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1
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Luo X, Wang J, Ju Q, Li T, Bi X. Molecular mechanisms and potential interventions during aging-associated sarcopenia. Mech Ageing Dev 2025; 223:112020. [PMID: 39667622 DOI: 10.1016/j.mad.2024.112020] [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: 07/12/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 12/14/2024]
Abstract
Sarcopenia, a common condition observed in the elderly, presenting a significant public health challenge due to its high prevalence, insidious onset and diverse systemic effects. Despite ongoing research, the precise etiology of sarcopenia remains elusive. Aging-related processes, which included inflammation, oxidative stress, compromised mitochondrial function and apoptosis, have been implicated in its development. Notably, effective pharmacological treatments for sarcopenia are currently lacking, highlighting the necessity for a deeper understanding of its pathogenesis and causative factors to enable proactive interventions. This article is aimed to provide an extensive overview of the pathogenesis of sarcopenia, along with a summary of current treatment and prevention strategies.
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Affiliation(s)
- Xiaoqin Luo
- College of Life Science, Liaoning University, Shenyang 110036, China
| | - Jin Wang
- College of Life Science, Liaoning University, Shenyang 110036, China
| | - Qingqing Ju
- College of Life Science, Liaoning University, Shenyang 110036, China
| | - Tianyu Li
- College of Life Science, Liaoning University, Shenyang 110036, China
| | - Xiuli Bi
- College of Life Science, Liaoning University, Shenyang 110036, China; Key Laboratory for Chronic Diseases Molecular Mechanism Research and Nutritional Intervention of Shenyang, Shenyang 110036, China.
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2
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Mao Y, Zhu P, Wang J, Fan C, Yu Z, Yao L, He W, Li X, Zhou F, Gan M, Wu X, Geng D. Protective effects of cannabinoid receptor 2 on annulus fibrosus degeneration by upregulating autophagy via AKT-mTOR-p70S6K signal pathway. Biochem Pharmacol 2025; 232:116734. [PMID: 39710272 DOI: 10.1016/j.bcp.2024.116734] [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: 08/19/2024] [Revised: 12/11/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
As an important pathological process, annulus fibrosus (AF) degeneration contributes greatly to intervertebral disc degeneration (IVDD). Moreover, extracellular matrix (ECM) degradation and AF cell (AFC) autophagy are of utmost importance. The involvement of cannabinoid receptor type 2 (CB2) in the pathological mechanisms underlying different diseases has been demonstrated dueto its capacity toregulateautophagy. The objective of this study was to explore the impact of CB2-induced autophagy on AF degeneration and its underlying mechanism. First, the expression of CB2 in human degenerative AF tissues decreased with increasing degeneration degree, whereas its expression in rat AFCs increased in a concentration- and time-dependent manner following H2O2 intervention. Activation of CB2 increased collagen Ⅰ and Ⅱ expression while decreasing MMP3 and MMP13 expression. In addition, p62 expression decreased, whereas beclin-1 and LC3-Ⅱ/LC3-Ⅰ expression increased after JWH133 intervention. After CB2 activation, the addition of 3-MA impeded the synthesis of collagen Ⅰ and Ⅱ while preserving the elevated levels of MMP3 and MMP13. The activation of CB2 greatly suppressed the protein levels of the AKT/mTOR/p70S6K signaling pathway. In vivo, the JWH133 group exhibited elevated disk height index (DHI) and MRI signals, along with a comparatively intact structure of the intervertebral disc in contrast to the vehicle group. In general, CB2 activation could modulate apoptosis and autophagy in rat AFCs, thereby mitigating the advancement of IVDD. Moreover, the AKT/mTOR/p70S6K signaling pathway plays a role in the development of AF degeneration through the regulation of autophagy. The findings suggest that CB2 is a potentially effective therapeutic target for IVDD.
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Affiliation(s)
- Yubo Mao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Department of Orthopedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, Jiangsu, China
| | - Pengfei Zhu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
| | - Jiale Wang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
| | - Chunyang Fan
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
| | - Zilin Yu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
| | - Lingye Yao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
| | - Wei He
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
| | - Xinyun Li
- Department of Orthopedics, Medical School of Nantong University Clinical Medicine, Nantong 226000, Jiangsu, China
| | - Feng Zhou
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.
| | - Minfeng Gan
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.
| | - Xiexing Wu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.
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3
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Roato I, Visca M, Mussano F. Suppressing the Aging Phenotype of Mesenchymal Stromal Cells: Are We Ready for Clinical Translation? Biomedicines 2024; 12:2811. [PMID: 39767719 PMCID: PMC11673080 DOI: 10.3390/biomedicines12122811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are involved in the maintenance and regeneration of a large variety of tissues due to their stemness and multi-lineage differentiation capability. Harnessing these advantageous features, a flurry of clinical trials have focused on MSCs to treat different pathologies, but only few protocols have received regulatory approval so far. Among the various causes hindering MSCs' efficacy is the emergence of cellular senescence, which has been correlated with specific characteristics, such as morphological and epigenetic alterations, DNA damage, ROS production, mitochondrial dysfunction, telomere shortening, non-coding RNAs, loss of proteostasis, and a peculiar senescence-associated secretory phenotype. Several strategies have been investigated for delaying or even hopefully reverting the onset of senescence, as assessed by the senescent phenotype of MSCs. Here, the authors reviewed the most updated literature on the potential causes of senescence, with a particular emphasis on the current and future therapeutic approaches aimed at reverting senescence and/or extending the functional lifespan of stem cells.
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Affiliation(s)
- Ilaria Roato
- Department of Surgical Sciences, CIR-Dental School, University of Turin, 10126 Turin, Italy; (M.V.); (F.M.)
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Bourebaba L, Bourebaba N, Galuppo L, Marycz K. Artificial mitochondrial transplantation (AMT) reverses aging of mesenchymal stromal cells and improves their immunomodulatory properties in LPS-induced synoviocytes inflammation. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119806. [PMID: 39098401 DOI: 10.1016/j.bbamcr.2024.119806] [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: 02/01/2024] [Revised: 07/26/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024]
Abstract
Nowadays, regenerative medicine techniques are usually based on the application of mesenchymal stromal cells (MSCs) for the repair or restoration of injured damaged tissues. However, the effectiveness of autologous therapy is limited as therapeutic potential of MSCs declines due to patient's age, health condition and prolonged in vitro cultivation as a result of decreased growth rate. For that reason, there is an urgent need to develop strategies enabling the in vitro rejuvenation of MSCs prior transplantation in order to enhance their in vivo therapeutic efficiency. In presented study, we attempted to mimic the naturally occurring mitochondrial transfer (MT) between neighbouring cells and verify whether artificial MT (AMT) could reverse MSCs aging and improve their biological properties. For that reason, mitochondria were isolated from healthy donor equine adipose-derived stromal cells (ASCs) and transferred into metabolically impaired recipient ASCs derived from equine metabolic syndrome (EMS) affected horses, which were subsequently subjected to various analytical methods in order to verify the cellular and molecular outcomes of the applied AMT. Mitochondria recipient cells were characterized by decreased apoptosis, senescence and endoplasmic reticulum stress while insulin sensitivity was enhanced. Furthermore, we observed increased mitochondrial fragmentation and associated PARKIN protein accumulation, which indicates on the elimination of dysfunctional organelles via mitophagy. AMT further promoted physioxia and regulated autophagy fluxes. Additionally, rejuvenated ASCs displayed an improved anti-inflammatory activity toward LPS-stimulated synoviocytes. The presented findings highlight AMT as a promising alternative and effective method for MSCs rejuvenation, for potential application in autologous therapies in which MSCs properties are being strongly deteriorated due to patients' condition.
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Affiliation(s)
- Lynda Bourebaba
- Department of Experimental Biology, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland.
| | - Nabila Bourebaba
- Department of Experimental Biology, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland
| | - Larry Galuppo
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95516, United States
| | - Krzysztof Marycz
- Department of Experimental Biology, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland; Department of Veterinary Medicine and Epidemiology, Veterinary Institute for Regenerative Cures, School of Veterinary Medicine, University of California, Davis, CA 95516, United States.
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5
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Qu Y, Wang Z, Dong L, Zhang D, Shang F, Li A, Gao Y, Bai Q, Liu D, Xie X, Ming L. Natural small molecules synergize mesenchymal stem cells for injury repair in vital organs: a comprehensive review. Stem Cell Res Ther 2024; 15:243. [PMID: 39113141 PMCID: PMC11304890 DOI: 10.1186/s13287-024-03856-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 07/17/2024] [Indexed: 08/10/2024] Open
Abstract
Mesenchymal stem cells (MSCs) therapy is a highly researched treatment that has the potential to promote immunomodulation and anti-inflammatory, anti-apoptotic, and antimicrobial activities. It is thought that it can enhance internal organ function, reverse tissue remodeling, and achieve significant organ repair and regeneration. However, the limited infusion, survival, and engraftment of transplanted MSCs diminish the effectiveness of MSCs-based therapy. Consequently, various preconditioning methods have emerged as strategies for enhancing the therapeutic effects of MSCs and achieving better clinical outcomes. In particular, the use of natural small molecule compounds (NSMs) as a pretreatment strategy is discussed in this narrative review, with a focus on their roles in regulating MSCs for injury repair in vital internal organs. Additionally, the discussion focuses on the future directions and challenges of transforming mesenchymal stem cell research into clinical applications.
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Affiliation(s)
- Yanling Qu
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Zhe Wang
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Lingjuan Dong
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Dan Zhang
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Fengqing Shang
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510000, China
| | - Afeng Li
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Yanni Gao
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Qinhua Bai
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Dan Liu
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China
| | - Xiaodong Xie
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu Province, China.
| | - Leiguo Ming
- Shaanxi Zhonghong, Institute of Regenerative Medicine, Xi'an, 710003, Shaanxi Province, China.
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu Province, China.
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6
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Meissner JM, Chmielińska A, Ofri R, Cisło-Sankowska A, Marycz K. Extracellular Vesicles Isolated from Equine Adipose-Derived Stromal Stem Cells (ASCs) Mitigate Tunicamycin-Induced ER Stress in Equine Corneal Stromal Stem Cells (CSSCs). Curr Issues Mol Biol 2024; 46:3251-3277. [PMID: 38666934 PMCID: PMC11048834 DOI: 10.3390/cimb46040204] [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: 02/26/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Corneal ulcers, characterized by severe inflammation of the cornea, can lead to serious, debilitating complications and may be vision-threatening for horses. In this study, we aimed to investigate the role of endoplasmic reticulum (ER) stress in corneal stem progenitor cell (CSSC) dysfunction and explore the potential of equine adipose-derived stromal stem cell (ASC)-derived extracellular vesicles (EVs) to improve corneal wound healing. We showed that CSSCs expressed high levels of CD44, CD45, and CD90 surface markers, indicating their stemness. Supplementation of the ER-stress-inducer tunicamycin to CSSCs resulted in reduced proliferative and migratory potential, accumulation of endoplasmic reticulum (ER)-stressed cells in the G0/G1 phase of the cell cycle, increased expression of proinflammatory genes, induced oxidative stress and sustained ER stress, and unfolded protein response (UPR). Importantly, treatment with EVs increased the proliferative activity and number of cells in the G2/Mitosis phase, enhanced migratory ability, suppressed the overexpression of proinflammatory cytokines, and upregulated the anti-inflammatory miRNA-146a-5p, compared to control and/or ER-stressed cells. Additionally, EVs lowered the expression of ER-stress master regulators and effectors (PERK, IRE1, ATF6, and XBP1), increased the number of mitochondria, and reduced the expression of Fis-1 and Parkin, thereby promoting metabolic homeostasis and protecting against apoptosis in equine CSSCs. Our findings demonstrate that MSCs-derived EVs represent an innovative and promising therapeutic strategy for the transfer of bioactive mediators which regulate various cellular and molecular signaling pathways.
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Affiliation(s)
- Justyna M. Meissner
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland;
| | - Aleksandra Chmielińska
- International Institute of Translational Medicine, Jesionowa 11, Malin, 55-114 Wisznia Mala, Poland; (A.C.); (A.C.-S.)
| | - Ron Ofri
- Koret School of Veterinary Medicine, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 7610001, Israel;
| | - Anna Cisło-Sankowska
- International Institute of Translational Medicine, Jesionowa 11, Malin, 55-114 Wisznia Mala, Poland; (A.C.); (A.C.-S.)
| | - Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland;
- International Institute of Translational Medicine, Jesionowa 11, Malin, 55-114 Wisznia Mala, Poland; (A.C.); (A.C.-S.)
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95516, USA
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7
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Li W, Xiang Z, Yu W, Huang X, Jiang Q, Abumansour A, Yang Y, Chen C. Natural compounds and mesenchymal stem cells: implications for inflammatory-impaired tissue regeneration. Stem Cell Res Ther 2024; 15:34. [PMID: 38321524 PMCID: PMC10848428 DOI: 10.1186/s13287-024-03641-3] [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: 10/07/2023] [Accepted: 01/21/2024] [Indexed: 02/08/2024] Open
Abstract
Inflammation is a common and important pathological process occurring in any part of the body and relating to a variety of diseases. Effective tissue repair is critical for the survival of impaired organisms. Considering the side effects of the currently used anti-inflammatory medications, new therapeutic agents are urgently needed for the improvement of regenerative capacities of inflammatory-impaired tissues. Mesenchymal stromal stem/progenitor cells (MSCs) are characterized by the capabilities of self-renewal and multipotent differentiation and exhibit immunomodulatory capacity. Due to the ability to modulate inflammatory phenotypes and immune responses, MSCs have been considered as a potential alternative therapy for autoimmune and inflammatory diseases. Natural compounds (NCs) are complex small multiple-target molecules mostly derived from plants and microorganisms, exhibiting therapeutic effects in many disorders, such as osteoporosis, diabetes, cancer, and inflammatory/autoimmune diseases. Recently, increasing studies focused on the prominent effects of NCs on MSCs, including the regulation of cell survival and inflammatory response, as well as osteogenic/adipogenic differentiation capacities, which indicate the roles of NCs on MSC-based cytotherapy in several inflammatory diseases. Their therapeutic effects and fewer side effects in numerous physiological processes, compared to chemosynthetic drugs, made them to be a new therapeutic avenue combined with MSCs for impaired tissue regeneration. Here we summarize the current understanding of the influence of NCs on MSCs and related downstream signaling pathways, specifically in pathological inflammatory conditions. In addition, the emerging concepts through the combination of NCs and MSCs to expand the therapeutic perspectives are highlighted. A promising MSC source from oral/dental tissues is also discussed, with a remarkable potential for MSC-based therapy in future clinical applications.
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Affiliation(s)
- Wen Li
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Zichao Xiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Wenjing Yu
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St., Philadelphia, PA, 19104, USA
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Xiaobin Huang
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St., Philadelphia, PA, 19104, USA
| | - Qian Jiang
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St., Philadelphia, PA, 19104, USA
| | - Arwa Abumansour
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St., Philadelphia, PA, 19104, USA
- Department of Endodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ying Yang
- Research and Innovation Oral Care, Colgate-Palmolive Company, Piscataway, NJ, USA
| | - Chider Chen
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St., Philadelphia, PA, 19104, USA.
- Center of Innovation and Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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8
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Zhang C, Meng Y, Han J. Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate. Cell Mol Life Sci 2024; 81:26. [PMID: 38212548 PMCID: PMC11072137 DOI: 10.1007/s00018-023-05070-6] [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: 11/01/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 01/13/2024]
Abstract
Mitochondria serve as essential organelles that play a key role in regulating stem cell fate. Mitochondrial dysfunction and stem cell exhaustion are two of the nine distinct hallmarks of aging. Emerging research suggests that epigenetic modification of mitochondria-encoded genes and the regulation of epigenetics by mitochondrial metabolites have an impact on stem cell aging or differentiation. Here, we review how key mitochondrial metabolites and behaviors regulate stem cell fate through an epigenetic approach. Gaining insight into how mitochondria regulate stem cell fate will help us manufacture and preserve clinical-grade stem cells under strict quality control standards, contributing to the development of aging-associated organ dysfunction and disease.
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Affiliation(s)
- Chensong Zhang
- State Key Laboratory of Biotherapy and Cancer Center, Frontiers Science Center for Disease-Related Molecular Network, and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yang Meng
- State Key Laboratory of Biotherapy and Cancer Center, Frontiers Science Center for Disease-Related Molecular Network, and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Junhong Han
- State Key Laboratory of Biotherapy and Cancer Center, Frontiers Science Center for Disease-Related Molecular Network, and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
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9
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Kohandel Z, Darrudi M, Naseri K, Samini F, Aschner M, Pourbagher-Shahri AM, Samarghandian S. The Role of Resveratrol in Aging and Senescence: A Focus on Molecular Mechanisms. Curr Mol Med 2024; 24:867-875. [PMID: 37278035 DOI: 10.2174/1566524023666230602162949] [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: 01/18/2023] [Revised: 05/01/2023] [Accepted: 05/04/2023] [Indexed: 06/07/2023]
Abstract
Resveratrol (Res), a polyphenol found in red wine, has been shown to decelerate aging, the progressive loss of physiological integrity and cellular senescence, characterized by the inability to progress through the cell cycle. No successful clinical trials have yet to be completed in humans on dose limitations. Yet, the potent anti-aging and anti-senescence efficacy of Res has been documented in several in vivo animal models. In this review, we highlight the molecular mechanisms of Res efficacy in antiaging disorders, such as diabetes, neurodegenerative disorders, eye diseases, and cardiovascular diseases.
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Affiliation(s)
- Zeynab Kohandel
- Department of Biology, Faculty of Sciences, University of Tehran, Iran
| | - Majid Darrudi
- Department of Basic Sciences, Neyshabur University of Medical Sciences, Neyshabur, 9318614139, Iran
| | - Kobra Naseri
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Fariborz Samini
- Department of Neurosurgery, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
| | | | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran
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10
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Liang J, Zhao J, Chen Y, Li B, Li Y, Lu F, Dong Z. New Insights and Advanced Strategies for In Vitro Construction of Vascularized Tissue Engineering. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:692-709. [PMID: 37409413 DOI: 10.1089/ten.teb.2023.0044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
Inadequate vascularization is a significant barrier to clinical application of large-volume tissue engineered grafts. In contrast to in vivo vascularization, in vitro prevascularization shortens the time required for host vessels to grow into the graft core and minimizes necrosis in the core region of the graft. However, the challenge of prevascularization is to construct hierarchical perfusable vascular networks, increase graft volume, and form a vascular tip that can anastomose with host vessels. Understanding advances in in vitro prevascularization techniques and new insights into angiogenesis could overcome these obstacles. In the present review, we discuss new perspectives on angiogenesis, the differences between in vivo and in vitro tissue vascularization, the four elements of prevascularized constructs, recent advances in perfusion-based in vitro prevascularized tissue fabrication, and prospects for large-volume prevascularized tissue engineering.
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Affiliation(s)
- Jiancong Liang
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Jing Zhao
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Yunzi Chen
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Bin Li
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Ye Li
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Feng Lu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Ziqing Dong
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
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11
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Mas-Bargues C. Mitochondria pleiotropism in stem cell senescence: Mechanisms and therapeutic approaches. Free Radic Biol Med 2023; 208:657-671. [PMID: 37739140 DOI: 10.1016/j.freeradbiomed.2023.09.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/10/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
Aging is a complex biological process characterized by a progressive decline in cellular and tissue function, ultimately leading to organismal aging. Stem cells, with their regenerative potential, play a crucial role in maintaining tissue homeostasis and repair throughout an organism's lifespan. Mitochondria, the powerhouses of the cell, have emerged as key players in the aging process, impacting stem cell function and contributing to age-related tissue dysfunction. Here are discuss the mechanisms through which mitochondria influence stem cell fate decisions, including energy production, metabolic regulation, ROS signalling, and epigenetic modifications. Therefore, this review highlights the role of mitochondria in driving stem cell senescence and the subsequent impact on tissue function, leading to overall organismal aging and age-related diseases. Finally, we explore potential anti-aging therapies targeting mitochondrial health and discuss their implications for promoting healthy aging. This comprehensive review sheds light on the critical interplay between mitochondrial function, stem cell senescence, and organismal aging, offering insights into potential strategies for attenuating age-related decline and promoting healthy longevity.
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Affiliation(s)
- Cristina Mas-Bargues
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010, Valencia, Spain.
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12
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Huang X, Liu Y, Li Z, Lerman LO. Mesenchymal Stem/Stromal Cells Therapy for Metabolic Syndrome: Potential Clinical Application? Stem Cells 2023; 41:893-906. [PMID: 37407022 PMCID: PMC10560401 DOI: 10.1093/stmcls/sxad052] [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: 01/31/2023] [Accepted: 06/21/2023] [Indexed: 07/07/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs), a class of cells with proliferative, immunomodulatory, and reparative functions, have shown therapeutic potential in a variety of systemic diseases, including metabolic syndrome (MetS). The cluster of morbidities that constitute MetS might be particularly amenable for the application of MSCs, which employ an arsenal of reparative actions to target multiple pathogenic pathways simultaneously. Preclinical studies have shown that MSCs can reverse pathological changes in MetS mainly by inhibiting inflammation, improving insulin resistance, regulating glycolipid metabolism, and protecting organ function. However, several challenges remain to overcome before MSCs can be applied for treating MetS. For example, the merits of autologous versus allogeneic MSCs sources remain unclear, particularly with autologous MSCs obtained from the noxious MetS milieu. The distinct characteristics and relative efficacy of MSCs harvested from different tissue sources also require clarification. Moreover, to improve the therapeutic efficacy of MSCs, investigators have explored several approaches that improved therapeutic efficacy but may involve potential safety concerns. This review summarized the potentially useful MSCs strategy for treating MetS, as well as some hurdles that remain to be overcome. In particular, larger-scale studies are needed to determine the therapeutic efficacy and safety of MSCs for clinical application.
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Affiliation(s)
- Xiuyi Huang
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Yunchong Liu
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Zilun Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
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Han X, Li W, He X, Lu X, Zhang Y, Li Y, Bi G, Ma X, Huang X, Bai R, Zhang H. Blockade of TGF-β signalling alleviates human adipose stem cell senescence induced by native ECM in obesity visceral white adipose tissue. Stem Cell Res Ther 2023; 14:291. [PMID: 37807066 PMCID: PMC10561428 DOI: 10.1186/s13287-023-03525-y] [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: 01/03/2023] [Accepted: 09/27/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND Abdominal obesity is appreciated as a major player in insulin resistance and metabolically dysfunctional adipose tissue. Inappropriate extracellular matrix (ECM) remodelling and functional alterations in human adipose stromal/stem cells (hASCs) have been linked with visceral white adipose tissue (vWAT) dysfunction in obesity. Understanding the interactions between hASCs and the native ECM environment in obese vWAT is required for the development of future therapeutic approaches for obesity-associated metabolic complications. METHODS The phenotypes and transcriptome properties of hASCs from the vWAT of obese patients and lean donors were assessed. The hASC-derived matrix from vWAT of obese or lean patients was generated in vitro using a decellularized method. The topography and the major components of the hASC-derived matrix were determined. The effects of the obese hASC-derived matrix on cell senescence and mitochondrial function were further determined. RESULTS We showed that hASCs derived from the vWAT of obese patients exhibited senescence and were accompanied by the increased production of ECM. The matrix secreted by obese hASCs formed a fibrillar suprastructure with an abundance of fibronectin, type I collagen, and transforming growth factor beta 1 (TGF-β1), which resembles the native matrix microenvironment of hASCs in vWAT derived from obese patients. Furthermore, the obese hASC-derived matrix promoted lean hASC ageing and induced mitochondrial dysfunction compared to the lean hASC-derived matrix. Blockade of TGF-β1 signalling using an anti-TGF-β1 neutralizing antibody alleviated the lean hASC senescence and mitochondrial dysfunction induced by the obese hASC-derived matrix. CONCLUSIONS Native ECM in obesity vWAT initiates hASC senescence through TGF-β1-mediated mitochondrial dysfunction. These data provide a key mechanism for understanding the importance of cell-ECM interactions in hASCs senescence in obesity.
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Affiliation(s)
- Xueya Han
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
| | - Weihong Li
- Experimental Center for Basic Medical Teaching, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
| | - Xu He
- Experimental Center for Basic Medical Teaching, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
| | - Xin Lu
- Experimental Center for Basic Medical Teaching, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
| | - Yu Zhang
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
| | - Yaqiong Li
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
| | - Guoyun Bi
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
| | - Xuqing Ma
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
| | - Xiaowu Huang
- Fu Xing Hospital, Capital Medical University, Beijing, 100038, China
| | - Rixing Bai
- Department of General Surgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, 100070, China
| | - Haiyan Zhang
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China.
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Bourebaba L, Zyzak M, Sikora M, Serwotka-Suszczak A, Mularczyk M, Al Naem M, Marycz K. Sex Hormone-Binding Globulin (SHBG) Maintains Proper Equine Adipose-Derived Stromal Cells (ASCs)' Metabolic Functions and Negatively Regulates their Basal Adipogenic Potential. Stem Cell Rev Rep 2023; 19:2251-2273. [PMID: 37402098 PMCID: PMC10579166 DOI: 10.1007/s12015-023-10580-8] [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: 06/17/2023] [Indexed: 07/05/2023]
Abstract
BACKGROUND Sex hormone binding globulin (SHBG) deteriorated expression has been recently strongly correlated to increased level of circulating pro-inflammatory cytokines and insulin resistance, which are typical manifestations of equine metabolic syndrome (EMS). Despite previous reports demonstrated the potential therapeutic application of SHBG for liver-related dysfunctions, whether SHBG might modulate equine adipose-derived stem/stromal cells (EqASCs) metabolic machinery remains unknown. Therefore, we evaluated for the first time the impact of SHBG protein on metabolic changes in ASCs isolated from healthy horses. METHODS Beforehand, SHBG protein expression has been experimentally lowered using a predesigned siRNA in EqASCs to verify its metabolic implications and potential therapeutic value. Then, apoptosis profile, oxidative stress, mitochondrial network dynamics and basal adipogenic potential have been evaluated using various molecular and analytical techniques. RESULTS The SHBG knockdown altered the proliferative and metabolic activity of EqASCs, while dampening basal apoptosis via Bax transcript suppression. Furthermore, the cells treated with siRNA were characterized by senescent phenotype, accumulation of reactive oxygen species (ROS), nitric oxide, as well as decreased mitochondrial potential that was shown by mitochondrial membrane depolarization and lower expression of key mitophagy factors: PINK, PARKIN and MFN. The addition of SHBG protein reversed the impaired and senescent phenotype of EMS-like cells that was proven by enhanced proliferative activity, reduced apoptosis resistance, lower ROS accumulation and greater mitochondrial dynamics, which is proposed to be related to a normalization of Bax expression. Crucially, SHBG silencing enhanced the expression of key pro-adipogenic effectors, while decreased the abundance of anti-adipogenic factors namely HIF1-α and FABP4. The addition of exogenous SHBG further depleted the expression of PPARγ and C/EBPα and restored the levels of FABP4 and HIF1-α evoking a strong inhibitory potential toward ASCs adipogenesis. CONCLUSION Herein, we provide for the first time the evidence that SHBG protein in importantly involved in various key metabolic pathways governing EqASCs functions, and more importantly we showed that SHBG negatively affect the basal adipogenic potential of tested ASCs through a FABP4-dependant pathway, and provide thus new insights for the development of potential anti-obesity therapeutic approach in both animals and humans.
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Affiliation(s)
- Lynda Bourebaba
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland
| | - Magdalena Zyzak
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland
| | - Mateusz Sikora
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland
| | - Anna Serwotka-Suszczak
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland
| | - Malwina Mularczyk
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland
| | - Mohamad Al Naem
- Faculty of Veterinary Medicine, Equine Clinic - Equine Surgery, Justus-Liebig-University, 35392, Gießen, Germany
| | - Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.
- Department of Veterinary Medicine and Epidemiology, Veterinary Institute for Regenerative Cures, School of Veterinary Medicine, University of California, Davis, CA, USA.
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15
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TAMURA N, HEIDARI N, FARAGHER RG, SMITH RK, DUDHIA J. Effects of resveratrol and its analogues on the cell cycle of equine mesenchymal stem/stromal cells. J Equine Sci 2023; 34:67-72. [PMID: 37781569 PMCID: PMC10534064 DOI: 10.1294/jes.34.67] [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: 01/04/2023] [Accepted: 04/28/2023] [Indexed: 10/03/2023] Open
Abstract
Resveratrol (RSV; trans-3,5,4'-trihydroxystilbene) strongly activates sirtuin 1, and it and its analogue V29 enhance the proliferation of mesenchymal stem/stromal cells (MSCs).Although culture medium containing 5-azacytydine and RSV inhibits senescence of adipose tissue-derived MSCs isolated from horses with metabolic syndrome, few studies have reported the effects of RSV on equine bone marrow-derived MSCs (eBMMSCs) isolated from horses without metabolic syndrome. The aim of this study was to investigate the effects of RSV and V29 on the cell cycle of eBMMSCs. Following treatment with 5 µM RSV or 10 µM V29, the cell proliferation capacity of eBMMSCs derived from seven horses was evaluated by EdU (5-ethynyl-2'-deoxyuridine) and Ki-67 antibody assays. Brightfield images of cells and immunofluorescent images of EdU, Ki-67, and DAPI staining were recorded by fluorescence microscopy, and the number of cells positive for each was quantified and compared by Friedman's test at P<0.05. The growth fraction of eBMMSCs was significantly increased by RSV and V29 as measured by the EdU assay (control 28.1% ± 13.8%, V29 31.8% ± 14.6%, RSV 32.0% ± 10.8%; mean ± SD; P<0.05) but not as measured by the Ki-67 antibody assay (control 27.0% ± 11.2%, V29 27.4% ± 10.8%, RSV 27.7% ± 6.8%). RSV and V29 promoted progression of the cell cycle of eBMMSCs into the S phase and may be useful for eBMMSC expansion.
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Affiliation(s)
- Norihisa TAMURA
- Clinical Veterinary Medicine Division, Equine
Research Institute, Japan Racing Association, Tochigi 329-0412,
Japan
- Department of Clinical Sciences and Services,
Royal Veterinary College, University of London, Hatfield AL9 7TA, UK
| | - Neda HEIDARI
- Department of Clinical Sciences and Services,
Royal Veterinary College, University of London, Hatfield AL9 7TA, UK
| | - Richard G.A. FARAGHER
- School of Pharmacy and Biomolecular Sciences,
University of Brighton, Brighton BN2 4GJ, UK
| | - Roger K.W. SMITH
- Department of Clinical Sciences and Services,
Royal Veterinary College, University of London, Hatfield AL9 7TA, UK
| | - Jayesh DUDHIA
- Department of Clinical Sciences and Services,
Royal Veterinary College, University of London, Hatfield AL9 7TA, UK
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Jeremic D, Jiménez-Díaz L, Navarro-López JD. Targeting epigenetics: A novel promise for Alzheimer's disease treatment. Ageing Res Rev 2023; 90:102003. [PMID: 37422087 DOI: 10.1016/j.arr.2023.102003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/30/2023] [Accepted: 07/03/2023] [Indexed: 07/10/2023]
Abstract
So far, the search for a cure for Alzheimer Disease (AD) has been unsuccessful. The only approved drugs attenuate some symptoms, but do not halt the progress of this disease, which affects 50 million people worldwide and will increase its incidence in the coming decades. Such scenario demands new therapeutic approaches to fight against this devastating dementia. In recent years, multi-omics research and the analysis of differential epigenetic marks in AD subjects have contributed to our understanding of AD; however, the impact of epigenetic research is yet to be seen. This review integrates the most recent data on pathological processes and epigenetic changes relevant for aging and AD, as well as current therapies targeting epigenetic machinery in clinical trials. Evidence shows that epigenetic modifications play a key role in gene expression, which could provide multi-target preventative and therapeutic approaches in AD. Both novel and repurposed drugs are employed in AD clinical trials due to their epigenetic effects, as well as increasing number of natural compounds. Given the reversible nature of epigenetic modifications and the complexity of gene-environment interactions, the combination of epigenetic-based therapies with environmental strategies and drugs with multiple targets might be needed to properly help AD patients.
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Affiliation(s)
- Danko Jeremic
- University of Castilla-La Mancha, NeuroPhysiology & Behavior Lab, Biomedical Research Center (CRIB), School of Medicine of Ciudad Real, Spain
| | - Lydia Jiménez-Díaz
- University of Castilla-La Mancha, NeuroPhysiology & Behavior Lab, Biomedical Research Center (CRIB), School of Medicine of Ciudad Real, Spain.
| | - Juan D Navarro-López
- University of Castilla-La Mancha, NeuroPhysiology & Behavior Lab, Biomedical Research Center (CRIB), School of Medicine of Ciudad Real, Spain.
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Glasstetter LM, Oderinde TS, Mirchandani M, Rajagopalan KS, Barsom SH, Thaler R, Siddiqi S, Zhu XY, Tang H, Jordan KL, Saadiq IM, van Wijnen AJ, Eirin A, Lerman LO. Obesity and dyslipidemia are associated with partially reversible modifications to DNA hydroxymethylation of apoptosis- and senescence-related genes in swine adipose-derived mesenchymal stem/stromal cells. Stem Cell Res Ther 2023; 14:143. [PMID: 37231414 PMCID: PMC10214739 DOI: 10.1186/s13287-023-03372-x] [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: 06/16/2022] [Accepted: 05/09/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND Obesity dysregulates key biological processes underlying the functional homeostasis, fate decisions, and reparative potential of mesenchymal stem/stromal cells (MSCs). Mechanisms directing obesity-induced phenotypic alterations in MSCs remain unclear, but emerging drivers include dynamic modification of epigenetic marks, like 5-hydroxymethylcytosine (5hmC). We hypothesized that obesity and cardiovascular risk factors induce functionally relevant, locus-specific changes in 5hmC of swine adipose-derived MSCs and evaluated their reversibility using an epigenetic modulator, vitamin-C. METHODS Female domestic pigs were fed a 16-week Lean or Obese diet (n = 6 each). MSCs were harvested from subcutaneous adipose tissue, and 5hmC profiles were examined through hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq) followed by an integrative (hMeDIP and mRNA sequencing) gene set enrichment analysis. For clinical context, we compared 5hmC profiles of adipose tissue-derived human MSCs harvested from patients with obesity and healthy controls. RESULTS hMeDIP-seq revealed 467 hyper- (fold change ≥ 1.4; p-value ≤ 0.05) and 591 hypo- (fold change ≤ 0.7; p-value ≤ 0.05) hydroxymethylated loci in swine Obese- versus Lean-MSCs. Integrative hMeDIP-seq/mRNA-seq analysis identified overlapping dysregulated gene sets and discrete differentially hydroxymethylated loci with functions related to apoptosis, cell proliferation, and senescence. These 5hmC changes were associated with increased senescence in cultured MSCs (p16/CDKN2A immunoreactivity, senescence-associated β-galactosidase [SA-β-Gal] staining), were partly reversed in swine Obese-MSCs treated with vitamin-C, and shared common pathways with 5hmC changes in human Obese-MSCs. CONCLUSIONS Obesity and dyslipidemia are associated with dysregulated DNA hydroxymethylation of apoptosis- and senescence-related genes in swine and human MSCs, potentially affecting cell vitality and regenerative functions. Vitamin-C may mediate reprogramming of this altered epigenomic landscape, providing a potential strategy to improve the success of autologous MSC transplantation in obese patients.
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Affiliation(s)
- Logan M Glasstetter
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Tomiwa S Oderinde
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Mohit Mirchandani
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | | | - Samer H Barsom
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Roman Thaler
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Sarosh Siddiqi
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Kyra L Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Ishran M Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | | | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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18
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Punzón E, García-Castillo M, Rico MA, Padilla L, Pradera A. Local, systemic and immunologic safety comparison between xenogeneic equine umbilical cord mesenchymal stem cells, allogeneic canine adipose mesenchymal stem cells and placebo: a randomized controlled trial. Front Vet Sci 2023; 10:1098029. [PMID: 37266387 PMCID: PMC10229832 DOI: 10.3389/fvets.2023.1098029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 04/26/2023] [Indexed: 06/03/2023] Open
Abstract
Mesenchymal stem cells are multipotent cells with a wide range of therapeutic applications, including, among others, tissue regeneration. This work aims to test the safety (EUC-MSC) of intra-articular administration of equine umbilical cord mesenchymal stem cells in young healthy dogs under field conditions following single and repeated administration. This was compared with the safety profile of allogenic canine adipose derived mesenchymal stem cells (CAD-MSC) and placebo in order to define the safety of xenogeneic use of mesenchymal stem cells when administered intra-articular. Twenty-four police working dogs were randomized in three groups in a proportion 1:1:1. EUC-MSCs and CAD-MSCs were obtained from healthy donors and were manufactured following company SOPs and under GMP and GMP-like conditions, respectively, and compliant all necessary controls to ensure the quality of the treatment. The safety of the treatment was evaluated locally, systemically and immunologically. For this purpose, an orthopedic examination and Glasgow test for the assessment of pain in the infiltrated joint, blood tests, clinical examination and analysis of the humoral and cellular response to treatment were performed. No adverse events were detected following single and repeated MSC administration despite both equine and canine MSC generate antibody titres in the dogs. The intra-articular administration of equine umbilical cord mesenchymal stem cells in dogs has demonstrated to be safe.
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Shao C, Liu Y, Zhao Y, Jing Y, Li J, Lv Z, Fu T, Wang Z, Li G. DNA methyltransferases inhibitor azacitidine improves the skeletal phenotype of mild osteogenesis imperfecta by reversing the impaired osteogenesis and excessive osteoclastogenesis. Bone 2023; 170:116706. [PMID: 36822490 DOI: 10.1016/j.bone.2023.116706] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 02/06/2023] [Accepted: 02/12/2023] [Indexed: 02/24/2023]
Abstract
BACKGROUND Osteogenesis imperfecta (OI), as a disease of congenital bone dysplasia, is often accompanied by the abnormal alteration of bone absorption and bone formation. DNA methyltransferases (Dnmts) can regulate the gene expression involved in osteogenesis and osteoclastogenesis. Dnmts changes and their effects on bone cells under OI is poorly understood. METHODS The Dnmts expression in adipose derived mesenchymal stem cells (ADSCs), bone marrow derived pre-osteoclasts (pre-Ocs) and femurs of Col1a2oim/+ and Col1a1+/-365 mice, both modeling mild OI types, were determined. The effects of azacitidine (Aza) administration and Dnmt3a knockdown by ShRNA on the osteogenic differentiation of ADSCs together with osteoclasts (Ocs) production of pre-Ocs were studied in vitro. The synthesis and secretion of collagen fibers of OI derived ADSCs were examined. The therapeutic outcomes of intraperitoneal (i.p.) infused Aza (1 mg/kg/2d) for 30 days were evaluated in OI mice. RESULTS Obviously elevated expression of Dnmts, especially Dnmt3a, existed in ADSCs, pre-Ocs, and femurs isolated from OI modeled mice. Much more collagen molecules of mutant ADSCs were secreted into the extracellular medium post Aza addition. Both Aza administration and Dnmt3a knockdown effectively enhanced the bone-forming capacity of affected ADSCs and reduced Ocs formation of OI mice in vitro. Aza treatment apparently improved the femora microstructure and biomechanical properties, increased bone formation and decreased the number of Ocs in mice with OI. CONCLUSION Highly expressed Dnmt3a contributed to the impaired osteogenesis and enhanced osteoclastogenesis of collagen defect-related OI. Aza medication effectively improved the femora phenotype of the two types of OI modeled mice partly by Dnmts inhibition and modulating cell stress response. These findings facilitated understanding the role of Dnmts alteration in skeletal pathological development of mild OI and preliminary confirmed the therapeutic potential of Dnmts depressants in mild OI treatment. Still, further researches are needed to explore the specific function of Dnmts in OI bones and clarify the benefits of Aza administration in OI treatment.
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Affiliation(s)
- Chenyi Shao
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Yi Liu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Yuxia Zhao
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Yaqing Jing
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Jiaci Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Zhe Lv
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Ting Fu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Zihan Wang
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Guang Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China.
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Rajagopalan KS, Kazeminia S, Glasstetter LM, Farahani RA, Zhu XY, Tang H, Jordan KL, Chade AR, Lerman A, Lerman LO, Eirin A. Metabolic Syndrome Induces Epigenetic Alterations in Mitochondria-Related Genes in Swine Mesenchymal Stem Cells. Cells 2023; 12:1274. [PMID: 37174674 PMCID: PMC10177475 DOI: 10.3390/cells12091274] [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: 01/26/2023] [Revised: 04/12/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Autologous mesenchymal stem/stromal cells (MSCs) have demonstrated important therapeutic effects in several diseases. Cardiovascular risk factors may impair MSC mitochondrial structure and function, but the underlying mechanisms remain unknown. We hypothesized that metabolic syndrome (MetS) induces epigenetic alterations in mitochondria-related genes in swine MSCs. Pigs were fed a Lean or MetS diet (n = 6 each) for 16 weeks. MSCs were collected from subcutaneous abdominal fat, and DNA hydroxymethylation (5 hmC) profiles of mitochondria-related genes (MitoCarta-2.0) were analyzed by hydroxymethylated DNA immunoprecipitation and next-generation sequencing (hMeDIP-seq) in Lean- and MetS-MSCs untreated or treated with the epigenetic modulator vitamin (Vit)-C (n = 3 each). Functional analysis of genes with differential 5 hmC regions was performed using DAVID6.8. Mitochondrial structure (electron microscopy), oxidative stress, and membrane potential were assessed. hMeDIP-seq identified 172 peaks (associated with 103 mitochondrial genes) with higher and 416 peaks (associated with 165 mitochondrial genes) with lower 5 hmC levels in MetS-MSCs versus Lean-MSCs (≥2-fold, p < 0.05). Genes with higher 5 hmC levels in MetS + MSCs were primarily implicated in fatty acid metabolism, whereas those with lower 5 hmC levels were associated with electron transport chain activity. Vit-C increased 5 hmC levels in mitochondrial antioxidant genes, improved mitochondrial structure and membrane potential, and decreased oxidative stress. MetS alters 5 hmC levels of mitochondria-related genes in swine MSCs. Vit-C modulated 5 hmC levels in these genes and preserved mitochondrial structure and function in MetS-MSCs. These observations may contribute to development of strategies to overcome the deleterious effects of MetS on MSCs.
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Affiliation(s)
| | - Sara Kazeminia
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Rahele A. Farahani
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA
| | - Kyra L. Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA
| | - Alejandro R. Chade
- Department of Medical Pharmacology and Physiology and Department of Medicine, University of Missouri-Columbia, Columbia, MO 65211, USA
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA
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21
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Kowalczuk A, Marycz K, Kornicka J, Groborz S, Meissner J, Mularczyk M. Tetrahydrocannabivarin (THCV) Protects Adipose-Derived Mesenchymal Stem Cells (ASC) against Endoplasmic Reticulum Stress Development and Reduces Inflammation during Adipogenesis. Int J Mol Sci 2023; 24:ijms24087120. [PMID: 37108282 PMCID: PMC10138341 DOI: 10.3390/ijms24087120] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/01/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
The endoplasmic reticulum (ER) fulfills essential duties in cell physiology, and impairment of this organelle's functions is associated with a wide number of metabolic diseases. When ER stress is generated in the adipose tissue, it is observed that the metabolism and energy homeostasis of the adipocytes are altered, leading to obesity-associated metabolic disorders such as type 2 diabetes (T2D). In the present work, we aimed to evaluate the protective effects of Δ9-tetrahydrocannabivarin (THCV, a cannabinoid compound isolated from Cannabis sativa L.) against ER stress in adipose-derived mesenchymal stem cells. Our results show that pre-treatment with THCV prevents the subcellular alteration of cell components such as nuclei, F-actin, or mitochondria distribution, and restores cell migration, cell proliferation and colony-forming capacity upon ER stress. In addition, THCV partially reverts the effects that ER stress induces regarding the activation of apoptosis and the altered anti- and pro-inflammatory cytokine profile. This indicates the protective characteristics of this cannabinoid compound in the adipose tissue. Most importantly, our data demonstrate that THCV decreases the expression of genes involved in the unfolded protein response (UPR) pathway, which were upregulated upon induction of ER stress. Altogether, our study shows that the cannabinoid THCV is a promising compound that counters the harmful effects triggered by ER stress in the adipose tissue. This work paves the way for the development of new therapeutic means based on THCV and its regenerative properties to create a favorable environment for the development of healthy mature adipocyte tissue and to reduce the incidence and clinical outcome of metabolic diseases such as diabetes.
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Affiliation(s)
- Anna Kowalczuk
- National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland
| | - Krzysztof Marycz
- International Institute of Translational Medicine, Jesionowa 11, 55-114 Malin, Poland
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland
| | - Justyna Kornicka
- Faculty of Electronics, Photonics and Microsystems, Wrocław University of Science and Technology, Smoluchowskiego 25, 50-372 Wrocław, Poland
| | - Sylwia Groborz
- International Institute of Translational Medicine, Jesionowa 11, 55-114 Malin, Poland
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland
| | - Justyna Meissner
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland
| | - Malwina Mularczyk
- International Institute of Translational Medicine, Jesionowa 11, 55-114 Malin, Poland
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland
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22
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Soltero-Rivera M, Groborz S, Janeczek M, Kornicka J, Wierzgon M, Arzi B, Marycz K. Gingiva-derived Stromal Cells Isolated from Cats Affected with Tooth Resorption Exhibit Increased Apoptosis, Inflammation, and Oxidative Stress while Experiencing Deteriorated Expansion and Anti-Oxidative Defense. Stem Cell Rev Rep 2023:10.1007/s12015-023-10537-x. [PMID: 37039946 DOI: 10.1007/s12015-023-10537-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2023] [Indexed: 04/12/2023]
Abstract
Gingiva-derived mesenchymal stromal cells (GMSCs) are multipotent cells characterized by multilineage differentiation potential, proliferative expansion, and unique immunomodulatory ability, making them attractive as a new treatment of periodontal regeneration. In this study, GMSCs obtained from the gingiva of healthy cats (HE) as well as from cats affected by tooth resorption (TR) were isolated and characterized. Feline GMSCs (fGMSCs) from HE patients exhibited fibroblast-like morphology, developed cellular body, specific growth pattern, high expansion, and proliferative potential as well as reduced senescence signature. fGMSCs demonstrated high s-100 and IL-10 positive cells, while simultaneously having low activity of IL-1. Moreover, high activity of ki-67 combined with reduced senescence markers were noted. In comparison, GMSCs from cats with TR exhibited enlarged nuclei and flat, irregular shape along with increased expression of CD44, s-100 and CD45 and downregulation of CD73. GMSCs from TR cats showed lower ability to form colonies, increased incidence of apoptosis, higher number of senescent cells, and reduced cell migration. Upregulation of pro-inflammatory cytokines was also noted in the TR group along with lower expression of mTOR and miR-17 and upregulation of miR-378. Mitochondrial dynamics, biogenesis and antioxidant properties are also negatively impacted in this group. Collectively, our findings suggest that GMSCs isolated from the gingiva of cats affected with TR have deteriorated functionality caused by impaired proliferation and growth and possibly mediated via mitochondrial dysfunction. fGMSCs or their EV's should be further investigated for their role in the pathophysiology of TR in cats.
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Affiliation(s)
- Maria Soltero-Rivera
- Veterinary Surgical and Radiological Sciences, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Sylwia Groborz
- International Institute of Translational Medicine (MIMT), Jesionowa 16 Str, 55-114, Wisznia Mala, Poland
| | - Maciej Janeczek
- Department of Biostructure and Animal Physiology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Kozuchowska 1/3, 51-631, Wrocław, Poland
| | - Justyna Kornicka
- International Institute of Translational Medicine (MIMT), Jesionowa 16 Str, 55-114, Wisznia Mala, Poland
| | - Monika Wierzgon
- Department of Biostructure and Animal Physiology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Kozuchowska 1/3, 51-631, Wrocław, Poland
| | - Boaz Arzi
- Veterinary Surgical and Radiological Sciences, University of California, One Shields Avenue, Davis, CA, 95616, USA
- Veterinary Institute for Regenerative Cures, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Krzysztof Marycz
- Veterinary Surgical and Radiological Sciences, University of California, One Shields Avenue, Davis, CA, 95616, USA.
- International Institute of Translational Medicine (MIMT), Jesionowa 16 Str, 55-114, Wisznia Mala, Poland.
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.
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23
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Branco A, Moniz I, Ramalho-Santos J. Mitochondria as biological targets for stem cell and organismal senescence. Eur J Cell Biol 2023; 102:151289. [PMID: 36696809 DOI: 10.1016/j.ejcb.2023.151289] [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: 12/20/2022] [Revised: 01/19/2023] [Accepted: 01/19/2023] [Indexed: 01/22/2023] Open
Abstract
Organismal aging is impacted by the deterioration of tissue turnover mechanisms due, in part, to the decline in stem cell function. This decline can be related to mitochondrial dysfunction and underlying energetic defects that, in concert, help drive biological aging. Thus, mitochondria have been described as a potential interventional target to hinder the loss of stem cell robustness, and subsequently, decrease tissue turnover decline and age-associated pathologies. In this review, we focused our analysis on the most recent literature on mitochondria and stem cell aging and discuss the potential benefits of targeting mitochondria in preventing stem cell dysfunction and thus influencing aging.
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Affiliation(s)
- Ana Branco
- CNC-Centre for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Azinhaga de Santa Comba, Polo 3, 3000-548 Coimbra, Portugal
| | - Inês Moniz
- CNC-Centre for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Azinhaga de Santa Comba, Polo 3, 3000-548 Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemão, Polo 2, 3030-789 Coimbra, Portugal
| | - João Ramalho-Santos
- CNC-Centre for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Azinhaga de Santa Comba, Polo 3, 3000-548 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal.
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24
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Wang K, Liu H, Hu Q, Wang L, Liu J, Zheng Z, Zhang W, Ren J, Zhu F, Liu GH. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduct Target Ther 2022; 7:374. [PMID: 36336680 PMCID: PMC9637765 DOI: 10.1038/s41392-022-01211-8] [Citation(s) in RCA: 238] [Impact Index Per Article: 79.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/14/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022] Open
Abstract
Aging is accompanied by the decline of organismal functions and a series of prominent hallmarks, including genetic and epigenetic alterations. These aging-associated epigenetic changes include DNA methylation, histone modification, chromatin remodeling, non-coding RNA (ncRNA) regulation, and RNA modification, all of which participate in the regulation of the aging process, and hence contribute to aging-related diseases. Therefore, understanding the epigenetic mechanisms in aging will provide new avenues to develop strategies to delay aging. Indeed, aging interventions based on manipulating epigenetic mechanisms have led to the alleviation of aging or the extension of the lifespan in animal models. Small molecule-based therapies and reprogramming strategies that enable epigenetic rejuvenation have been developed for ameliorating or reversing aging-related conditions. In addition, adopting health-promoting activities, such as caloric restriction, exercise, and calibrating circadian rhythm, has been demonstrated to delay aging. Furthermore, various clinical trials for aging intervention are ongoing, providing more evidence of the safety and efficacy of these therapies. Here, we review recent work on the epigenetic regulation of aging and outline the advances in intervention strategies for aging and age-associated diseases. A better understanding of the critical roles of epigenetics in the aging process will lead to more clinical advances in the prevention of human aging and therapy of aging-related diseases.
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Affiliation(s)
- Kang Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Huicong Liu
- School of Biomedical Engineering, Shanghai Jiao Tong University, 200030, Shanghai, China
| | - Qinchao Hu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, 100101, Beijing, China
- Hospital of Stomatology, Sun Yat-sen University, 510060, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, 510060, Guangzhou, China
| | - Lingna Wang
- School of Biomedical Engineering, Shanghai Jiao Tong University, 200030, Shanghai, China
| | - Jiaqing Liu
- School of Biomedical Engineering, Shanghai Jiao Tong University, 200030, Shanghai, China
| | - Zikai Zheng
- University of Chinese Academy of Sciences, 100049, Beijing, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, 100101, Beijing, China
| | - Weiqi Zhang
- University of Chinese Academy of Sciences, 100049, Beijing, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, 100101, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China
| | - Jie Ren
- University of Chinese Academy of Sciences, 100049, Beijing, China.
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, 100101, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China.
| | - Fangfang Zhu
- School of Biomedical Engineering, Shanghai Jiao Tong University, 200030, Shanghai, China.
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China.
- University of Chinese Academy of Sciences, 100049, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China.
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, 100101, Beijing, China.
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25
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Kornicka-Garbowska K, Groborz S, Lynda B, Galuppo L, Marycz K. Mitochondria transfer restores fibroblasts-like synoviocytes (FLS) plasticity in LPS-induced, in vitro synovitis model. Cell Commun Signal 2022; 20:137. [PMID: 36071528 PMCID: PMC9450291 DOI: 10.1186/s12964-022-00923-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 06/16/2022] [Indexed: 11/10/2022] Open
Abstract
Background Synovitis (SI) is one of the most common and serious orthopedic diseases in horses of different age, breed and sex, which contributes to the development of osteoarthritis. The burden of SI includes economic loss and represents a real challenge for current veterinary health care. At the molecular level, fibroblasts-like synoviocytes (FLS) are recognized as major cell populations involved in SI pathogenesis. In the course of SI, FLSs are losing their protective and pro-regenerative cytological features, become highly proliferative and initiate various stress signaling pathways. Methods Fibroblast-like synoviocytes were treated with LPS in order to generate SI in vitro model. Mitochondria were isolated from peripheral blood derived mononuclear cells and co-cultured with FLS. After 24 h of culture, cells were subjected to RT-qPCR, western blot, cytometric and confocal microscopy analysis.
Results Mitochondrial transfer (MT) was observed in vitro studies using confocal microscopy. Further studies revealed, that MT to LPS-treated FLS reduced cell proliferation, modulated apoptosis and decreased inflammatory response. Overall, MT Resulted in the considerable recovery of recipient cells cytophysiological properties.
Conclusions Presented data provides evidence that mitochondria transfersignificantly modulate FLS proliferative and metabolic activity through improved mitochondrial biogenesis and dynamics in activated FLS. Obtained results for the first time demonstrate that horizontal MT might be considered as a therapeutic tool for synovitis treatment; however, further clinical studies are strongly required.
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