Liang
- Institute of Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bei Hu
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Weifeng Li
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Xin Li
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Yuelin Zhang
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
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23
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López-Seijas J, Miranda-Balbuena D, Iglesias-Fente A, Sacristán-Santos M, Carballo-Pedrares N, Arufe MC, Rey-Rico A, Fafián-Labora J. Development of new non-viral systems for genetic modification of senescent cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 32:302-317. [PMID: 37096164 PMCID: PMC10122050 DOI: 10.1016/j.omtn.2023.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 03/16/2023] [Indexed: 04/08/2023]
Abstract
Senescence is a process characterized by a prolonged irreversible cell-cycle arrest. The accumulation of senescent cells in tissues is related to aging and to the development of age-related diseases. Recently, gene therapy has emerged as a powerful tool for treating age-associated diseases by the transference of specific genes into the target cell population. However, the high sensitivity of senescent cells significantly precludes their genetic modification via classical viral and non-viral systems. Niosomes are self-assembled non-viral nanocarriers that exhibit important advantages due to their elevated cytocompatibility, versatility, and cost-efficiency, arising as a new alternative for genetic modification of senescent cells. In this work, we explore for the first time the use of niosomes for genetic modification of senescent umbilical cord-derived mesenchymal stem cells. We report that niosome composition greatly affected transfection efficiency; those formulations prepared in medium with sucrose and containing cholesterol as helper lipid being the most suitable to transfect senescent cells. Moreover, resulting niosome formulations exhibited a superior transfection efficiency with a markedly less cytotoxicity than the commercial reagent Lipofectamine. These findings highlight the potentiality of niosomes as effective vectors for genetic modification of senescent cells, providing new tools for the prevention and/or treatment of age-related diseases.
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Affiliation(s)
- Junquera López-Seijas
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Diego Miranda-Balbuena
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Alba Iglesias-Fente
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Marta Sacristán-Santos
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Natalia Carballo-Pedrares
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - María C. Arufe
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain. Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Ana Rey-Rico
- Gene and Cell Therapy Research Group (G-CEL), Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
| | - Juan Fafián-Labora
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Servizo Galego de Saúde (SERGAS), 15006 A Coruña, Spain. Centro Interdisciplinar de Química e Bioloxía - CICA, Universidade da Coruña, 15071 A Coruña, Spain
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24
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Zong Q, Bundkirchen K, Neunaber C, Noack S. Are the Properties of Bone Marrow-Derived Mesenchymal Stem Cells Influenced by Overweight and Obesity? Int J Mol Sci 2023; 24:ijms24054831. [PMID: 36902259 PMCID: PMC10003331 DOI: 10.3390/ijms24054831] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/22/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) are promising candidates for cell-based therapies. Growing evidence has indicated that overweight/obesity can change the bone marrow microenvironment, which affects some properties of BMSCs. As the overweight/obese population rapidly increases, they will inevitably become a potential source of BMSCs for clinical application, especially when receiving autologous BMSC transplantation. Given this situation, the quality control of these cells has become particularly important. Therefore, it is urgent to characterize BMSCs isolated from overweight/obese bone marrow environments. In this review, we summarize the evidence of the effects of overweight/obesity on the biological properties of BMSCs derived from humans and animals, including proliferation, clonogenicity, surface antigen expression, senescence, apoptosis, and trilineage differentiation, as well as the underlying mechanisms. Overall, the conclusions of existing studies are not consistent. Most studies demonstrate that overweight/obesity can influence one or more characteristics of BMSCs, while the involved mechanisms are still unclear. Moreover, insufficient evidence proves that weight loss or other interventions can rescue these qualities to baseline status. Thus, further research should address these issues and prioritize developing methods to improve functions of overweight- or obesity-derived BMSCs.
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25
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Musa M, Zeppieri M, Enaholo ES, Salati C, Parodi PC. Adipose Stem Cells in Modern-Day Ophthalmology. Clin Pract 2023; 13:230-245. [PMID: 36826163 PMCID: PMC9955457 DOI: 10.3390/clinpract13010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/30/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Stem cells (SCs) have evolved as an interesting and viable factor in ophthalmologic patient care in the past decades. SCs have been classified as either embryonic, mesenchymal, tissue-specific, or induced pluripotent cells. Multiple novel management techniques and clinical trials have been established to date. While available publications are predominantly animal-model-based, significant material is derived from human studies and case-selected scenarios. This possibility of explanting cells from viable tissue to regenerate/repair damaged tissue points to an exciting future of therapeutic options in all fields of medicine, and ophthalmology is surely not left out. Adipose tissue obtained from lipo-aspirates has been shown to produce mesenchymal SCs that are potentially useful in different body parts, including the oculo-visual system. An overview of the anatomy, physiology, and extraction process for adipose-tissue-derived stem cells (ADSC) is important for better understanding the potential therapeutic benefits. This review examines published data on ADSCs in immune-modulatory, therapeutic, and regenerative treatments. We also look at the future of ADSC applications for ophthalmic patient care. The adverse effects of this relatively novel therapy are also discussed.
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Affiliation(s)
- Mutali Musa
- Department of Optometry, University of Benin, Benin City 300238, Nigeria
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy
| | | | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy
| | - Pier Camillo Parodi
- Department of Plastic Surgery, University Hospital of Udine, 33100 Udine, Italy
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26
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Wong PF, Dharmani M, Ramasamy TS. Senotherapeutics for mesenchymal stem cell senescence and rejuvenation. Drug Discov Today 2023; 28:103424. [PMID: 36332835 DOI: 10.1016/j.drudis.2022.103424] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 10/04/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.
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Affiliation(s)
- Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Murugan Dharmani
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia.
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27
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Song Y, Li R, Ye M, Pan C, Zheng L, Wang ZW, Zhu X. Differences in chemotaxis of human mesenchymal stem cells and cervical cancer cells. Apoptosis 2022; 27:840-851. [PMID: 35849265 DOI: 10.1007/s10495-022-01749-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2022] [Indexed: 11/30/2022]
Abstract
In the last decade, there has been a rapid expansion in tumor targeted therapy using mesenchymal stem cells (MSCs) based on their unique tropism towards cancer cells. Despite similarities in morphology, immunophenotype, and differential potent in vitro, MSCs originated from different tissues do not necessarily have equivalent biological behaviors. It is important to screen the most chemotactic MSCs to cancer cells. In this study, different MSCs were isolated from various human tissues including adipose, umbilical cord, amniotic membrane, and chorion. The chemotaxis of human MSCs to cervical cancer cells was measured by CCK-8, ELISA and Transwell invasion assays. Western blotting was performed to explore the underlying mechanisms. MSCs derived from distinct sources can be differently recruited to cervical cancer cells, among which chorion-derived MSC (CD-MSC) possessed the strongest tropic capacity. CXCL12 was found to be highly secreted by cervical cancer cells, in parallel with the expression of CXCR4 in all MSCs. CD-MSC displayed the highest level of CXCR4. These results indicated that CXCL12/CXCR4 pathway contributed to the different chemotaxis to cervical cancer cells of each MSCs. This study proposed that CD-MSC with the highest CXCR4 expression is a promising therapeutic vehicle for targeted therapy in cervical cancer.
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Affiliation(s)
- Yizuo Song
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Ruyi Li
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Miaomiao Ye
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Chunyu Pan
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Lihong Zheng
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Zhi-Wei Wang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China.
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China.
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Fraile M, Eiro N, Costa LA, Martín A, Vizoso FJ. Aging and Mesenchymal Stem Cells: Basic Concepts, Challenges and Strategies. BIOLOGY 2022; 11:1678. [PMID: 36421393 PMCID: PMC9687158 DOI: 10.3390/biology11111678] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/08/2022] [Accepted: 11/15/2022] [Indexed: 08/27/2023]
Abstract
Aging and frailty are complex processes implicating multifactorial mechanisms, such as replicative senescence, oxidative stress, mitochondrial dysfunction, or autophagy disorder. All of these mechanisms drive dramatic changes in the tissue environment, such as senescence-associated secretory phenotype factors and inflamm-aging. Thus, there is a demand for new therapeutic strategies against the devastating effects of the aging and associated diseases. Mesenchymal stem cells (MSC) participate in a "galaxy" of tissue signals (proliferative, anti-inflammatory, and antioxidative stress, and proangiogenic, antitumor, antifibrotic, and antimicrobial effects) contributing to tissue homeostasis. However, MSC are also not immune to aging. Three strategies based on MSC have been proposed: remove, rejuvenate, or replace the senescent MSC. These strategies include the use of senolytic drugs, antioxidant agents and genetic engineering, or transplantation of younger MSC. Nevertheless, these strategies may have the drawback of the adverse effects of prolonged use of the different drugs used or, where appropriate, those of cell therapy. In this review, we propose the new strategy of "Exogenous Restitution of Intercellular Signalling of Stem Cells" (ERISSC). This concept is based on the potential use of secretome from MSC, which are composed of molecules such as growth factors, cytokines, and extracellular vesicles and have the same biological effects as their parent cells. To face this cell-free regenerative therapy challenge, we have to clarify key strategy aspects, such as establishing tools that allow us a more precise diagnosis of aging frailty in order to identify the therapeutic requirements adapted to each case, identify the ideal type of MSC in the context of the functional heterogeneity of these cellular populations, to optimize the mass production and standardization of the primary materials (cells) and their secretome-derived products, to establish the appropriate methods to validate the anti-aging effects and to determine the most appropriate route of administration for each case.
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Affiliation(s)
- Maria Fraile
- Research Unit, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijon, Spain
| | - Noemi Eiro
- Research Unit, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijon, Spain
| | - Luis A. Costa
- Research Unit, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijon, Spain
| | - Arancha Martín
- Research Unit, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijon, Spain
- Department of Emergency, Hospital Universitario de Cabueñes, Los Prados, 395, 33394 Gijon, Spain
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijon, Spain
- Department of Surgery, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijon, Spain
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Paracrine Senescence of Mesenchymal Stromal Cells Involves Inflammatory Cytokines and the NF-κB Pathway. Cells 2022; 11:cells11203324. [PMID: 36291189 PMCID: PMC9600401 DOI: 10.3390/cells11203324] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/15/2022] [Accepted: 10/19/2022] [Indexed: 12/28/2022] Open
Abstract
It has been known that senescence-associated secretory phenotype (SASP) triggers senescence of the surrounding normal cells. However, SASP signaling regarding mesenchymal stromal cell aging remains to be fully elucidated. Therefore, the present study aimed to clarify the molecular mechanism of late (passage) MSC-induced paracrine SASP-mediated senescence of early (passage) MSCs during ex vivo expansion. Here, we conducted an extensive characterization of senescence features in bone-marrow (BM)-derived MSCs from healthy human donors. Late MSCs displayed an enlarged senescent-like morphology, induced SASP-related proinflammatory cytokines (IL-1α and IL-8), and reduced clonogenic capacity and osteogenic differentiation when compared to early MSCs. Of note, paracrine effects of SASP-related IL-1α and IL-8 from late MSCs induced cellular senescence of early MSCs via an NF-κB-dependent manner. Moreover, cellular senescence of early MSCs was promoted by the synergistic action of IL-1α and IL-8. However, inhibition of NF-κB by shRNA transfection or using inhibitors in early MSCs blocked early MSCs cellular senescence caused by paracrine SASP of late MSCs. In conclusion, these findings reveal that late MSCs display features of senescence and that, during ex vivo expansion, SASP-related proinflammatory cytokines contribute to activate a cellular senescence program in early MSCs that may ultimately impair their functionality.
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Maioli M, Rinaldi S, Cruciani S, Necas A, Fontani V, Corda G, Santaniello S, Rinaldi A, Barcessat A, Necasova A, Castagna A, Filipejova Z, Ventura C, Fozza C. Antisenescence effect of REAC biomodulation to counteract the evolution of myelodysplastic syndrome. Physiol Res 2022; 71:539-549. [PMID: 35899943 PMCID: PMC9616590 DOI: 10.33549/physiolres.934903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 07/15/2022] [Indexed: 11/25/2022] Open
Abstract
About 30 percent of patients diagnosed with myelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML). The senescence of bone marrow?derived mesenchymal stem cells (BMSCs) seems to be one of the determining factors in inducing this drift. Research is continuously looking for new methodologies and technologies that can use bioelectric signals to act on senescence and cell differentiation towards the phenotype of interest. The Radio Electric Asymmetric Conveyer (REAC) technology, aimed at reorganizing the endogenous bioelectric activity, has already shown to be able to determine direct cell reprogramming effects and counteract the senescence mechanisms in stem cells. Aim of the present study was to prove if the anti-senescence results previously obtained in different kind of stem cells with the REAC Tissue optimization - regenerative (TO-RGN) treatment, could also be observed in BMSCs, evaluating cell viability, telomerase activity, p19ARF, P21, P53, and hTERT gene expression. The results show that the REAC TO-RGN treatment may be a useful tool to counteract the BMSCs senescence which can be the basis of AML drift. Nevertheless, further clinical studies on humans are needed to confirm this hypothesis.
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Affiliation(s)
- M Maioli
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
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Yang G, Fan X, Mazhar M, Yang S, Xu H, Dechsupa N, Wang L. Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage. Front Cell Neurosci 2022; 16:898497. [PMID: 35769327 PMCID: PMC9234141 DOI: 10.3389/fncel.2022.898497] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/18/2022] [Indexed: 12/15/2022] Open
Abstract
Intracerebral hemorrhage (ICH), a common lethal subtype of stroke accounting for nearly 10–15% of the total stroke disease and affecting two million people worldwide, has a high mortality and disability rate and, thus, a major socioeconomic burden. However, there is no effective treatment available currently. The role of mesenchymal stem cells (MSCs) in regenerative medicine is well known owing to the simplicity of acquisition from various sources, low immunogenicity, adaptation to the autogenic and allogeneic systems, immunomodulation, self-recovery by secreting extracellular vesicles (EVs), regenerative repair, and antioxidative stress. MSC therapy provides an increasingly attractive therapeutic approach for ICH. Recently, the functions of MSCs such as neuroprotection, anti-inflammation, and improvement in synaptic plasticity have been widely researched in human and rodent models of ICH. MSC transplantation has been proven to improve ICH-induced injury, including the damage of nerve cells and oligodendrocytes, the activation of microglia and astrocytes, and the destruction of blood vessels. The improvement and recovery of neurological functions in rodent ICH models were demonstrated via the mechanisms such as neurogenesis, angiogenesis, anti-inflammation, anti-apoptosis, and synaptic plasticity. Here, we discuss the pathological mechanisms following ICH and the therapeutic mechanisms of MSC-based therapy to unravel new cues for future therapeutic strategies. Furthermore, some potential strategies for enhancing the therapeutic function of MSC transplantation have also been suggested.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Acupuncture and Rehabilitation, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Sijin Yang
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Houping Xu
- Preventive Treatment Center, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- *Correspondence: Nathupakorn Dechsupa,
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
- Li Wang,
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Olmedo-Moreno L, Aguilera Y, Baliña-Sánchez C, Martín-Montalvo A, Capilla-González V. Heterogeneity of In Vitro Expanded Mesenchymal Stromal Cells and Strategies to Improve Their Therapeutic Actions. Pharmaceutics 2022; 14:1112. [PMID: 35631698 PMCID: PMC9146397 DOI: 10.3390/pharmaceutics14051112] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 12/12/2022] Open
Abstract
Beneficial properties of mesenchymal stromal cells (MSCs) have prompted their use in preclinical and clinical research. Accumulating evidence has been provided for the therapeutic effects of MSCs in several pathologies, including neurodegenerative diseases, myocardial infarction, skin problems, liver disorders and cancer, among others. Although MSCs are found in multiple tissues, the number of MSCs is low, making in vitro expansion a required step before MSC application. However, culture-expanded MSCs exhibit notable differences in terms of cell morphology, physiology and function, which decisively contribute to MSC heterogeneity. The changes induced in MSCs during in vitro expansion may account for the variability in the results obtained in different MSC-based therapy studies, including those using MSCs as living drug delivery systems. This review dissects the different changes that occur in culture-expanded MSCs and how these modifications alter their therapeutic properties after transplantation. Furthermore, we discuss the current strategies developed to improve the beneficial effects of MSCs for successful clinical implementation, as well as potential therapeutic alternatives.
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Affiliation(s)
| | | | | | | | - Vivian Capilla-González
- Department of Regeneration and Cell Therapy, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, 41092 Seville, Spain; (L.O.-M.); (Y.A.); (C.B.-S.); (A.M.-M.)
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Chang X, Zhou YF, Wang L, Liu J, Yuan JM, Khor CC, Heng CK, Pan A, Koh WP, Dorajoo R. Genetic associations with healthy ageing among Chinese adults. NPJ AGING 2022; 8:6. [PMID: 35927272 PMCID: PMC9158790 DOI: 10.1038/s41514-022-00086-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 04/04/2022] [Indexed: 12/15/2022]
Abstract
The genetic basis of overall healthy ageing, especially among the East-Asian population is understudied. We conducted a genome-wide association study among 1618 Singapore Chinese elderly participants (65 years or older) ascertained to have aged healthily and compared their genome-wide genotypes to 6221 participants who did not age healthily, after a 20-year follow-up. Two genetic variants were identified (PMeta < 2.59 × 10-8) to be associated with healthy aging, including the LRP1B locus previously associated in long-lived individuals without cognitive decline. Our study sheds additional insights on the genetic basis of healthy ageing.
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Affiliation(s)
- Xuling Chang
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, 119074, Singapore
| | - Yan-Feng Zhou
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Ling Wang
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
| | - Jianjun Liu
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Jian-Min Yuan
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Chiea-Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 169856, Singapore
| | - Chew-Kiat Heng
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, 119074, Singapore
| | - An Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
- State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Woon-Puay Koh
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore.
- Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, 117609, Singapore.
| | - Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore.
- Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore.
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Mato-Basalo R, Lucio-Gallego S, Alarcón-Veleiro C, Sacristán-Santos M, Quintana MDPM, Morente-López M, de Toro FJ, Silva-Fernández L, González-Rodríguez A, Arufe MC, Labora JAF. Action Mechanisms of Small Extracellular Vesicles in Inflammaging. Life (Basel) 2022; 12:546. [PMID: 35455036 PMCID: PMC9028066 DOI: 10.3390/life12040546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 02/05/2023] Open
Abstract
The accumulation process of proinflammatory components in the body due to aging influences intercellular communication and is known as inflammaging. This biological mechanism relates the development of inflammation to the aging process. Recently, it has been reported that small extracellular vesicles (sEVs) are mediators in the transmission of paracrine senescence involved in inflammatory aging. For this reason, their components, as well as mechanisms of action of sEVs, are relevant to develop a new therapy called senodrugs (senolytics and senomorphic) that regulates the intercellular communication of inflammaging. In this review, we include the most recent and relevant studies on the role of sEVs in the inflammatory aging process and in age-related diseases such as cancer and type 2 diabetes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - María C. Arufe
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Centro de Invesigaciones Científicas Avanzadas (CICA), Universidade da Coruña, INIBIC-Complejo Hospitalario Universitario A Coruña (CHUAC), 15006 A Coruña, Spain; (R.M.-B.); (S.L.-G.); (C.A.-V.); (M.S.-S.); (M.d.P.M.Q.); (M.M.-L.); (F.J.d.T.); (L.S.-F.); (A.G.-R.)
| | - Juan Antonio Fafián Labora
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias de la Salud, Centro de Invesigaciones Científicas Avanzadas (CICA), Universidade da Coruña, INIBIC-Complejo Hospitalario Universitario A Coruña (CHUAC), 15006 A Coruña, Spain; (R.M.-B.); (S.L.-G.); (C.A.-V.); (M.S.-S.); (M.d.P.M.Q.); (M.M.-L.); (F.J.d.T.); (L.S.-F.); (A.G.-R.)
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Wu SH, Yu JH, Liao YT, Liu KH, Chiang ER, Chang MC, Wang JP. Comparison of the Infant and Adult Adipose-Derived Mesenchymal Stem Cells in Proliferation, Senescence, Anti-oxidative Ability and Differentiation Potential. Tissue Eng Regen Med 2022; 19:589-601. [PMID: 35247199 PMCID: PMC9130449 DOI: 10.1007/s13770-022-00431-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 12/26/2021] [Accepted: 01/05/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Infant adipose-derived mesenchymal stem cells (ADSCs) collected from excised polydactyly fat tissue, which was surgical waste, could be cultured and expanded in vitro in this study. In addition, the collecting process would not cause pain in the host. In this study, the proliferation, reduction of senescence, anti-oxidative ability, and differentiation potential in the infant ADSCs were compared with those in the adult ADSCs harvested from thigh liposuction to determine the availability of infant ADSCs. METHODS Proliferation was determined by detecting the fold changes in cell numbers and doubling time periods. Senescence was analyzed by investigating the age-related gene expression levels and the replicative stress. The superoxide dismutase (SOD) gene expression, adipogenic, neurogenic, osteogenic, and tenogenic differentiation were compared by RT-qPCR. The chondrogenic differentiation efficiency was also determined using RT-qPCR and immunohistochemical staining. RESULTS The proliferation, SOD (SOD1, SOD2 and SOD3) gene expression, the stemness-related gene (c-MYC) and telomerase reverse transcriptase of the infant ADSCs at early passages were enhanced compared with those of the adults'. Cellular senescence related genes, including p16, p21 and p53, and replicative stress were reduced in the infant ADSCs. The adipogenic genes (PPARγ and LPL) and neurogenic genes (MAP2 and NEFH) of the infant ADSC differentiated cells were significantly higher than those of the adults' while the expression of the osteogenic genes (OCN and RUNX) and tenogenic genes (TNC and COL3A1) of both demonstrated opposite results. The chondrogenic markers (SOX9, COL2 and COL10) were enhanced in the infant ADSC differentiated chondrogenic pellets, and the expression levels of SODs were decreased during the differentiation process. CONCLUSION Cultured infant ADSCs demonstrate less cellular senescence and replicative stress, higher proliferation rates, better antioxidant defense activity, and higher potential of chondrogenic, adipogenic and neurogenic differentiation.
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Affiliation(s)
- Szu-Hsien Wu
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, 112 Taiwan ,Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112 Taiwan ,Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Jin-Huei Yu
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, 33004 Taiwan
| | - Yu-Ting Liao
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, 112 Taiwan
| | - Kuo-Hao Liu
- Department of Orthopaedics, National Yang Ming Chiao Tung University Hospital, Yilan, 260 Taiwan
| | - En-Rung Chiang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112 Taiwan ,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, 112 Taiwan
| | - Ming-Chau Chang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112 Taiwan ,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, 112 Taiwan
| | - Jung-pan Wang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112 Taiwan ,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, 112 Taiwan
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Elliot SJ, Catanuto P, Pereira-Simon S, Xia X, Pastar I, Thaller S, Head CR, Stojadinovic O, Tomic-Canic M, Glassberg MK. Catalase, a therapeutic target in the reversal of estrogen-mediated aging. Mol Ther 2022; 30:947-962. [PMID: 34174444 PMCID: PMC8821897 DOI: 10.1016/j.ymthe.2021.06.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 01/30/2021] [Accepted: 06/09/2021] [Indexed: 02/04/2023] Open
Abstract
Despite increasing interest in the reversal of age-related processes, there is a paucity of data regarding the effects of post-menopausal-associated estrogen loss on cellular function. We studied human adipose-derived mesenchymal stem cells (hASCs) isolated from women younger than 45 years old (pre-menopause, pre-hASC) or older than 55 years old (post-menopause, post-hASC). In this study, we provide proof of concept that the age-related ineffective functionality of ASCs can be reversed to improve their ability in promoting tissue repair. We found reduced estrogen receptor expression, decreased estrogen receptor activation, and reduced sensitivity to 17β-estradiol in post-hASCs. This correlated with decreased antioxidants (catalase and superoxide dismutase [SOD] expression) and increased oxidative stress compared with pre-hASCs. Increasing catalase expression in post-hASCs restored estrogen receptor (ER) expression and their functional capacity to promote tissue repair as shown in human skin ex vivo wound healing and in vivo mouse model of lung injury. Our results suggest that the consequences of 17β-estradiol decline on the function of hASCs may be reversible by changing the oxidative stress/antioxidant composition.
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Affiliation(s)
- Sharon J. Elliot
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA,Corresponding author: Sharon J. Elliot, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
| | - Paola Catanuto
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Simone Pereira-Simon
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Xiaomei Xia
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Seth Thaller
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Cheyanne R. Head
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Olivera Stojadinovic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Marjana Tomic-Canic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Marilyn K. Glassberg
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA,Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA,Corresponding author: Marilyn K. Glassberg, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA.
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Adipose-Derived Stem Cells for Facial Rejuvenation. J Pers Med 2022; 12:jpm12010117. [PMID: 35055432 PMCID: PMC8781097 DOI: 10.3390/jpm12010117] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/08/2021] [Accepted: 12/30/2021] [Indexed: 01/27/2023] Open
Abstract
The interest in regenerative medicine is increasing, and it is a dynamically developing branch of aesthetic surgery. Biocompatible and autologous-derived products such as platelet-rich plasma or adult mesenchymal stem cells are often used for aesthetic purposes. Their application originates from wound healing and orthopaedics. Adipose-derived stem cells are a powerful agent in skin rejuvenation. They secrete growth factors and anti-inflammatory cytokines, stimulate tissue regeneration by promoting the secretion of extracellular proteins and secrete antioxidants that neutralize free radicals. In an office procedure, without cell incubation and counting, the obtained product is stromal vascular fraction, which consists of not only stem cells but also other numerous active cells such as pericytes, preadipocytes, immune cells, and extra-cellular matrix. Adipose-derived stem cells, when injected into dermis, improved skin density and overall skin appearance, and increased skin hydration and number of capillary vessels. The main limitation of mesenchymal stem cell transfers is the survival of the graft. The final outcomes are dependent on many factors, including the age of the patient, technique of fat tissue harvesting, technique of lipoaspirate preparation, and technique of fat graft injection. It is very difficult to compare available studies because of the differences and multitude of techniques used. Fat harvesting is associated with potentially life-threatening complications, such as massive bleeding, embolism, or clots. However, most of the side effects are mild and transient: primarily hematomas, oedema, and mild pain. Mesenchymal stem cells that do not proliferate when injected into dermis promote neoangiogenesis, that is why respectful caution should be taken in the case of oncologic patients. A longer clinical observation on a higher number of participants should be performed to develop reliable indications and guidelines for transferring ADSCs.
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Mas-Bargues C, Alique M, Barrús-Ortiz MT, Borrás C, Rodrigues-Díez R. Exploring New Kingdoms: The Role of Extracellular Vesicles in Oxi-Inflamm-Aging Related to Cardiorenal Syndrome. Antioxidants (Basel) 2021; 11:78. [PMID: 35052582 PMCID: PMC8773353 DOI: 10.3390/antiox11010078] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/20/2021] [Accepted: 12/23/2021] [Indexed: 12/12/2022] Open
Abstract
The incidence of age associated chronic diseases has increased in recent years. Although several diverse causes produce these phenomena, abundant evidence shows that oxidative stress plays a central role. In recent years, numerous studies have focused on elucidating the role of oxidative stress in the development and progression of both aging and chronic diseases, opening the door to the discovery of new underlying mechanisms and signaling pathways. Among them, senolytics and senomorphics, and extracellular vesicles offer new therapeutic strategies to slow the development of aging and its associated chronic diseases by decreasing oxidative stress. In this review, we aim to discuss the role of extracellular vesicles in human cardiorenal syndrome development and their possible role as biomarkers, targets, or vehicles of drugs to treat this syndrome.
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Affiliation(s)
- Cristina Mas-Bargues
- Grupo de Investigación Freshage, Departmento de Fisiología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain; (C.M.-B.); (C.B.)
- Instituto Sanitario de Investigación INCLIVA, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable, Instituto de Salud Carlos III (CIBERFES, ISCIII), 28029 Madrid, Spain
| | - Matilde Alique
- Departamento de Biología de Sistemas, Universidad de Alcalá, 28871 Madrid, Spain;
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain
| | - María Teresa Barrús-Ortiz
- Área de Fisiología, Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Univesidad Rey Juan Carlos, Avenida de Atenas s/n, 28922 Madrid, Spain
| | - Consuelo Borrás
- Grupo de Investigación Freshage, Departmento de Fisiología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain; (C.M.-B.); (C.B.)
- Instituto Sanitario de Investigación INCLIVA, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable, Instituto de Salud Carlos III (CIBERFES, ISCIII), 28029 Madrid, Spain
| | - Raquel Rodrigues-Díez
- Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
- Instituto de Investigación Hospital La Paz (IdiPAZ), 28046 Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 08036 Barcelona, Spain
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Aghali A. Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy. Cells 2021; 10:cells10112993. [PMID: 34831216 PMCID: PMC8616509 DOI: 10.3390/cells10112993] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/16/2021] [Accepted: 10/22/2021] [Indexed: 01/10/2023] Open
Abstract
Craniofacial bone defects can result from various disorders, including congenital malformations, tumor resection, infection, severe trauma, and accidents. Successfully regenerating cranial defects is an integral step to restore craniofacial function. However, challenges managing and controlling new bone tissue formation remain. Current advances in tissue engineering and regenerative medicine use innovative techniques to address these challenges. The use of biomaterials, stromal cells, and growth factors have demonstrated promising outcomes in vitro and in vivo. Natural and synthetic bone grafts combined with Mesenchymal Stromal Cells (MSCs) and growth factors have shown encouraging results in regenerating critical-size cranial defects. One of prevalent growth factors is Bone Morphogenetic Protein-2 (BMP-2). BMP-2 is defined as a gold standard growth factor that enhances new bone formation in vitro and in vivo. Recently, emerging evidence suggested that Megakaryocytes (MKs), induced by Thrombopoietin (TPO), show an increase in osteoblast proliferation in vitro and bone mass in vivo. Furthermore, a co-culture study shows mature MKs enhance MSC survival rate while maintaining their phenotype. Therefore, MKs can provide an insight as a potential therapy offering a safe and effective approach to regenerating critical-size cranial defects.
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Affiliation(s)
- Arbi Aghali
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA;
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47908, USA
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Guenther R, Dreschers S, Maassen J, Reibert D, Skazik-Voogt C, Gutermuth A. The Treasury of Wharton's Jelly. Stem Cell Rev Rep 2021; 18:1627-1638. [PMID: 34647276 PMCID: PMC9209346 DOI: 10.1007/s12015-021-10217-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2021] [Indexed: 11/11/2022]
Abstract
Background Postnatal umbilical cord tissue contains valuable mesenchymal progenitor cells of various differentiation stages. While mesenchymal stem cells are plastic-adherent and tend to differentiate into myofibroblastic phenotypes, some round cells detach, float above the adherent cells, and build up cell aggregates, or form spheroids spontaneously. Very small luminescent cells are always involved as single cells or within collective forms and resemble the common well-known very small embryonic-like cells (VSELs). In this study, we investigated these VSELs-like cells in terms of their pluripotency phenotype and tri-lineage differentiation potential. Methods VSELs-like cells were isolated from cell-culture supernatants by a process that combines filtering, up concentration, and centrifugation. To determine their pluripotency character, we measured the expression of Nanog, Sox-2, Oct-4, SSEA-1, CXCR4, SSEA-4 on gene and protein level. In addition, the cultured cells derived from UC tissue were examined regarding their potential to differentiate into three germ layers. Result The VSELs-like cells express all of the pluripotency-associated markers we investigated and are able to differentiate into meso- endo- and ectodermal precursor cells. Conclusions Umbilical cord tissue hosts highly potent VSELs-like stem cells. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1007/s12015-021-10217-8.
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Affiliation(s)
- Rebecca Guenther
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Stephan Dreschers
- Clinic for Gynaecology, University Hospital Aachen, Pauwelsstr 30, 52074, Aachen, Germany
| | - Jessika Maassen
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Daniel Reibert
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Claudia Skazik-Voogt
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Angela Gutermuth
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany.
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Carvalho MS, Alves L, Bogalho I, Cabral JMS, da Silva CL. Impact of Donor Age on the Osteogenic Supportive Capacity of Mesenchymal Stromal Cell-Derived Extracellular Matrix. Front Cell Dev Biol 2021; 9:747521. [PMID: 34676216 PMCID: PMC8523799 DOI: 10.3389/fcell.2021.747521] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/10/2021] [Indexed: 12/27/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have been proposed as an emerging cell-based therapeutic option for regenerative medicine applications as these cells can promote tissue and organ repair. In particular, MSC have been applied for the treatment of bone fractures. However, the healing capacity of these fractures is often compromised by patient's age. Therefore, considering the use of autologous MSC, we evaluated the impact of donor age on the osteogenic potential of bone marrow (BM)-derived MSC. MSC from older patients (60 and 80 years old) demonstrated impaired proliferative and osteogenic capacities compared to MSC isolated from younger patients (30 and 45 years old), suggesting that aging potentially changes the quantity and quality of MSC. Moreover, in this study, we investigated the capacity of the microenvironment [i.e., extracellular matrix (ECM)] to rescue the impaired proliferative and osteogenic potential of aged MSC. In this context, we aimed to understand if BM MSC features could be modulated by exposure to an ECM derived from cells obtained from young or old donors. When aged MSC were cultured on decellularized ECM derived from young MSC, their in vitro proliferative and osteogenic capacities were enhanced, which did not happen when cultured on old ECM. Our results suggest that the microenvironment, specifically the ECM, plays a crucial role in the quality (assessed in terms of osteogenic differentiation capacity) and quantity of MSC. Specifically, the aging of ECM is determinant of osteogenic differentiation of MSC. In fact, old MSC maintained on a young ECM produced higher amounts of extracellularly deposited calcium (9.10 ± 0.22 vs. 4.69 ± 1.41 μg.μl-1.10-7 cells for young ECM and old ECM, respectively) and up-regulated the expression of osteogenic gene markers such as Runx2 and OPN. Cell rejuvenation by exposure to a functional ECM might be a valuable clinical strategy to overcome the age-related decline in the osteogenic potential of MSC by recapitulating a younger microenvironment, attenuating the effects of aging on the stem cell niche. Overall, this study provides new insights on the osteogenic potential of MSC during aging and opens new possibilities for developing clinical strategies for elderly patients with limited bone formation capacity who currently lack effective treatments.
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Affiliation(s)
- Marta S. Carvalho
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Laura Alves
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Isabel Bogalho
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Joaquim M. S. Cabral
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Cláudia L. da Silva
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
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Lim SK, Khoo BY. An overview of mesenchymal stem cells and their potential therapeutic benefits in cancer therapy. Oncol Lett 2021; 22:785. [PMID: 34594426 PMCID: PMC8456491 DOI: 10.3892/ol.2021.13046] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 07/27/2021] [Indexed: 12/15/2022] Open
Abstract
There has been increased interest in using stem cells for regenerative medicine and cancer therapy in the past decade. Mesenchymal stem cells (MSCs) are among the most studied stem cells due to their unique characteristics, such as self-renewal and developmental potency to differentiate into numerous cell types. MSC use has fewer ethical challenges compared with other types of stem cells. Although a number of studies have reported the beneficial effects of MSC-based therapies in treating various diseases, their contribution to cancer therapy remains controversial. The behaviour of MSCs is determined by the interaction between intrinsic transcriptional genes and extrinsic environmental factors. Numerous studies continue to emerge, as there is no denying the potential of MSCs to treat a wide variety of human afflictions. Therefore, the present review article provided an overview of MSCs and their differences compared with embryonic stem cells, and described the molecular mechanisms involved in maintaining their stemness. In addition, the article examined the therapeutic application of stem cells in the field of cancer. The present article also discussed the current divergent roles of MSCs in cancer therapy and the future potential in this field.
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Affiliation(s)
- Shern Kwok Lim
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Penang, Malaysia
| | - Boon Yin Khoo
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Penang, Malaysia
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Teh SW, Koh AEH, Tong JB, Wu X, Samrot AV, Rampal S, Mok PL, Subbiah SK. Hypoxia in Bone and Oxygen Releasing Biomaterials in Fracture Treatments Using Mesenchymal Stem Cell Therapy: A Review. Front Cell Dev Biol 2021; 9:634131. [PMID: 34490233 PMCID: PMC8417697 DOI: 10.3389/fcell.2021.634131] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
Bone fractures have a high degree of severity. This is usually a result of the physical trauma of diseases that affect bone tissues, such as osteoporosis. Due to its highly vascular nature, the bone is in a constant state of remodeling. Although those of younger ages possess bones with high regenerative potential, the impact of a disrupted vasculature can severely affect the recovery process and cause osteonecrosis. This is commonly seen in the neck of femur, scaphoid, and talus bone. In recent years, mesenchymal stem cell (MSC) therapy has been used to aid in the regeneration of afflicted bone. However, the cut-off in blood supply due to bone fractures can lead to hypoxia-induced changes in engrafted MSCs. Researchers have designed several oxygen-generating biomaterials and yielded varying degrees of success in enhancing tissue salvage and preserving cellular metabolism under ischemia. These can be utilized to further improve stem cell therapy for bone repair. In this review, we touch on the pathophysiology of these bone fractures and review the application of oxygen-generating biomaterials to further enhance MSC-mediated repair of fractures in the three aforementioned parts of the bone.
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Affiliation(s)
- Seoh Wei Teh
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Avin Ee-Hwan Koh
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Jia Bei Tong
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Xiaoyun Wu
- Department of Technology, Research Center for Hua-Da Precision Medicine of Inner Mongolia Autonomous Region, Hohhot, China
| | - Antony V Samrot
- School of Bioscience, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Malaysia
| | - Sanjiv Rampal
- Department of Orthopedics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Pooi Ling Mok
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Suresh Kumar Subbiah
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.,Center for Materials Engineering and Regenerative Medicine, Bharath Institute of Higher Education and Research, Bharath University, Chennai, India
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Opportunities and Challenges in Stem Cell Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1341:143-175. [PMID: 33748933 DOI: 10.1007/5584_2021_624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Studying aging, as a physiological process that can cause various pathological phenotypes, has attracted lots of attention due to its increasing burden and prevalence. Therefore, understanding its mechanism to find novel therapeutic alternatives for age-related disorders such as neurodegenerative and cardiovascular diseases is essential. Stem cell senescence plays an important role in aging. In the context of the underlying pathways, mitochondrial dysfunction, epigenetic and genetic alterations, and other mechanisms have been studied and as a consequence, several rejuvenation strategies targeting these mechanisms like pharmaceutical interventions, genetic modification, and cellular reprogramming have been proposed. On the other hand, since stem cells have great potential for disease modeling, they have been useful for representing aging and its associated disorders. Accordingly, the main mechanisms of senescence in stem cells and promising ways of rejuvenation, along with some examples of stem cell models for aging are introduced and discussed. This review aims to prepare a comprehensive summary of the findings by focusing on the most recent ones to shine a light on this area of research.
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Belyavsky A, Petinati N, Drize N. Hematopoiesis during Ontogenesis, Adult Life, and Aging. Int J Mol Sci 2021; 22:ijms22179231. [PMID: 34502137 PMCID: PMC8430730 DOI: 10.3390/ijms22179231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/13/2021] [Accepted: 08/24/2021] [Indexed: 12/17/2022] Open
Abstract
In the bone marrow of vertebrates, two types of stem cells coexist-hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Hematopoiesis only occurs when these two stem cell types and their descendants interact. The descendants of HSCs supply the body with all the mature blood cells, while MSCs give rise to stromal cells that form a niche for HSCs and regulate the process of hematopoiesis. The studies of hematopoiesis were initially based on morphological observations, later extended by the use of physiological methods, and were subsequently augmented by massive application of sophisticated molecular techniques. The combination of these methods produced a wealth of new data on the organization and functional features of hematopoiesis in the ontogenesis of mammals and humans. This review summarizes the current views on hematopoiesis in mice and humans, discusses the development of blood elements and hematopoiesis in the embryo, and describes how the hematopoietic system works in the adult organism and how it changes during aging.
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Affiliation(s)
- Alexander Belyavsky
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | | | - Nina Drize
- National Research Center for Hematology, 125167 Moscow, Russia;
- Correspondence:
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Reyes-Farias M, Fos-Domenech J, Serra D, Herrero L, Sánchez-Infantes D. White adipose tissue dysfunction in obesity and aging. Biochem Pharmacol 2021; 192:114723. [PMID: 34364887 DOI: 10.1016/j.bcp.2021.114723] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/30/2021] [Accepted: 08/03/2021] [Indexed: 12/19/2022]
Abstract
Both obesity and aging are associated with the development of metabolic diseases such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation of adipose tissue is one of the mechanisms implicated in the progression of these diseases. Obesity and aging trigger adipose tissue alterations that ultimately lead to a pro-inflammatory phenotype of the adipose tissue-resident immune cells. Obesity and aging also share other features such as a higher visceral vs. subcutaneous adipose tissue ratio and a decreased lifespan. Here, we review the common characteristics of obesity and aging and the alterations in white adipose tissue and resident immune cells. We focus on the adipose tissue metabolic derangements in obesity and aging such as inflammation and adipose tissue remodeling.
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Affiliation(s)
- Marjorie Reyes-Farias
- Department of Endocrinology and Nutrition, Germans Trias i Pujol Research Institute, Barcelona, Spain; Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain
| | - Julia Fos-Domenech
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain
| | - Dolors Serra
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain
| | - Laura Herrero
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain.
| | - David Sánchez-Infantes
- Department of Endocrinology and Nutrition, Germans Trias i Pujol Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain; Department of Health Sciences, Campus Alcorcón, University Rey Juan Carlos (URJC), E-28922 Madrid, Spain.
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Hu Y, Zhu Y, Gerber SD, Osland JM, Chen M, Rao KA, Gu H, Yuan R. Deletion of Nrip1 delays skin aging by reducing adipose-derived mesenchymal stem cells (ADMSCs) senescence, and maintaining ADMSCs quiescence. GeroScience 2021; 43:1815-1833. [PMID: 33704619 PMCID: PMC8492836 DOI: 10.1007/s11357-021-00344-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 02/15/2021] [Indexed: 12/18/2022] Open
Abstract
Our previous studies found that deletion of nuclear receptor interacting protein 1 (Nrip1) extended longevity in female mice and delayed cell senescence. The current study investigates the role of NRIP1 in regulating functions of adipose-derived mesenchymal stem cells (ADMSCs) and explores the mechanisms of NRIP1 in skin aging. We first verified the skin aging phenotypes in young (6 months) and old (20 months) C57BL/6J (B6) mice and found deletion of Nrip1 can delay skin aging phenotypes, including reduced thickness of dermis and subcutaneous white adipose tissue (sWAT), as well as the accumulation of senescent cells in sWAT. In ADMSCs isolated from sWAT, we found that deletion of Nrip1 could decrease cell proliferation, prevent cell apoptosis, and suppress adipogenesis. Interestingly, deletion of Nrip1 also reduced cell senescence and maintain cell quiescence of ADMSCs. Moreover, the expressions of genes associated with senescence (p21, and p53), inflammation (p65, IL6, and IL1a), and growth factor (mTOR, Igf1) were reduced in Nrip1 knockout ADMSCs, as well as in siNrip1-treated ADMSCs. Suppression of Nrip1 by siNrip1 also decreased the expressions of mTOR, p-mTOR, p65, and p-p65 in ADMSCs. Reduced expressions of p65 and p-p65 were also confirmed in the skin of Nrip1 knockout mice. These findings suggest that NRIP1 plays an important role in delaying skin aging by reducing ADMSCs senescence and maintaining ADMSCs quiescence.
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Affiliation(s)
- Yu Hu
- Division of Geriatric Research, Department of Internal Medicine, Southern Illinois University School of Medicine, 801 N. Rutledge Street Room 4361, Springfield, IL, 62702, USA
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street, Nanjing, Jiangsu, China
| | - Yun Zhu
- Division of Geriatric Research, Department of Internal Medicine, Southern Illinois University School of Medicine, 801 N. Rutledge Street Room 4361, Springfield, IL, 62702, USA
| | - Skyler D Gerber
- Division of Geriatric Research, Department of Internal Medicine, Southern Illinois University School of Medicine, 801 N. Rutledge Street Room 4361, Springfield, IL, 62702, USA
| | - Jared M Osland
- Division of Geriatric Research, Department of Internal Medicine, Southern Illinois University School of Medicine, 801 N. Rutledge Street Room 4361, Springfield, IL, 62702, USA
| | - Min Chen
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street, Nanjing, Jiangsu, China
| | - Krishna A Rao
- Division of Hematology/Oncology, Department of Internal Medicine, Simmons Cancer Institute at Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Heng Gu
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street, Nanjing, Jiangsu, China.
| | - Rong Yuan
- Division of Geriatric Research, Department of Internal Medicine, Southern Illinois University School of Medicine, 801 N. Rutledge Street Room 4361, Springfield, IL, 62702, USA.
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Barik P, Shibu MA, Hsieh DJY, Day CH, Chen RJ, Kuo WW, Chang YM, Padma VV, Ho TJ, Huang CY. Cardioprotective effects of transplanted adipose-derived stem cells under Ang II stress with Danggui administration augments cardiac function through upregulation of insulin-like growth factor 1 receptor in late-stage hypertension rats. ENVIRONMENTAL TOXICOLOGY 2021; 36:1466-1475. [PMID: 33881220 DOI: 10.1002/tox.23145] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/18/2021] [Accepted: 04/02/2021] [Indexed: 06/12/2023]
Abstract
In aging hypertensive conditions, deterioration of insulin-like growth factor 1 receptor (IGF1R) cause a pathological impact on hypertensive hearts with an increased Ang II level. Recovering these adverse conditions through transplanted adipose-derived stem cells is a challenging approach. Moreover, Danggui, a Traditional Chinese medicine (TCM), is used for the treatment of cardioprotective effects. In this study, to evaluate whether the combined effect of MSCs and TCM can recover the cardiac function in late-stage hypertension rats. We observed that lower dose of Danggui crude extract treatment showed an increased level of cell viability with maintained stemness properties and growth rate in rat adipose-derived stem cells (rADSCs). Further, we cocultured the H9c2 cells with rADSCs and the results revealed that Danggui-treated MSCs enhanced the IGF1R expression and attenuated the hypertrophy in H9c2 cells against Ang II challenge by immunoblot and rhodamine-phalloidin staining. In addition, Danggui crude extract was also quantified and characterized by HPLC and LC-MS analysis. Furthermore, the in vivo study was performed by considering 11 months old rats (n = 7). Importantly, the oral administration of Danggui crude extract with stem cells intravenous injection in SHR-D-ADSCs group showed a combination effect to augment the cardiac function through enhancement of ejection fraction, fractional shortening, contractility function in the late-stage hypertension conditions. We have also observed a decreased apoptosis rate in the heart tissue of SHR-D-ADSCs group. Taken together, these results indicate that the combinatorial effects of Danggui crude extract and stem cell therapy enhanced cardiac function in late-stage SHR rats.
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Affiliation(s)
- Parthasarathi Barik
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Marthandam Asokan Shibu
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Dennis Jine-Yuan Hsieh
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | | | - Ray-Jade Chen
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Yung-Ming Chang
- The School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan
| | - V Vijaya Padma
- Department of Biotechnology, Bharathiar University, Coimbatore, India
| | - Tsung-Jung Ho
- Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
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Yeo GEC, Ng MH, Nordin FB, Law JX. Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System. Int J Mol Sci 2021; 22:5749. [PMID: 34072224 PMCID: PMC8198707 DOI: 10.3390/ijms22115749] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 12/14/2022] Open
Abstract
Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence.
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Affiliation(s)
| | | | | | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras 56000, Malaysia; (G.E.C.Y.); (M.H.N.); (F.B.N.)
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Age-Related Changes in Bone-Marrow Mesenchymal Stem Cells. Cells 2021; 10:cells10061273. [PMID: 34063923 PMCID: PMC8223980 DOI: 10.3390/cells10061273] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/14/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
The use of stem cells is part of a strategy for the treatment of a large number of diseases. However, the source of the original stem cells for use is extremely important and determines their therapeutic potential. Mesenchymal stromal cells (MSC) have proven their therapeutic effectiveness when used in a number of pathological models. However, it remains an open question whether the chronological age of the donor organism affects the effectiveness of the use of MSC. The asymmetric division of stem cells, the result of which is some residential stem cells acquiring a non-senile phenotype, means that stem cells possess an intrinsic ability to preserve juvenile characteristics, implying an absence or at least remarkable retardation of senescence in stem cells. To test whether residential MSC senesce, we evaluated the physiological changes in the MSC from old rats, with a further comparison of the neuroprotective properties of MSC from young and old animals in a model of traumatic brain injury. We found that, while the effect of administration of MSC on lesion volume was minimal, functional recovery was remarkable, with the highest effect assigned to fetal cells; the lowest effect was recorded for cells isolated from adult rats and postnatal cells, having intermediate potency. MSC from the young rats were characterized by a faster growth than adult MSC, correlating with levels of proliferating cell nuclear antigen (PCNA). However, there were no differences in respiratory activity of MSC from young and old rats, but young cells showed much higher glucose utilization than old ones. Autophagy flux was almost the same in both types of cells, but there were remarkable ultrastructural differences in old and young cells.
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