1
|
Hoseini SM, Montazeri F. The influence of cell source on the senescence of human mesenchymal stem/stromal cells. Hum Cell 2025; 38:87. [PMID: 40221541 DOI: 10.1007/s13577-025-01213-y] [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: 10/24/2024] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
While mesenchymal stem/stromal cells (MSCs) exhibit the ability to self-renew, they are not immortal; they eventually reach a point of irreversible growth cessation and functional deterioration following a limited series of population doublings, referred to as replicative senescence. When evaluated according to the criteria set by the International Society for Cell Therapy (ISCT), MSCs show significant differences in their senescence patterns and other characteristics related to their phenotype and function. These differences are attributed to the source of the MSCs and the conditions in which they are grown. MSCs derived from fetal or adult sources have variations in their genome stability, as well as in the expression and epigenetic profile of the cells, which in turn affects their secretome. Understanding the key factors of MSC senescence based on cell source can help to develop effective strategies for regulating senescence and improving the therapeutic potential.
Collapse
Affiliation(s)
- Seyed Mehdi Hoseini
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Hematology and Oncology Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, No. 1. Safaeyeh. Bou-Al Ave., Yazd, 8916877391, Iran.
| |
Collapse
|
2
|
Chen W, Zou H, Xu H, Cao R, Zhang Y, Ma Y, Lin W, Zhang H, Zhao J. Exploring the Mechanisms of Testicular Aging: Advances in Biomarker Research. Aging Dis 2025:AD.2025.0070. [PMID: 40153586 DOI: 10.14336/ad.2025.0070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 03/07/2025] [Indexed: 03/30/2025] Open
Abstract
Aging biomarkers quantify aging progression and provide actionable targets for therapeutic interventions to mitigate age-related decline. This review synthesizes emerging evidence on testicular aging biomarkers, focusing on cellular senescence (Leydig, Sertoli, and endothelial cells), protein homeostasis disruption, mitochondrial dysfunction, germ stem cell depletion, sperm telomere length, epigenetic alterations, oxidative stress, inflammation, and gut microbiota dysbiosis. We propose that testicular aging serves as a critical nexus linking reproductive decline with systemic aging processes, with its pathological progression being quantifiable through specific biomarkers including the Leydig, Sertoli, and endothelial cells, INSL3, ribosomal protein RPL39L, sperm telomere length, relative telomere length mitochondrial translocator protein, and sialic acid. By bridging systemic aging paradigms with testis-specific mechanisms, we emphasize the urgency to identify organ-selective biomarkers for targeted interventions, advancing strategies to preserve male fertility and address population aging challenges.
Collapse
Affiliation(s)
- Wenkang Chen
- Graduate School of China Academy of Chinese Medical Sciences, Beijing, China
| | - Hede Zou
- Graduate School of China Academy of Chinese Medical Sciences, Beijing, China
| | - Haoran Xu
- Graduate School of Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Rui Cao
- Graduate School of Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yapeng Zhang
- Graduate School of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yongjie Ma
- Graduate School of China Academy of Chinese Medical Sciences, Beijing, China
| | - Wei Lin
- Graduate School of China Academy of Chinese Medical Sciences, Beijing, China
| | - Hekun Zhang
- Graduate School of Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Jiayou Zhao
- Graduate School of China Academy of Chinese Medical Sciences, Beijing, China
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
3
|
Izadi M, Sadri N, Abdi A, Serajian S, Jalalei D, Tahmasebi S. Epigenetic biomarkers in aging and longevity: Current and future application. Life Sci 2024; 351:122842. [PMID: 38879158 DOI: 10.1016/j.lfs.2024.122842] [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: 12/29/2023] [Revised: 06/06/2024] [Accepted: 06/12/2024] [Indexed: 06/20/2024]
Abstract
The aging process has been one of the most necessary research fields in the current century, and knowing different theories of aging and the role of different genetic, epigenetic, molecular, and environmental modulating factors in increasing the knowledge of aging mechanisms and developing appropriate diagnostic, therapeutic, and preventive ways would be helpful. One of the most conserved signs of aging is epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, noncoding RNAs, and extracellular RNAs. Numerous biological processes and hallmarks are vital in aging development, but epigenomic alterations are especially notable because of their importance in gene regulation and cellular identity. The mounting evidence points to a possible interaction between age-related epigenomic alterations and other aging hallmarks, like genome instability. To extend a healthy lifespan and possibly reverse some facets of aging and aging-related diseases, it will be crucial to comprehend global and locus-specific epigenomic modifications and recognize corresponding regulators of health and longevity. In the current study, we will aim to discuss the role of epigenomic mechanisms in aging and the most recent developments in epigenetic diagnostic biomarkers, which have the potential to focus efforts on reversing the destructive signs of aging and extending the lifespan.
Collapse
Affiliation(s)
- Mehran Izadi
- Department of Infectious and Tropical Diseases, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
| | - Nariman Sadri
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirhossein Abdi
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; Royan Institute for Stem Cell Biology and Technology, Tehran, Iran
| | - Sahar Serajian
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; Royan Institute for Stem Cell Biology and Technology, Tehran, Iran
| | - Dorsa Jalalei
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Safa Tahmasebi
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
4
|
Sun Y, Xu L, Li Y, Jia S, Wang G, Cen X, Xu Y, Cao Z, Wang J, Shen N, Hu L, Zhang J, Mao J, Xia H, Liu Z, Fu X. Mitophagy defect mediates the aging-associated hallmarks in Hutchinson-Gilford progeria syndrome. Aging Cell 2024; 23:e14143. [PMID: 38482753 PMCID: PMC11296130 DOI: 10.1111/acel.14143] [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: 10/16/2023] [Revised: 02/03/2024] [Accepted: 03/01/2024] [Indexed: 06/13/2024] Open
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for aging. The cellular machinery mediating age-associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-associated phenotypes of HGPS-MSCs by inhibiting the STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI-77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging-associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging-associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.
Collapse
Affiliation(s)
- Yingying Sun
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
| | - Le Xu
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
| | - Yi Li
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
| | - Shunze Jia
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
| | - Gang Wang
- National Clinical Research Center of Kidney Diseases, Jinling HospitalNanjing University School of MedicineNanjingJiangsuChina
| | - Xufeng Cen
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
| | - Yuyan Xu
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
| | - Zhongkai Cao
- Department of Nephrology, The Children's Hospital, Zhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouZhejiangChina
| | - Jingjing Wang
- Department of Nephrology, The Children's Hospital, Zhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouZhejiangChina
| | - Ning Shen
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
| | - Lidan Hu
- Department of Nephrology, The Children's Hospital, Zhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouZhejiangChina
| | - Jin Zhang
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical SciencesZhejiang University School of MedicineHangzhouChina
| | - Jianhua Mao
- Department of Nephrology, The Children's Hospital, Zhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhouZhejiangChina
| | - Hongguang Xia
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling HospitalNanjing University School of MedicineNanjingJiangsuChina
| | - Xudong Fu
- The First Affiliated HospitalZhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Department of Geriatrics, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| |
Collapse
|
5
|
Zhang Y, Zhang J, Lesani P, Lu Z, Zreiqat H. Osteopontin Rejuvenates Senescent Adipose-Derived Stem Cells and Restores their Bone Tissue Regenerative Function. Stem Cell Rev Rep 2024; 20:1106-1120. [PMID: 38472643 PMCID: PMC11087332 DOI: 10.1007/s12015-024-10707-5] [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: 02/26/2024] [Indexed: 03/14/2024]
Abstract
The regenerative function of stem cells is compromised when the proportion of senescent stem cells increases with ageing advance. Therefore, combating stem cell senescence is of great importance for stem cell-based tissue engineering in the elderly, but remains largely unexplored. Osteopontin (OPN), a glycosylated phosphoprotein, is one of the key extracellular matrix molecules in bone tissue. OPN activates various signalling pathways and modulates cellular activities, including cell senescence. However, the role of OPN in stem cell senescence remains largely unknown. This study aims to investigate if OPN modulates cell senescence and bone regenerative function in human adipose-derived mesenchymal stem cells (ASCs), and to determine the underlying mechanisms. We first developed a senescent ASC model using serial passaging until passage 10 (P10), in which senescent cells were characterised by reduced proliferation and osteogenic differentiation capacity compared to P4 ASCs. The conditioned medium from P10 ASCs exhibited a diminished trophic effect on human osteoblasts (HOBs), compared to that from P4 ASCs. P10 ASCs on OPN-coated surface showed rejuvenated phenotype and enhanced osteogenic differentiation. The conditioned medium from P10 ASCs on OPN-coating improved trophic effects on HOBs. OPN regulated the morphology of senescent ASCs, transforming them from a more rounded and flattened cell shape to an elongated shape with a smaller area. These findings demonstrated the effects of OPN in restoring senescent ASCs functions, possibly through a mechanism that involves the modulation of cell morphology, indicating that OPN might hold a great potential for rejuvenating senescent stem cells and could potentially open a new venue for regenerating bone tissue in age-related diseases.
Collapse
Affiliation(s)
- Yiran Zhang
- Tissue Engineering & Biomaterials Research Unit, School of Biomedical Engineering, Faculty of Engineering and IT, The University of Sydney, Darlington, NSW, 2006, Australia
| | - Junni Zhang
- Tissue Engineering & Biomaterials Research Unit, School of Biomedical Engineering, Faculty of Engineering and IT, The University of Sydney, Darlington, NSW, 2006, Australia
| | - Pooria Lesani
- Tissue Engineering & Biomaterials Research Unit, School of Biomedical Engineering, Faculty of Engineering and IT, The University of Sydney, Darlington, NSW, 2006, Australia
| | - Zufu Lu
- Tissue Engineering & Biomaterials Research Unit, School of Biomedical Engineering, Faculty of Engineering and IT, The University of Sydney, Darlington, NSW, 2006, Australia.
| | - Hala Zreiqat
- Tissue Engineering & Biomaterials Research Unit, School of Biomedical Engineering, Faculty of Engineering and IT, The University of Sydney, Darlington, NSW, 2006, Australia.
| |
Collapse
|
6
|
Pereira B, Correia FP, Alves IA, Costa M, Gameiro M, Martins AP, Saraiva JA. Epigenetic reprogramming as a key to reverse ageing and increase longevity. Ageing Res Rev 2024; 95:102204. [PMID: 38272265 DOI: 10.1016/j.arr.2024.102204] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/18/2023] [Accepted: 01/19/2024] [Indexed: 01/27/2024]
Abstract
The pursuit for the fountain of youth has long been a fascination amongst scientists and humanity. Ageing is broadly characterized by a cellular decline with increased susceptibility to age-related diseases, being intimately associated with epigenetic modifications. Recently, reprogramming-induced rejuvenation strategies have begun to greatly alter longevity research not only to tackle age-related defects but also to possibly reverse the cellular ageing process. Hence, in this review, we highlight the major epigenetic changes during ageing and the state-of-art of the current emerging epigenetic reprogramming strategies leveraging on transcription factors. Notably, partial reprogramming enables the resetting of the ageing clock without erasing cellular identity. Promising chemical-based rejuvenation strategies harnessing small molecules, including DNA methyltransferase and histone deacetylase inhibitors are also discussed. Moreover, in parallel to longevity interventions, the foundations of epigenetic clocks for accurate ageing assessment and evaluation of reprogramming approaches are briefly presented. Going further, with such scientific breakthroughs, we are witnessing a rise in the longevity biotech industry aiming to extend the health span and ideally achieve human rejuvenation one day. In this context, we overview the main scenarios proposed for the future of the socio-economic and ethical challenges associated with such an emerging field. Ultimately, this review aims to inspire future research on interventions that promote healthy ageing for all.
Collapse
Affiliation(s)
- Beatriz Pereira
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | | | - Inês A Alves
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Margarida Costa
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Mariana Gameiro
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Ana P Martins
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Jorge A Saraiva
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal.
| |
Collapse
|
7
|
Uysal F, Sukur G, Bozdemir N, Cinar O. Unveiling the impact of DNA methylation machinery: Dnmt1 and Dnmt3a in orchestrating oocyte development and cellular homeostasis. Genesis 2024; 62:e23579. [PMID: 37985411 DOI: 10.1002/dvg.23579] [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: 09/30/2023] [Revised: 10/27/2023] [Accepted: 11/02/2023] [Indexed: 11/22/2023]
Abstract
DNA methylation can be considered the most prominent in controlling the gene expression responsible for the balance between cell proliferation and cell death. In this study, we aimed to analyze the distinct contributions of Dnmt1 and Dnmt3a enzymes in oocyte maturation, survival, autophagy, reactive oxygen species (ROS) production, and compensation capacity of Dnmt3b and Dnmt3l enzymes in mouse oocytes. Following confirming the suppression of Dnmt1or Dnmt3a through siRNA application, the assessment involved immunofluorescence staining for Dnmts, 5mC, p62, and ROS levels. Cell death rates showed a noticeable increase while oocyte maturation rates exhibited significant reduction. Global DNA methylation showed a decline, concomitant with elevated p62 and ROS levels upon Dnmt1 or Dnmt3a knockdown. Remarkably, silencing of Dnmt1 led to an upsurge in Dnmt3a expression, whereas Dnmt3a knockdown triggered an increase in Dnmt1 levels. Furthermore, Dnmt3l expression exhibited a notable decrease after silencing of either Dnmt1 or Dnmt3a, while Dnmt3b levels remained comparable between control and siRNA-treated groups. Collectively, this study underscores the pivotal roles of Dnmt1 and Dnmt3a in orchestrating various facets of oocyte development, encompassing maturation, survival, autophagy, and ROS production. These findings offer valuable insights into the intricate regulatory network governed by DNA methylation machinery within the context of oocyte physiology.
Collapse
Affiliation(s)
- Fatma Uysal
- Department of Histology and Embryology, Ankara Medipol University School of Medicine, Ankara, Turkey
| | - Gozde Sukur
- Department of Histology and Embryology, Ankara University School of Medicine, Ankara, Turkey
| | - Nazlican Bozdemir
- Department of Histology and Embryology, Ankara Medipol University School of Medicine, Ankara, Turkey
| | - Ozgur Cinar
- Department of Histology and Embryology, Ankara University School of Medicine, Ankara, Turkey
| |
Collapse
|
8
|
Torres-Guzman RA, Avila FR, Maita K, Garcia JP, De Sario GD, Borna S, Eldaly AS, Quinones-Hinojosa A, Zubair AC, Ho OA, Forte AJ. Mesenchymal Stromal Cell Healing Outcomes in Clinical and Pre-Clinical Models to Treat Pressure Ulcers: A Systematic Review. J Clin Med 2023; 12:7545. [PMID: 38137625 PMCID: PMC10743704 DOI: 10.3390/jcm12247545] [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: 04/21/2023] [Revised: 11/26/2023] [Accepted: 11/29/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Despite numerous measures used to prevent pressure ulcers, their growing prevalence in recent years is expected to continue as the population ages. This review aims to report the outcomes of the regenerative potential of MSCs in treating pressure ulcers, assessing the effectiveness of MSCs in treating pressure ulcers. METHODS A computerized search for articles on animal models that use MSCs as primary therapy to treat pressure ulcers, published from conception to present, was conducted using PubMed, MEDLINE, Embase, and CINAHL. Our search yielded 52 articles, narrowed to 44 after excluding duplicates. RESULTS Out of 52 articles collected from four databases, 11 met the inclusion criteria. A total of 11 articles published between 2008 and 2020 met the inclusion criteria. Eight studies were observational descriptive papers in animal models, and three were prospective. Six studies used autologous MSCs, while five used allogenic MSCs. Three studies were conducted in humans, and the remaining eight were conducted in animals. The most common method of cell delivery was an intradermal injection in the margins of the ulcer. All studies reported positive results, including improved wound healing, reduced inflammation, and improved tissue regeneration. CONCLUSIONS MSCs have shown promising results in treating pressure ulcers in animal and clinical trials. The combination of MSCs and scaffold materials has also been studied and found to be effective in wound healing. A standardized human wound model has been proposed further to investigate the efficacy of cell-based therapies for chronic wounds. However, more research is needed to determine the best quantity of cells to apply for pressure ulcers and to ensure the safety and efficacy of these treatments in clinical settings.
Collapse
Affiliation(s)
| | | | - Karla Maita
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - John P. Garcia
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | - Sahar Borna
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | | | - Abba C. Zubair
- Department of Laboratory Medicine and Pathology, Transfusion Medicines and Stem Cell Therapy, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Olivia A. Ho
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Antonio J. Forte
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| |
Collapse
|
9
|
Walewska A, Janucik A, Tynecka M, Moniuszko M, Eljaszewicz A. Mesenchymal stem cells under epigenetic control - the role of epigenetic machinery in fate decision and functional properties. Cell Death Dis 2023; 14:720. [PMID: 37932257 PMCID: PMC10628230 DOI: 10.1038/s41419-023-06239-4] [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: 06/01/2023] [Revised: 10/12/2023] [Accepted: 10/20/2023] [Indexed: 11/08/2023]
Abstract
Mesenchymal stem cells (mesenchymal stromal cells, MSC) are multipotent stem cells that can differentiate into cells of at least three mesodermal lineages, namely adipocytes, osteoblasts, and chondrocytes, and have potent immunomodulatory properties. Epigenetic modifications are critical regulators of gene expression and cellular differentiation of mesenchymal stem cells (MSCs). Epigenetic machinery controls MSC differentiation through direct modifications to DNA and histones. Understanding the role of epigenetic machinery in MSC is crucial for the development of effective cell-based therapies for degenerative and inflammatory diseases. In this review, we summarize the current understanding of the role of epigenetic control of MSC differentiation and immunomodulatory properties.
Collapse
Affiliation(s)
- Alicja Walewska
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Adrian Janucik
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Marlena Tynecka
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Marcin Moniuszko
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Bialystok, Poland
- Department of Allergology and Internal Medicine, Medical University of Bialystok, ul. M. Sklodowskiej-Curie 24A, 15-276, Bialystok, Poland
| | - Andrzej Eljaszewicz
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland.
- Tissue and Cell Bank, Medical University of Bialystok Clinical Hospital, ul. Waszyngtona 13, 15-069, Bialystok, Poland.
| |
Collapse
|
10
|
Gao E, Sun X, Thorne RF, Zhang XD, Li J, Shao F, Ma J, Wu M. NIPSNAP1 directs dual mechanisms to restrain senescence in cancer cells. J Transl Med 2023; 21:401. [PMID: 37340421 DOI: 10.1186/s12967-023-04232-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/27/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND Although the executive pathways of senescence are known, the underlying control mechanisms are diverse and not fully understood, particularly how cancer cells avoid triggering senescence despite experiencing exacerbated stress conditions within the tumor microenvironment. METHODS Mass spectrometry (MS)-based proteomic screening was used to identify differentially regulated genes in serum-starved hepatocellular carcinoma cells and RNAi employed to determine knockdown phenotypes of prioritized genes. Thereafter, gene function was investigated using cell proliferation assays (colony-formation, CCK-8, Edu incorporation and cell cycle) together with cellular senescence assays (SA-β-gal, SAHF and SASP). Gene overexpression and knockdown techniques were applied to examine mRNA and protein regulation in combination with luciferase reporter and proteasome degradation assays, respectively. Flow cytometry was applied to detect changes in cellular reactive oxygen species (ROS) and in vivo gene function examined using a xenograft model. RESULTS Among the genes induced by serum deprivation, NIPSNAP1 was selected for investigation. Subsequent experiments revealed that NIPSNAP1 promotes cancer cell proliferation and inhibits P27-dependent induction of senescence via dual mechanisms. Firstly, NIPSNAP1 maintains the levels of c-Myc by sequestering the E3 ubiquitin ligase FBXL14 to prevent the proteasome-mediated turnover of c-Myc. Intriguingly, NIPSNAP1 levels are restrained by transcriptional repression mediated by c-Myc-Miz1, with repression lifted in response to serum withdrawal, thus identifying feedback regulation between NIPSNAP1 and c-Myc. Secondly, NIPSNAP1 was shown to modulate ROS levels by promoting interactions between the deacetylase SIRT3 and superoxide dismutase 2 (SOD2). Consequent activation of SOD2 serves to maintain cellular ROS levels below the critical levels required to induce cell cycle arrest and senescence. Importantly, the actions of NIPSNAP1 in promoting cancer cell proliferation and preventing senescence were recapitulated in vivo using xenograft models. CONCLUSIONS Together, these findings reveal NIPSNAP1 as an important mediator of c-Myc function and a negative regulator of cellular senescence. These findings also provide a theoretical basis for cancer therapy where targeting NIPSNAP1 invokes cellular senescence.
Collapse
Affiliation(s)
- Enyi Gao
- Translational Research Institute, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, Zhengzhou, 450046, China
- School of Basic Medical Sciences, Henan University, Zhengzhou, 450046, China
| | - Xiaoya Sun
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Rick Francis Thorne
- Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, 450003, China
| | - Xu Dong Zhang
- Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, 450003, China
| | - Jinming Li
- Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, 450003, China
| | - Fengmin Shao
- Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, 450003, China.
| | - Jianli Ma
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
| | - Mian Wu
- Translational Research Institute, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, Zhengzhou, 450046, China.
- School of Basic Medical Sciences, Henan University, Zhengzhou, 450046, China.
| |
Collapse
|
11
|
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.
Collapse
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.
| |
Collapse
|
12
|
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.
Collapse
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
| |
Collapse
|
13
|
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.
Collapse
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.
| |
Collapse
|
14
|
Wang Z, Wen S, Zhong M, Yang Z, Xiong W, Zhang K, Yang S, Li H, Guo S. Epigenetics: Novel crucial approach for osteogenesis of mesenchymal stem cells. J Tissue Eng 2023; 14:20417314231175364. [PMID: 37342486 PMCID: PMC10278427 DOI: 10.1177/20417314231175364] [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: 02/23/2023] [Accepted: 04/26/2023] [Indexed: 06/23/2023] Open
Abstract
Bone has a robust regenerative potential, but its capacity to repair critical-sized bone defects is limited. In recent years, stem cells have attracted significant interest for their potential in tissue engineering. Applying mesenchymal stem cells (MSCs) for enhancing bone regeneration is a promising therapeutic strategy. However, maintaining optimal cell efficacy or viability of MSCs is limited by several factors. Epigenetic modification can cause changes in gene expression levels without changing its sequence, mainly including nucleic acids methylation, histone modification, and non-coding RNAs. This modification is believed to be one of the determinants of MSCs fate and differentiation. Understanding the epigenetic modification of MSCs can improve the activity and function of stem cells. This review summarizes recent advances in the epigenetic mechanisms of MSCs differentiation into osteoblast lineages. We expound that epigenetic modification of MSCs can be harnessed to treat bone defects and promote bone regeneration, providing potential therapeutic targets for bone-related diseases.
Collapse
Affiliation(s)
- Zhaohua Wang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Si Wen
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Meiqi Zhong
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ziming Yang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Wei Xiong
- Department of Plastic Surgery, The First Hospital of Shihezi University School of Medicine, Shihezi, China
| | - Kuo Zhang
- College of Humanities and Social Sciences, Dalian Medical University, Dalian, Liaoning Province, China
| | - Shude Yang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Huizheng Li
- Department of Otorhinolaryngology & Head and Neck Surgery, Dalian Friendship Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| |
Collapse
|
15
|
Al-Azab M, Safi M, Idiiatullina E, Al-Shaebi F, Zaky MY. Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting. Cell Mol Biol Lett 2022; 27:69. [PMID: 35986247 PMCID: PMC9388978 DOI: 10.1186/s11658-022-00366-0] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.
Collapse
|
16
|
Ceccarelli S, Gerini G, Megiorni F, Pontecorvi P, Messina E, Camero S, Anastasiadou E, Romano E, Onesti MG, Napoli C, Marchese C. Inhibiting DNA methylation as a strategy to enhance adipose-derived stem cells differentiation: Focus on the role of Akt/mTOR and Wnt/β-catenin pathways on adipogenesis. Front Cell Dev Biol 2022; 10:926180. [PMID: 36120582 PMCID: PMC9478209 DOI: 10.3389/fcell.2022.926180] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/28/2022] [Indexed: 01/10/2023] Open
Abstract
Adipose-derived mesenchymal stem cells (ASCs) represent a valid therapeutic option for clinical application in several diseases, due to their ability to repair damaged tissues and to mitigate the inflammatory/immune response. A better understanding of the underlying mechanisms regulating ASC biology might represent the chance to modulate their in vitro characteristics and differentiation potential for regenerative medicine purposes. Herein, we investigated the effects of the demethylating agent 5-azacytidine (5-aza) on proliferation, clonogenicity, migration, adipogenic differentiation and senescence of ASCs, to identify the molecular pathways involved. Through functional assays, we observed a detrimental effect of 5-aza on ASC self-renewal capacity and migration, accompanied by actin cytoskeleton reorganization, with decreased stress fibers. Conversely, 5-aza treatment enhanced ASC adipogenic differentiation, as assessed by lipid accumulation and expression of lineage-specific markers. We analyzed the involvement of the Akt/mTOR, MAPK and Wnt/β-catenin pathways in these processes. Our results indicated impairment of Akt and ERK phosphorylation, potentially explaining the reduced cell proliferation and migration. We observed a 5-aza-mediated inhibition of the Wnt signaling pathway, this potentially explaining the pro-adipogenic effect of the drug. Finally, 5-aza treatment significantly induced ASC senescence, through upregulation of the p53/p21 axis. Our data may have important translational implications, by helping in clarifying the potential risks and advantages of using epigenetic treatment to improve ASC characteristics for cell-based clinical approaches.
Collapse
Affiliation(s)
- S. Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- *Correspondence: S. Ceccarelli ,
| | - G. Gerini
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - F. Megiorni
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - P. Pontecorvi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - E. Messina
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - S. Camero
- Department of Maternal, Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - E. Anastasiadou
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - E. Romano
- Department of Sense Organs, Sapienza University of Rome, Rome, Italy
| | - M. G. Onesti
- Department of Surgery “P. Valdoni”, Unit of Plastic Surgery “P. Valdoni”, Sapienza University of Rome, Rome, Italy
| | - C. Napoli
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - C. Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
17
|
Kowalczuk A, Marycz K, Kornicka-Garbowska K, Kornicka J, Bujalska-Zadrożny M, Groborz S. Cannabidiol (CBD) Protects Adipose-Derived Mesenchymal Stem Cells (ASCs) against Endoplasmic Reticulum Stress Development and Its Complications. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph191710864. [PMID: 36078578 PMCID: PMC9518341 DOI: 10.3390/ijerph191710864] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 05/13/2023]
Abstract
BACKGROUND Recent studies suggested that individuals with metabolic disorders have altered function of adipocytes and adipose stem cell subpopulations, which impairs tissue homeostasis, promoting insulin resistance and diabetes development. The non-psychoactive phytocannabinoid CBD was found to modulate adipose tissue metabolism, however, its exact role in controlling ASCs' fate is still poorly understood. OBJECTIVES This investigation aimed to elucidate whether pretreatment of ASCs with CBD can protect against ER stress development and maintain the cytophysiological properties of cells. METHODS Human ASCs were cultured under control and adipogenic conditions. Prior to the experiments, cells in the experimental group were pretreated with CBD following the addition of an ER stress inducer-tunicamycin. After the experiments, the cells were subsequently tested for expression of the apoptotic, ER stress, and anti-inflammatory-related genes using RT-qPCR. Oxidative stress was analysed with flow cytometric assays. RESULTS Cells pretreated with CBD displayed decreased apoptosis and enhanced proliferation rate. Additionally, the expression of pro-inflammatory cytokines and miRNAs was significantly reduced. The obtained results also demonstrated an obvious reduction in intracellular accumulated ROS and NO, as well as mitigated ER stress through the down-regulation of IRE-1, PERK, CHOP, and ATF6 transcripts upon CBD treatment. CONCLUSION The presented data provide the evidence that CBD protects ASCs against ER stress development and its complications and, thus, offers new insights for the management of obesity through the regulation of adipose tissue dynamics.
Collapse
Affiliation(s)
- Anna Kowalczuk
- National Medicines Institute, 00-725 Warsaw, Poland
- Correspondence: ; Tel.: +48-22-851-43-69
| | - Krzysztof Marycz
- International Institute of Translational Medicine, 55-114 Wisznia Mała, Poland
| | - Katarzyna Kornicka-Garbowska
- International Institute of Translational Medicine, 55-114 Wisznia Mała, Poland
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, 50-375 Wrocław, Poland
| | - Justyna Kornicka
- Faculty of Electronics, Photonics and Microsystems, Wrocław University of Science and Technology, 50-372 Wrocław, Poland
| | - Magdalena Bujalska-Zadrożny
- Department of Pharmacodynamics, Centre for Preclinical, Research and Technology (CePT), Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Sylwia Groborz
- International Institute of Translational Medicine, 55-114 Wisznia Mała, Poland
| |
Collapse
|
18
|
Comparison of Sources and Methods for the Isolation of Equine Adipose Tissue-Derived Stromal/Stem Cells and Preliminary Results on Their Reaction to Incubation with 5-Azacytidine. Animals (Basel) 2022; 12:ani12162049. [PMID: 36009640 PMCID: PMC9404420 DOI: 10.3390/ani12162049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary The function of the equine heart is different from that in other species, and a species-specific in vitro model would simplify investigations in the field of equine cardiology. The recent advances in stem cell research and the availability of adipose tissue-derived stromal/stem cells (ASCs) could be a promising starting point for the development of such an in vitro model. In order to test the hypothesis that equine ASCs can be differentiated into cells resembling heart cells, we isolated ASCs from abdominal, retrobulbar, and subcutaneous adipose tissue after collagenase digestion or from direct cultivation of explants. Both techniques resulted in similar yields of cells displaying morphological, immunophenotypical, and molecular biological characteristics of mesenchymal stem cells. Abdominal adipose tissue was found to be most suitable for ASC isolation in equines. However, contrasting earlier studies performed with ASCs from other species, equine ASCs were refractory to 5-azacytidine-induced upregulation of markers characteristic for the differentiation into heart cells. Hence, further studies are required to establish equine cardiomyocyte induction. Abstract Physiological particularities of the equine heart justify the development of an in vitro model suitable for investigations of the species-specific equine cardiac electrophysiology. Adipose tissue-derived stromal/stem cells (ASCs) could be a promising starting point from which to develop such a cardiomyocyte (CM)-like cell model. Therefore, we compared abdominal, retrobulbar, and subcutaneous adipose tissue as sources for the isolation of ASCs applying two isolation methods: the collagenase digestion and direct explant culture. Abdominal adipose tissue was most suitable for the isolation of ASCs and both isolation methods resulted in comparable yields of CD45-/CD34-negative cells expressing the mesenchymal stem cell markers CD29, CD44, and CD90, as well as pluripotency markers, as determined by flow cytometry and real-time quantitative PCR. However, exposure of equine ASCs to 5-azacytidine (5-AZA), reportedly inducing CM differentiation from rats, rabbits, and human ASCs, was not successful in our study. More precisely, neither the early differentiation markers GATA4 and NKX2-5, nor the late CM differentiation markers TNNI3, MYH6, and MYH7 were upregulated in equine ASCs exposed to 10 µM 5-AZA for 48 h. Hence, further work focusing on the optimal conditions for CM differentiation of equine stem cells derived from adipose tissue, as well as possibly from other origins, are needed.
Collapse
|
19
|
Wu H, Li C, Masood M, Zhang Z, González-Almela E, Castells-Garcia A, Zou G, Xu X, Wang L, Zhao G, Yu S, Zhu P, Wang B, Qin D, Liu J. Static Magnetic Fields Regulate T-Type Calcium Ion Channels and Mediate Mesenchymal Stem Cells Proliferation. Cells 2022; 11:cells11152460. [PMID: 35954307 PMCID: PMC9368660 DOI: 10.3390/cells11152460] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 11/16/2022] Open
Abstract
The static magnetic fields (SMFs) impact on biological systems, induce a variety of biological responses, and have been applied to the clinical treatment of diseases. However, the underlying mechanisms remain largely unclear. In this report, by using human mesenchymal stem cells (MSCs) as a model, we investigated the biological effect of SMFs at a molecular and cellular level. We showed that SMF exposure promotes MSC proliferation and activates the expression of transcriptional factors such as FOS (Fos Proto-Oncogene, AP-1 Transcription Factor Subunit) and EGR1 (Early Growth Response 1). In addition, the expression of signal-transduction proteins p-ERK1/2 and p-JNK oscillate periodically with SMF exposure time. Furthermore, we found that the inhibition of the T-type calcium ion channels negates the biological effects of SMFs on MSCs. Together, we revealed that the SMFs regulate T-type calcium ion channels and mediate MSC proliferation via the MAPK signaling pathways.
Collapse
Affiliation(s)
- Haokaifeng Wu
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Chuang Li
- School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
| | - Muqaddas Masood
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
| | - Zhen Zhang
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | | | | | | | - Xiaoduo Xu
- School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
| | - Luqin Wang
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | | | - Shengyong Yu
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
| | - Bo Wang
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
| | - Dajiang Qin
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China
- Correspondence: (D.Q.); (J.L.)
| | - Jing Liu
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Bioland Laboratory, Guangzhou 510005, China
- Correspondence: (D.Q.); (J.L.)
| |
Collapse
|
20
|
Masroor S, Aalam MT, Khan O, Tanuj GN, Gandham RK, Dhara SK, Gupta PK, Mishra BP, Dutt T, Singh G, Sajjanar BK. Effect of acute heat shock on stress gene expression and DNA methylation in zebu (Bos indicus) and crossbred (Bos indicus × Bos taurus) dairy cattle. INTERNATIONAL JOURNAL OF BIOMETEOROLOGY 2022; 66:1797-1809. [PMID: 35796826 DOI: 10.1007/s00484-022-02320-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 05/15/2022] [Accepted: 06/21/2022] [Indexed: 05/19/2023]
Abstract
Environmental temperature is one of the major factors to affect health and productivity of dairy cattle. Gene expression networks within the cells and tissues coordinate stress response, metabolism, and milk production in dairy cattle. Epigenetic DNA methylations were found to mediate the effect of environment by regulating gene expression patterns. In the present study, we compared three Indian native zebu cattle, Bos indicus (Sahiwal, Tharparkar, and Hariana) and one crossbred Bos indicus × Bos taurus (Vrindavani) for stress gene expression and differences in the DNA methylation patterns. The results indicated acute heat shock to cultured PBMC affected their proliferation, stress gene expression, and DNA methylation. Interestingly, expressions of HSP70, HSP90, and STIP1 were found more pronounced in zebu cattle than the crossbred cattle. However, no significant changes were observed in global DNA methylation due to acute heat shock, even though variations were observed in the expression patterns of DNA methyltransferases (DNMT1, DNMT3a) and demethylases (TET1, TET2, and TET3) genes. The treatment 5-AzaC (5-azacitidine) that inhibit DNA methylation in proliferating PBMC caused significant increase in heat shock-induced HSP70 and STIP1 expression indicating that hypomethylation facilitated stress gene expression. Further targeted analysis DNA methylation in the promoter regions revealed no significant differences for HSP70, HSP90, and STIP1. However, there was a significant hypomethylation for BDNF in both zebu and crossbred cattle. Similarly, NR3C1 promoter region showed hypomethylation alone in crossbred cattle. Overall, the results indicated that tropically adapted zebu cattle had comparatively higher expression of stress genes than the crossbred cattle. Furthermore, DNA methylation may play a role in regulating expression of certain genes involved in stress response pathways.
Collapse
Affiliation(s)
- Sana Masroor
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India
| | - Mohd Tanzeel Aalam
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India
| | - Owais Khan
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India
| | - Gunturu Narasimha Tanuj
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India
| | - Ravi Kumar Gandham
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India
| | - Sujoy K Dhara
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India
| | - Praveen K Gupta
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India
| | - Bishnu Prasad Mishra
- ICAR-National Bureau of Animal Genetic Resources, Haryana, Karnal, 132001, India
| | - Triveni Dutt
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India
| | - Gynendra Singh
- Physiology and Climatology Division, ICAR-Indian Veterinary Research Institute, Izatnagar Bareilly, 243122, Uttar Pradesh, India
| | - Basavaraj K Sajjanar
- Veterinary Biotechnology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly-243122, Uttar Pradesh, India.
| |
Collapse
|
21
|
Baklaushev VP, Samoilova EM, Kalsin VA, Yusubalieva GM. Aging and “rejuvenation” of resident stem cells — a new way to active longevity? КЛИНИЧЕСКАЯ ПРАКТИКА 2022; 13:79-91. [DOI: 10.17816/clinpract104999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
This review presents the current data on the methodology for assessing the biological and epigenetic age, describes the concept of the epigenetic clock, and characterizes the main types of resident stem cells and the specifics of their aging. It has been shown that age-related changes in organs and tissues, as well as age-related diseases, are largely due to the aging of resident stem cells. The latter represent an attractive target for cell rejuvenation, as they can be isolated, cultured ex vivo, modified, and re-introduced into the resident niches. Two main methodologies for the cellular rejuvenation are presented: genetic reprogramming with zeroing the age of a cell using transient expression of transcription factors, and various approaches to epigenetic rejuvenation. The close relationship between aging, regeneration, and oncogenesis, and between these factors and the functioning of resident stem cell niches requires further precision studies, which, we are sure, can result in the creation of an effective anti-aging strategy and prolongation of human active life.
Collapse
|
22
|
Li M, Jiang Y, Hou Q, Zhao Y, Zhong L, Fu X. Potential pre-activation strategies for improving therapeutic efficacy of mesenchymal stem cells: current status and future prospects. Stem Cell Res Ther 2022; 13:146. [PMID: 35379361 PMCID: PMC8981790 DOI: 10.1186/s13287-022-02822-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/20/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy has been considered as a promising approach targeting a variety of intractable diseases due to remarkable multiple effect of MSCs, such as multilineage differentiation, immunomodulatory property, and pro-regenerative capacity. However, poor engraftment, low survival rate of transplanted MSC, and impaired donor-MSC potency under host age/disease result in unsatisfactory therapeutic outcomes. Enhancement strategies, including genetic manipulation, pre-activation, and modification of culture method, have been investigated to generate highly functional MSC, and approaches for MSC pre-activation are highlighted. In this review, we summarized the current approaches of MSC pre-activation and further classified, analysed the scientific principles and main characteristics of these manipulations, and described the pros and cons of individual pre-activation strategies. We also discuss the specialized tactics to solve the challenges in this promising field so that it improves MSC therapeutic functions to serve patients better.
Collapse
Affiliation(s)
- Meirong Li
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China. .,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China. .,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China.
| | - Yufeng Jiang
- Wound Repairing Department, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, China
| | - Qian Hou
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China.,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China.,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China
| | - Yali Zhao
- Central Laboratory, Trauma Treatment Center, Chinese PLA General Hospital, Hainan Hospital, Sanya, China
| | - Lingzhi Zhong
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China.,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China.,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China. .,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China. .,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China.
| |
Collapse
|
23
|
Xie H, Liu X, Zhou Q, Huang T, Zhang L, Gao J, Wang Y, Liu Y, Yan T, Zhang S, Wang CY. DNA Methylation Modulates Aging Process in Adipocytes. Aging Dis 2022; 13:433-446. [PMID: 35371604 PMCID: PMC8947842 DOI: 10.14336/ad.2021.0904] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 09/04/2021] [Indexed: 11/17/2022] Open
Abstract
Aging has been recognized to be a highly complex biological health problem with a high risk of chronic diseases, including type 2 diabetes, atherosclerosis, chronic bronchitis or emphysema, cancer and Alzheimer's disease. Particularly, age-related turnover in adipose tissue is a major contributor to metabolic syndromes and shortened lifespan. Adipocytes undergo senescence in early stage, which results in adipose tissue metabolic dysfunction, redistribution, and inflammation. The well-established association between DNA methylation (DNAm) and aging has been observed in the past few decades. Indeed, age-related alteration in DNAm is highly tissue-specific. This review intends to summarize the advancements how DNAm changes coupled with aging process in adipose tissue, by which DNAm regulates cellular senescence, metabolic function, adipokine secretion and beiging process in adipocytes. Elucidation of the effect of DNAm on adipose aging would have great potential to the development of epigenetic therapeutic strategies against aging-related diseases in clinical settings.
Collapse
Affiliation(s)
- Hao Xie
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xin Liu
- Department of Interventional Radiology, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Qing Zhou
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Teng Huang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Lu Zhang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jia Gao
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yuhan Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yanjun Liu
- The Center for Obesity and Metabolic Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Sichuan, China.,The Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People’s Hospital of Chengdu & The affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China.
| | - Tong Yan
- The Center for Obesity and Metabolic Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Sichuan, China.
| | - Shu Zhang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Correspondence should be addressed to: Drs. Cong-Yi Wang () or Shu Zhang (), the Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong-Yi Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Correspondence should be addressed to: Drs. Cong-Yi Wang () or Shu Zhang (), the Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
24
|
Wang QN, Yan YZ, Zhang XZ, Lv JX, Nie HP, Wu J, Wu D, Yuan SS, Tang CB. Rescuing effects of periostin in advanced glycation end-products (AGEs) caused osteogenic and oxidative damage through AGE receptor mediation and DNA methylation of the CALCA promoter. Chem Biol Interact 2022; 354:109835. [PMID: 35090876 DOI: 10.1016/j.cbi.2022.109835] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 01/15/2022] [Accepted: 01/24/2022] [Indexed: 11/19/2022]
Abstract
An in vitro model was established to simulate a diabetes-type environment by treating human periodontal stem cells with advanced glycation end-products (AGEs). Periostin (POSTN) plays a crucial role in maintaining the integrity of periodontal tissues. However, the role of POSTN in human periodontal stem cells stimulated by AGEs remains unknown. Diabetes mellitus is considered a metabolic disease, and DNA methylation of CpG islands is a biomarker of metabolic syndromes. Diabetes has been found to be closely related to the DNA methylation of certain genes. Here, we investigated the protective mechanism and effect of POSTN on osteogenesis and oxidative stress in the AGE environment, and further explored the CpG island methylation of specific genes potentially mediated by POSTN. The optimal concentration of AGEs was screened using CCK8. AGEs were found to contribute to oxidative stress. Conversely, reactive oxygen species production and malondialdehyde and superoxide activity indicated that the AGE + POSTN group decreased oxidative injury. According to an alkaline phosphatase assay, Alizarin Red S staining, and the expression of key genes and proteins involved in osteogenesis, POSTN mitigated the inhibitory effects of AGE on cell proliferation and osteogenic differentiation potential during osteogenic differentiation. In contrast, the growth and osteogenesis of human periodontal stem cells were notably suppressed by POSTN knockdown. Bisulfite sequencing PCR was used to evaluate the DNA methylation status. Moreover, AGE elevated the expression of DNA methyltransferas 1 (DNMT1) and inhibited the activation of CALAL promoter methylation, which was rescued by the addition of POSTN and 5-Azacytidine (5-AZA). In conclusion, POSTN attenuated the AGE-induced inhibition of osteogenesis in periodontal ligament stem cells by reducing AGE receptor levels and DNA methylation of the calcitonin-related polypeptide α (CALCA) promoter. Thus, POSTN is a promising candidate for dental bone regeneration, representing a novel therapeutic agent for diabetic patients. The mechanism underlying these processes may provide new insights into novel therapeutic targets for improving abnormal bone metabolism in patients with diabetes.
Collapse
Affiliation(s)
- Qiao-Na Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Oral Special Consultation, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China
| | - Yan-Zhe Yan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China
| | - Xiao-Zhen Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China
| | - Jia-Xin Lv
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China
| | - He-Peng Nie
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China
| | - Jin Wu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China
| | - Di Wu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China
| | - Shan-Shan Yuan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China
| | - Chun-Bo Tang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, China.
| |
Collapse
|
25
|
Roux B, Picou F, Debeissat C, Koubi M, Gallay N, Hirsch P, Ravalet N, Béné MC, Maigre M, Hunault M, Mosser J, Etcheverry A, Gyan E, Delhommeau F, Domenech J, Herault O. Aberrant DNA methylation impacts HOX genes expression in bone marrow mesenchymal stromal cells of myelodysplastic syndromes and de novo acute myeloid leukemia. Cancer Gene Ther 2022; 29:1263-1275. [PMID: 35194200 DOI: 10.1038/s41417-022-00441-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 12/12/2021] [Accepted: 02/08/2022] [Indexed: 11/09/2022]
Abstract
DNA methylation, a major biological process regulating the transcription, contributes to the pathophysiology of hematologic malignancies, and hypomethylating agents are commonly used to treat myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). In these diseases, bone marrow mesenchymal stromal cells (MSCs) play a key supportive role through the production of various signals and interactions. The DNA methylation status of MSCs, likely to reflect their functionality, might be relevant to understand their contribution to the pathophysiology of these diseases. Consequently, the aim of our study was to analyze the modifications of DNA methylation profiles of MSCs induced by MDS or AML. MSCs from MDS/AML patients were characterized via 5-methylcytosine quantification, gene expression profiles of key regulators of DNA methylation, identification of differentially methylated regions (DMRs) by methylome array, and quantification of DMR-coupled genes expression. MDS and AML-MSCs displayed global hypomethylation and under-expression of DNMT1 and UHRF1. Methylome analysis revealed aberrant methylation profiles in all MDS and in a subgroup of AML-MSCs. This aberrant methylation was preferentially found in the sequence of homeobox genes, especially from the HOX family (HOXA1, HOXA4, HOXA5, HOXA9, HOXA10, HOXA11, HOXB5, HOXC4, and HOXC6), and impacted on their expression. These results highlight modifications of DNA methylation in MDS/AML-MSCs, both at global and focal levels dysregulating the expression of HOX genes well known for their involvement in leukemogenesis. Such DNA methylation in MSCs could be the consequence of the malignant disease or could participate in its development through defective functionality or exosomal transfer of HOX transcription factors from MSCs to hematopoietic cells.
Collapse
Affiliation(s)
- Benjamin Roux
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France.,EA 7501 GICC, université de Tours, Tours, France.,CHU de Tours, Service d'Hématologie Biologique, Tours, France
| | - Frédéric Picou
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France.,EA 7501 GICC, université de Tours, Tours, France.,CHU de Tours, Service d'Hématologie Biologique, Tours, France
| | - Christelle Debeissat
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France.,EA 7501 GICC, université de Tours, Tours, France.,CHU de Tours, Service d'Hématologie Biologique, Tours, France
| | - Myriam Koubi
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France.,EA 7501 GICC, université de Tours, Tours, France
| | - Nathalie Gallay
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France.,EA 7501 GICC, université de Tours, Tours, France.,CHU de Tours, Service d'Hématologie Biologique, Tours, France
| | - Pierre Hirsch
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Service d'Hématologie Biologique, Paris, France
| | - Noémie Ravalet
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France.,EA 7501 GICC, université de Tours, Tours, France.,CHU de Tours, Service d'Hématologie Biologique, Tours, France
| | - Marie C Béné
- CHU de Nantes, Service d'Hématologie Biologique, CRCINA, Nantes, France.,FHU GOAL, Angers, France
| | | | - Mathilde Hunault
- FHU GOAL, Angers, France.,CHU d'Angers, Service d'Hématologie, Angers, France
| | - Jean Mosser
- CHU de Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France.,Cancéropôle Grand Ouest, Nantes, France
| | - Amandine Etcheverry
- CHU de Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France
| | - Emmanuel Gyan
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France.,EA 7501 GICC, université de Tours, Tours, France.,CHU de Tours, Service d'Hématologie et Thérapie Cellulaire, Tours, France
| | - François Delhommeau
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Service d'Hématologie Biologique, Paris, France.,CNRS GDR 3697 Micronit "Microenvironment of tumor niches", Tours, France.,OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Hôpital Saint-Louis, Paris, France
| | - Jorge Domenech
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France.,EA 7501 GICC, université de Tours, Tours, France.,CHU de Tours, Service d'Hématologie Biologique, Tours, France
| | - Olivier Herault
- CNRS EMR 7001 LNOx "Leukemic niche & redox metabolism", Tours, France. .,EA 7501 GICC, université de Tours, Tours, France. .,CHU de Tours, Service d'Hématologie Biologique, Tours, France. .,FHU GOAL, Angers, France. .,Cancéropôle Grand Ouest, Nantes, France. .,CNRS GDR 3697 Micronit "Microenvironment of tumor niches", Tours, France. .,OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Hôpital Saint-Louis, Paris, France.
| |
Collapse
|
26
|
Galow AM, Peleg S. How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span. Cells 2022; 11:468. [PMID: 35159278 PMCID: PMC8915189 DOI: 10.3390/cells11030468] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
Epigenetic alterations pose one major hallmark of organismal aging. Here, we provide an overview on recent findings describing the epigenetic changes that arise during aging and in related maladies such as neurodegeneration and cancer. Specifically, we focus on alterations of histone modifications and DNA methylation and illustrate the link with metabolic pathways. Age-related epigenetic, transcriptional and metabolic deregulations are highly interconnected, which renders dissociating cause and effect complicated. However, growing amounts of evidence support the notion that aging is not only accompanied by epigenetic alterations, but also at least in part induced by those. DNA methylation clocks emerged as a tool to objectively determine biological aging and turned out as a valuable source in search of factors positively and negatively impacting human life span. Moreover, specific epigenetic signatures can be used as biomarkers for age-associated disorders or even as targets for therapeutic approaches, as will be covered in this review. Finally, we summarize recent potential intervention strategies that target epigenetic mechanisms to extend healthy life span and provide an outlook on future developments in the field of longevity research.
Collapse
Affiliation(s)
- Anne-Marie Galow
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - Shahaf Peleg
- Research Group Epigenetics, Metabolism and Longevity, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
- Institute of Neuroregeneration and Neurorehabilitation of Qingdao University, Qingdao 266071, China
| |
Collapse
|
27
|
Pouikli A, Tessarz P. Epigenetic alterations in stem cell ageing-a promising target for age-reversing interventions? Brief Funct Genomics 2022; 21:35-42. [PMID: 33738480 PMCID: PMC8789308 DOI: 10.1093/bfgp/elab010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Ageing is accompanied by loss of tissue integrity and organismal homeostasis partly due to decline in stem cell function. The age-associated decrease in stem cell abundance and activity is often referred to as stem cell exhaustion and is considered one major hallmark of ageing. Importantly, stem cell proliferation and differentiation potential are tightly coupled to the cellular epigenetic state. Thus, research during the last years has started to investigate how the epigenome regulates stem cell function upon ageing. Here, we summarize the role of epigenetic regulation in stem cell fate decisions and we review the impact of age-related changes of the epigenome on stem cell activity. Finally, we discuss how targeted interventions on the epigenetic landscape might delay ageing and extend health-span.
Collapse
Affiliation(s)
| | - Peter Tessarz
- Corresponding author: Peter Tessarz, Max Planck Research Group ``Chromatin and Ageing'', Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany. Tel: +4922137970680; Fax: +492213797088680; E-mail:
| |
Collapse
|
28
|
Gao Q, Chen F, Zhang L, Wei A, Wang Y, Wu Z, Cao W. Inhibition of DNA methyltransferase aberrations reinstates antioxidant aging suppressors and ameliorates renal aging. Aging Cell 2022; 21:e13526. [PMID: 34874096 PMCID: PMC8761007 DOI: 10.1111/acel.13526] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/07/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
DNA methylation alterations play mechanistic roles in aging; however, the epigenetic regulators/mediators causally involved in renal aging remain elusive. Here, we report that natural and D-galactose (D-gal)-induced aging kidneys display marked suppression of antiaging factor NRF2 (nuclear factor erythroid-derived 2-like 2) and KLOTHO, accompanied by upregulations of DNA methyltransferase (DNMT) 1/3a/3b and NRF2/KLOTHO gene promoter hypermethylations. Administration of a DNMT inhibitor SGI-1072 effectively hypomethylated the promoters, derepressed NRF2/KLOTHO, and mitigated the structural and functional alterations of renal aging in D-gal mice. Moreover, oleuropein (OLP), an olive-derived polyphenol, also displayed similar epigenetic modulation and antiaging effects. OLP inhibited the epigenetic NRF2/KLOTHO suppressions in a gain of DNMT-sensitive manner in cultured renal cells, demonstrating a strong DNA-demethylating capacity. In NRF2 knockout and KLOTHO knockdown D-gal mice, OLP exhibited reduced antiaging effects with KLOTHO displaying a prominent gene effect and effect size; consistently in KLOTHO knockdown mice, the antiaging effects of SGI-1027 were largely abrogated. Therefore, the KLOTHO recovery is critical for the antiaging effects of DNA demethylation. Collectively, our data indicate that aberrant DNMT1/3a/3b elevations and the resultant suppression of antiaging factors contribute significantly to epigenetic renal aging, which might be targeted for epigenetic intervention by synthetic or natural DNA-demethylating agents.
Collapse
Affiliation(s)
- Qi Gao
- Jiangsu Key Lab of Molecular MedicineNanjing University Medical SchoolNorthern Jiangsu People's HospitalNanjingChina
| | - Fang Chen
- Jiangsu Key Lab of Molecular MedicineNanjing University Medical SchoolNorthern Jiangsu People's HospitalNanjingChina
| | - Lijun Zhang
- Jiangsu Key Lab of Molecular MedicineNanjing University Medical SchoolNorthern Jiangsu People's HospitalNanjingChina
| | - Ai Wei
- Jiangsu Key Lab of Molecular MedicineNanjing University Medical SchoolNorthern Jiangsu People's HospitalNanjingChina
| | - Yongxiang Wang
- Jiangsu Key Lab of Molecular MedicineNanjing University Medical SchoolNorthern Jiangsu People's HospitalNanjingChina
| | - Zhiwei Wu
- Jiangsu Key Lab of Molecular MedicineNanjing University Medical SchoolNorthern Jiangsu People's HospitalNanjingChina
| | - Wangsen Cao
- Jiangsu Key Lab of Molecular MedicineNanjing University Medical SchoolNorthern Jiangsu People's HospitalNanjingChina
| |
Collapse
|
29
|
Tumorigenic Aspects of MSC Senescence-Implication in Cancer Development and Therapy. J Pers Med 2021; 11:jpm11111133. [PMID: 34834485 PMCID: PMC8618265 DOI: 10.3390/jpm11111133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/13/2022] Open
Abstract
As an organism ages, many physiological processes change, including the immune system. This process, called immunosenescence, characterized by abnormal activation and imbalance of innate and adaptive immunity, leads to a state of chronic low-grade systemic inflammation, termed inflammaging. Aging and inflammaging are considered to be the root of many diseases of the elderly, as infections, autoimmune and chronic inflammatory diseases, degenerative diseases, and cancer. The role of mesenchymal stromal/stem cells (MSCs) in the inflammaging process and the age-related diseases is not completely established, although numerous features of aging MSCs, including altered immunomodulatory properties, impeded MSC niche supporting functions, and senescent MSC secretory repertoire are consistent with inflammaging development. Although senescence has its physiological function and can represent a mechanism of tumor prevention, in most cases it eventually transforms into a deleterious (para-)inflammatory process that promotes tumor growth. In this review we are going through current literature, trying to explore the role of senescent MSCs in making and/or sustaining a microenvironment permissive to tumor development and to analyze the therapeutic options that could target this process.
Collapse
|
30
|
Samoilova EM, Belopasov VV, Ekusheva EV, Zhang C, Troitskiy AV, Baklaushev VP. Epigenetic Clock and Circadian Rhythms in Stem Cell Aging and Rejuvenation. J Pers Med 2021; 11:1050. [PMID: 34834402 PMCID: PMC8620936 DOI: 10.3390/jpm11111050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, Sirt1) accelerates the aging process, while the overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.
Collapse
Affiliation(s)
- Ekaterina M. Samoilova
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| | | | - Evgenia V. Ekusheva
- Academy of Postgraduate Education of the Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies, FMBA of Russia, 125371 Moscow, Russia;
| | - Chao Zhang
- Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China;
| | - Alexander V. Troitskiy
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| | - Vladimir P. Baklaushev
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| |
Collapse
|
31
|
Analysis of Gene Expression Patterns of Epigenetic Enzymes Dnmt3a, Tet1 and Ogt in Murine Chondrogenic Models. Cells 2021; 10:cells10102678. [PMID: 34685658 PMCID: PMC8534543 DOI: 10.3390/cells10102678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/27/2021] [Accepted: 10/02/2021] [Indexed: 12/30/2022] Open
Abstract
We investigated the gene expression pattern of selected enzymes involved in DNA methylation and the effects of the DNA methylation inhibitor 5-azacytidine during in vitro and in vivo cartilage formation. Based on the data of a PCR array performed on chondrifying BMP2-overexpressing C3H10T1/2 cells, the relative expressions of Tet1 (tet methylcytosine dioxygenase 1), Dnmt3a (DNA methyltransferase 3), and Ogt (O-linked N-acetylglucosamine transferase) were further examined with RT-qPCR in murine cell line-based and primary chondrifying micromass cultures. We found very strong but gradually decreasing expression of Tet1 throughout the entire course of in vitro cartilage differentiation along with strong signals in the cartilaginous embryonic skeleton using specific RNA probes for in situ hybridization on frozen sections of 15-day-old mouse embryos. Dnmt3a and Ogt expressions did not show significant changes with RT-qPCR and gave weak in situ hybridization signals. The DNA methylation inhibitor 5-azacytidine reduced cartilage-specific gene expression and cartilage formation when applied during the early stages of chondrogenesis. In contrast, it had a stimulatory effect when added to differentiated chondrocytes, and quantitative methylation-specific PCR proved that the DNA methylation pattern of key chondrogenic marker genes was altered by the treatment. Our results indicate that the DNA demethylation inducing Tet1 plays a significant role during chondrogenesis, and inhibition of DNA methylation exerts distinct effects in different phases of in vitro cartilage formation.
Collapse
|
32
|
Li Z, Tang M, Luo D, Kashif MH, Cao S, Zhang W, Hu Y, Huang Z, Yue J, Li R, Chen P. Integrated Methylome and Transcriptome Analyses Reveal the Molecular Mechanism by Which DNA Methylation Regulates Kenaf Flowering. FRONTIERS IN PLANT SCIENCE 2021; 12:709030. [PMID: 34512693 PMCID: PMC8428968 DOI: 10.3389/fpls.2021.709030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/26/2021] [Indexed: 05/03/2023]
Abstract
DNA methylation regulates key biological processes in plants. In this study, kenaf seedlings were pretreated with the DNA methylation inhibitor 5-azacytidine (5-azaC) (at concentrations of 0, 100, 200, 400, and 600 μM), and the results showed that pretreatment with 200 μM 5-azaC promoted flowering most effectively. To elucidate the underlying mechanism, phytohormone, adenosine triphosphate (ATP), and starch contents were determined, and genome-wide DNA methylation and transcriptome analyses were performed on anthers pretreated with 200 μM 5-azaC (5-azaC200) or with no 5-azaC (control conditions; 5-azaC0). Biochemical analysis revealed that 5-azaC pretreatment significantly reduced indoleacetic acid (IAA) and gibberellic acid (GA) contents and significantly increased abscisic acid (ABA) and ATP contents. The starch contents significantly increased in response to 200 and 600 μM 5-azaC. Further genome-wide DNA methylation analysis revealed 451 differentially methylated genes (DMGs) with 209 up- and 242 downregulated genes. Transcriptome analysis showed 3,986 differentially expressed genes (DEGs), with 2,171 up- and 1,815 downregulated genes. Integrated genome-wide DNA methylation and transcriptome analyses revealed 72 genes that were both differentially methylated and differentially expressed. These genes, which included ARFs, PP2C, starch synthase, FLC, PIF1, AGL80, and WRKY32, are involved mainly in plant hormone signal transduction, starch and sucrose metabolism, and flowering regulation and may be involved in early flowering. This study serves as a reference and theoretical basis for kenaf production and provides insights into the effects of DNA methylation on plant growth and development.
Collapse
Affiliation(s)
- Zengqiang Li
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Meiqiong Tang
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Dengjie Luo
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Muhammad Haneef Kashif
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Shan Cao
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Wenxian Zhang
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Yali Hu
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Zhen Huang
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Jiao Yue
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| | - Ru Li
- College of Life Science and Technology, Guangxi University, Nanning, China
| | - Peng Chen
- Key Laboratory of Plant Genetics and Breeding, College of Agriculture, Guangxi University, Nanning, China
| |
Collapse
|
33
|
Karamini A, Bakopoulou A, Andreadis D, Gkiouras K, Kritis A. Therapeutic Potential of Mesenchymal Stromal Stem Cells in Rheumatoid Arthritis: a Systematic Review of In Vivo Studies. Stem Cell Rev Rep 2021; 16:276-287. [PMID: 31950339 DOI: 10.1007/s12015-020-09954-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Standard treatment options for rheumatoid arthritis (RA) often fail to deliver a long-term therapeutic outcome and in many cases cause intractable adverse events leading to treatment discontinuation or readjustment. Treatment with mesenchymal stem cells (MSCs) has been recently studied in RA due to its immunomodulatory and anti-inflammatory capacities. Thus, this study aims at systematically search and review the literature for randomized or non-randomized clinical trials comparing interventions of MSCs with placebo in RA patients. Electronic searches were conducted on PubMed, SCOPUS, Cochrane-CENTRAL, registries of clinical trials and grey literature. Selected studies were estimated for risk of bias with the Cochrane RoB tool 2 or the ROBINS-I tool. Four trials met the eligibility criteria and entered the review process. Identified MSCs treatments varied from allogeneic to autologous or umbilical cord-derived cells. Enrolled patients had an active RA and had poor responses to previous standard medications. In general, the safety evaluation revealed that treatment with MSCs was safe and well tolerated. Regarding the efficacy measurements, modest improvements were found in RA symptoms and RA-related indices. Significant decreases were found in inflammatory molecules such as C-reactive protein, tumor necrosis factor alpha and interleukin 6. However, clinical response criteria related to RA were achieved by a low-to-moderate percentage of patients. In conclusion, treatment of RA with MSCs appears to have a short-term therapeutic effect. Better-designed randomized trials with sufficient follow-up periods are needed so that the long-term safety and efficacy interventions with MSCs would be elucidated.
Collapse
Affiliation(s)
- Alexia Karamini
- Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece.
| | - Athina Bakopoulou
- cGMP Regenerative Medicine Facility, Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece
- Department of Prosthodontics, School of Dentistry, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), GR-54124, Thessaloniki, Greece
| | - Dimitrios Andreadis
- Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece
| | - Konstantinos Gkiouras
- Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece
| | - Aristeidis Kritis
- Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece.
- cGMP Regenerative Medicine Facility, Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece.
| |
Collapse
|
34
|
Konuma T, Ogawa K, Okada Y. Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates. Hum Mol Genet 2021; 30:294-304. [PMID: 33577681 PMCID: PMC7928862 DOI: 10.1093/hmg/ddab049] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 01/13/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
Approaches toward new therapeutics using disease genomics, such as genome-wide association study (GWAS), are anticipated. Here, we developed Trans-Phar [integration of transcriptome-wide association study (TWAS) and pharmacological database], achieving in silico screening of compounds from a large-scale pharmacological database (L1000 Connectivity Map), which have inverse expression profiles compared with tissue-specific genetically regulated gene expression. Firstly we confirmed the statistical robustness by the application of the null GWAS data and enrichment in the true-positive drug–disease relationships by the application of UK-Biobank GWAS summary statistics in broad disease categories, then we applied the GWAS summary statistics of large-scale European meta-analysis (17 traits; naverage = 201 849) and the hospitalized COVID-19 (n = 900 687), which has urgent need for drug development. We detected potential therapeutic compounds as well as anisomycin in schizophrenia (false discovery rate (FDR)-q = 0.056) and verapamil in hospitalized COVID-19 (FDR-q = 0.068) as top-associated compounds. This approach could be effective in disease genomics-driven drug development.
Collapse
Affiliation(s)
- Takahiro Konuma
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.,Central Pharmaceutical Research Institute, JAPAN TOBACCO INC., Takatsuki 569-1125, Japan
| | - Kotaro Ogawa
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.,Department of Neurology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
| | - Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.,Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita 565-0871, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita 565-0871, Japan
| |
Collapse
|
35
|
Expression Profile of Long Noncoding RNAs and Circular RNAs in Mouse C3H10T1/2 Mesenchymal Stem Cells Undergoing Myogenic and Cardiomyogenic Differentiation. Stem Cells Int 2021; 2021:8882264. [PMID: 34012468 PMCID: PMC8105102 DOI: 10.1155/2021/8882264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 03/15/2021] [Accepted: 04/11/2021] [Indexed: 12/28/2022] Open
Abstract
Background Currently, a heterogeneous category of noncoding RNAs (ncRNA) that directly regulate the expression or function of protein-coding genes is shown to have an effect on the fate decision of stem cells. However, the detailed regulatory roles of ncRNAs in myogenic and cardiomyogenic differentiation of mouse C3H10T1/2 mesenchymal stem cells (MSCs) are far from clear. Methods In this study, 5-azacytidine- (5-AZA-) treated C3H10T1/2 cells were differentiated into myocyte-like and cardiomyocyte-like cells. Next, ncRNA associated with myogenic and cardiomyogenic differentiation was identified using high-throughput RNA sequencing (RNA-seq) data. Bioinformatics analysis was conducted to identify the differentially expressed ncRNAs and the related signaling pathways. Results Myotube-like structure was formed after 5-AZA treatment of C3H10T1/2 cells. In addition, myogenic and cardiomyogenic differentiation-related genes like GATA4, cTnt, MyoD, and Desmin were upregulated significantly after the 5-AZA treatment. Totally, 1538 differentially expressed lncRNAs and 3398 differentially expressed mRNAs were identified, including 1175 upregulated and 363 downregulated lncRNAs and 2429 upregulated and 969 downregulated mRNAs. In addition, 46 differentially expressed circRNAs were identified, including 25 upregulated and 21 downregulated circRNAs. Moreover, the differentially expressed mRNAs were enriched into 5 significant pathways, including those for focal adhesion, ECM-receptor interaction, PI3K-AKT signaling pathway, PPAR signaling pathway, and Tyrosine metabolism. Conclusions A systematic view of the expression of ncRNAs in myogenic and cardiomyogenic differentiation of MSCs was provided in the study.
Collapse
|
36
|
Kelsey MMG. Reconsidering LINE-1's role in cancer: does LINE-1 function as a reporter detecting early cancer-associated epigenetic signatures? EVOLUTION MEDICINE AND PUBLIC HEALTH 2021; 9:78-82. [PMID: 33717489 PMCID: PMC7937435 DOI: 10.1093/emph/eoab004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 01/17/2021] [Indexed: 11/24/2022]
Abstract
Long interspersed nuclear element-1 (LINE-1 or L1) is the only autonomously active retrotransposon in humans. While L1 has been implicated in several pathologies and the aging process, I present a model which challenges an understanding of L1 as predominantly antagonistic to human health. I hypothesize that L1 serves as a reporter in an early cancer alert system: a tripwire strung throughout the genome poised to trigger p53 and a type I interferon (IFN-1) response when the epigenetic landscape portends cancer. Cell proliferation and a shift to aerobic glycolysis cause dramatic changes in the epigenome which are permissive to L1’s escape from suppression. L1 has several properties which make it particularly apt to fulfill this hypothesized sentinel function. Being present in many copies spread throughout the genome allows it to monitor many regions for epigenetic instability and renders it robust to deactivation by mutation. This proposed cancer alert system would alter the cancer cell fitness landscape discouraging the use of growth-favoring aerobic glycolysis by threatening the activation of tumor-suppressive mechanisms. It also imposes costs on a strategy of non-specific global transcriptional derepression aimed at activating oncogenes. Erroneous activations of this system are predicted to increase the rate of aging, suggesting this represents a case of antagonistic pleiotropy trading prolonged youth for cancer prevention. More research is needed to assess this model. Lay summary: During carcinogenesis the epigenome is remodeled by the Warburg effect and cellular proliferation. These processes globally relax chromatin. This epigenetic environment is permissive to the retrotransposon long interspersed nuclear element-1’s (LINE-1 or L1) escape from suppression. I hypothesize and present evidence for the notion that L1 has been co-opted to serve as a reporter in an early cancer alert system, poised to trigger tumor suppressive mechanisms when the epigenetic landscape portends cancer. This hypothesis describes a potentially major means by which transformation is thwarted early on.
Collapse
Affiliation(s)
- Maxfield M G Kelsey
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
- Corresponding author. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. Tel: 1-818-397-5181; E-mail:
| |
Collapse
|
37
|
赵 健, 李 东, 安 阳. [Roles of ten eleven translocation proteins family and 5-hydroxymethylcytosine in epigenetic regulation of stem cells and regenerative medicine]. BEIJING DA XUE XUE BAO. YI XUE BAN = JOURNAL OF PEKING UNIVERSITY. HEALTH SCIENCES 2021; 53:420-424. [PMID: 33879920 PMCID: PMC8072413 DOI: 10.19723/j.issn.1671-167x.2021.02.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Indexed: 06/12/2023]
Abstract
The methylation of cytosine is one of the most fundamental epigenetic modifications in mammalian genomes, and is involved in multiple crucial processes including gene expression, cell differentiation, embryo development and oncogenesis. In the past, DNA methylation was thought to be an irreversible process, which could only be diluted passively through DNA replication. It is now becoming increa-singly obvious that DNA demethylation can be an active process and plays a crucial role in biological processes. Ten eleven translocation (TET) proteins are the key factors modulating DNA demethylation. This family contains three members: TET1, TET2 and TET3. Although three TET proteins have relatively conserved catalytic domains, their roles in organisms are not repeated, and their expression has significant cell/organ specificity. TET1 is mainly expressed in embryonic stem cells, TET2 is mainly expressed in hematopoietic system, and TET3 is widely expressed in cerebellum, cortex and hippocampus. This family catalyzes 5-methylcytosine to 5-hydroxymethylcytosine and other oxidative products, reactivates silenced-gene expression, in turn maintains stem cell pluripotency and regulates lineage specification. With the development of tissue engineering, organ transplantation, autologous tissue transplantation and artificial prosthesis have been widely used in clinical treatment, but these technologies have limitations. Regenerative medicine, which uses stem cells and stem cell related factors for treatment, may provide alternative therapeutic strategies for multiple diseases. Among all kinds of human stem cells, adipose-derived stem cells (ADSCs) are the most prospective stem cell lineage since they have no ethical issues and can be easily obtained with large quantities. To date, ADSCs have been shown to have strong proli-feration capacity, secrete numerous soluble factors and have multipotent differentiation ability. However, the underlying mechanism of the proliferation, secretion, acquired pluripotency, and lineage specific differentiation of ADSCs are still largely unknown. Some studies have explored the role of epigenetic regulation and TET protein in embryonic stem cells, but little is known about its role in ADSCs. By studying the roles of TET proteins and 5-hydroxymethylcytosine in ADSCs, we could provide new theoretical foundation for the clinical application of ADSCs and the stem cell-based therapy. In the future, combined with bioprinting technology, ADSCs may be used in tissue and organ regeneration, plastic surgery reconstruction and other broader fields.
Collapse
Affiliation(s)
- 健芳 赵
- 北京大学第三医院成形外科,北京 100191Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
- 北京大学第一医院整形烧伤外科,北京 100034Department of Plastic Surgery and Burns, Peking University First Hospital, Beijing 100034, China
| | - 东 李
- 北京大学第三医院成形外科,北京 100191Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
| | - 阳 安
- 北京大学第三医院成形外科,北京 100191Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
| |
Collapse
|
38
|
5-Azacytidine pretreatment confers transient upregulation of proliferation and stemness in human mesenchymal stem cells. Cells Dev 2021; 165:203659. [PMID: 34024336 DOI: 10.1016/j.cdev.2021.203659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 12/24/2020] [Accepted: 01/07/2021] [Indexed: 11/22/2022]
Abstract
Successful outcomes of cell-based therapeutic is highly-dependent on quality and quantity of the cells. Epigenetic modifiers are known to modulate cell fates via reprogramming, hence it is plausible to use them in enhancing the plasticity of mesenchymal stem cells. In this study, we aimed to study the effects of 5-Azacytidine (5-AzaCR), an epigenetic modifier, pretreatment on mesenchymal stem cells-derived from Wharton's Jelly (WJMSCs) fates. WJMSCs were pretreated with 5-AzaCR for 24 h and subsequently cultured in culture media mixtures. The proliferative and stemness characteristics of the pretreated WJMSCs were assessed through morphological and gene expression analyses. Results showed that cells pretreated with 5 μM to 20 μM of 5-AzaCR showed to acquire higher proliferative state transiently when cultured in embryonic-mesenchymal stem cell (ESC-MSC) media, but not in MSC medium alone, and this coincides with significant transitional upregulation of stemness transcription factors. 5-AzaCR pretreatment has potential to confer initial induction of higher state of stemness and proliferation in WJMSCs, influenced by the culture media.
Collapse
|
39
|
Chakraborty S, Sinha S, Sengupta A. Emerging trends in chromatin remodeler plasticity in mesenchymal stromal cell function. FASEB J 2020; 35:e21234. [PMID: 33337557 DOI: 10.1096/fj.202002232r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/10/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022]
Abstract
Emerging evidences highlight importance of epigenetic regulation and their integration with transcriptional and cell signaling machinery in determining tissue resident adult pluripotent mesenchymal stem/stromal cell (MSC) activity, lineage commitment, and multicellular development. Histone modifying enzymes and large multi-subunit chromatin remodeling complexes and their cell type-specific plasticity remain the central defining features of gene regulation and establishment of tissue identity. Modulation of transcription factor expression gradient ex vivo and concomitant flexibility of higher order chromatin architecture in response to signaling cues are exciting approaches to regulate MSC activity and tissue rejuvenation. Being an important constituent of the adult bone marrow microenvironment/niche, pathophysiological perturbation in MSC homeostasis also causes impaired hematopoietic stem/progenitor cell function in a non-cell autonomous mechanism. In addition, pluripotent MSCs can function as immune regulatory cells, and they reside at the crossroad of innate and adaptive immune response pathways. Research in the past few years suggest that MSCs/stromal fibroblasts significantly contribute to the establishment of immunosuppressive microenvironment in shaping antitumor immunity. Therefore, it is important to understand mesenchymal stromal epigenome and transcriptional regulation to leverage its applications in regenerative medicine, epigenetic memory-guided trained immunity, immune-metabolic rewiring, and precision immune reprogramming. In this review, we highlight the latest developments and prospects in chromatin biology in determining MSC function in the context of lineage commitment and immunomodulation.
Collapse
Affiliation(s)
- Sayan Chakraborty
- Stem Cell & Leukemia Laboratory, Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,Translational Research Unit of Excellence (TRUE), Kolkata, India
| | - Sayantani Sinha
- Stem Cell & Leukemia Laboratory, Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,Translational Research Unit of Excellence (TRUE), Kolkata, India
| | - Amitava Sengupta
- Stem Cell & Leukemia Laboratory, Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,Translational Research Unit of Excellence (TRUE), Kolkata, India
| |
Collapse
|
40
|
Liu Y, Chen Q. Senescent Mesenchymal Stem Cells: Disease Mechanism and Treatment Strategy. CURRENT MOLECULAR BIOLOGY REPORTS 2020; 6:173-182. [PMID: 33816065 PMCID: PMC8011589 DOI: 10.1007/s40610-020-00141-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW Mesenchymal stem cells (MSCs) have been extensively studied for therapeutic application in tissue engineering and regenerative medicine. Despite their promise, recent findings suggest that MSC replication during repair process may lead to replicative senescence and stem cell exhaustion. Here, we review the basic mechanisms of MSC senescence, how it leads to degenerative diseases, and potential treatments for such diseases. RECENT FINDINGS Emerging evidence has shown a link between senescent MSCs and degenerative diseases, especially age-related diseases such as osteoarthritis and idiopathic pulmonary fibrosis. During these disease processes, MSCs undergo cell senescence and mediate Senescence Associated Secretory Phenotypes (SASP) to affect the surrounding microenvironment. Thus, senescent MSCs can accelerate tissue aging by increasing the number of senescent cells and spreading inflammation to neighboring cells. SUMMARY Senescent MSCs not only hamper tissue repair through cell senescence associated stem cell exhaustion, but also mediate tissue degeneration by initiating and spreading senescence-associated inflammation. It suggests new strategies of MSC-based cell therapy to remove, rejuvenate, or replace (3Rs) the senescent MSCs.
Collapse
Affiliation(s)
- Yajun Liu
- Laboratory of Molecular Biology and Nanomedicine, Department of Orthopaedics, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA
| | - Qian Chen
- Laboratory of Molecular Biology and Nanomedicine, Department of Orthopaedics, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA
| |
Collapse
|
41
|
Hasunuma H, Shimizu N, Yokota H, Tatsuno I. Azacitidine decreases reactive oxygen species production in peripheral white blood cells: A case report. World J Clin Cases 2020; 8:5657-5662. [PMID: 33344557 PMCID: PMC7716315 DOI: 10.12998/wjcc.v8.i22.5657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/22/2020] [Accepted: 10/13/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND In myelodysplastic syndrome (MDS), oxidative stress is closely related to iron overload and DNA damage. A recent study suggested the possibility that increased oxidative stress causes not only iron overload but also disease progression of MDS with DNA damage. We present a case of MDS with decreased reactive oxygen species (ROS) production in peripheral white blood cells (WBCs) and decreased diacron-reactive oxygen metabolites (d-ROMs) in serum after azacitidine therapy.
CASE SUMMARY A 74-year-old man presented to the hematological department with the chief complaint of anemia. His vital signs were within normal limits at admission with a heart rate of 80 bpm and blood pressure of 135/60 mmHg. Laboratory tests indicated pancytopenia, a WBC count of 2190 cells/µL, a hemoglobin level of 6.2 g/dL and a platelet count of 7.4 × 104/µL. The patient was diagnosed with MDS with fibrosis after a bone marrow examination. This case showed decreased ROS production in WBCs, d-ROMs in serum and Wilms’ tumor 1 after azacitidine therapy, after which his hematopoiesis recovered.
CONCLUSION Azacitidine therapy can improve hematopoiesis and decrease ROS and d-ROM production.
Collapse
Affiliation(s)
- Hidekazu Hasunuma
- Department of Blood Transfusion, Toho University Medical Center Sakura Hospital, Sakura 2858741, Japan
| | - Naomi Shimizu
- Department of Hematology, Toho University Medical Center Sakura Hospital, Sakura 2858741, Japan
| | - Hiromitsu Yokota
- Clinical Laboratory Program, Education Development Center, Faculty of Science Toho University, Funabashi 2748510, Japan
| | - Ichiro Tatsuno
- Center for Diabetes, Metabolism and Endocrinology, Toho University Medical Center Sakura Hospital, Sakura 2858741, Japan
| |
Collapse
|
42
|
Valenti MT, Dalle Carbonare L, Dorelli G, Mottes M. Effects of physical exercise on the prevention of stem cells senescence. Stem Cell Rev Rep 2020; 16:33-40. [PMID: 31832933 DOI: 10.1007/s12015-019-09928-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Regular physical activity is essential for maintaining wellbeing; physical inactivity, on the contrary, is considered by the World Health Organization (WHO) as one of the most important risk factors for global mortality. During physical exercise different growth factors, cytokines and hormones are released, which affect positively the functions of heart, bone, brain and skeletal muscle. It has been reported that physical activity is able to stimulate tissue remodeling. Therefore, in this scenario, it is important to deepen the topic of physical activity-induced effects on stem cells.
Collapse
Affiliation(s)
- Maria Teresa Valenti
- Department of Medicine, University of Verona, Ple Scuro 10, 37100, Verona, Italy
| | - Luca Dalle Carbonare
- Department of Medicine, University of Verona, Ple Scuro 10, 37100, Verona, Italy.
| | - Gianluigi Dorelli
- Department of Medicine, University of Verona, Ple Scuro 10, 37100, Verona, Italy
| | - Monica Mottes
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100, Verona, Italy
| |
Collapse
|
43
|
Epigenetic Regulation in Mesenchymal Stem Cell Aging and Differentiation and Osteoporosis. Stem Cells Int 2020; 2020:8836258. [PMID: 32963550 PMCID: PMC7501554 DOI: 10.1155/2020/8836258] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/17/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a reliable source for cell-based regenerative medicine owing to their multipotency and biological functions. However, aging-induced systemic homeostasis disorders in vivo and cell culture passaging in vitro induce a functional decline of MSCs, switching MSCs to a senescent status with impaired self-renewal capacity and biased differentiation tendency. MSC functional decline accounts for the pathogenesis of many diseases and, more importantly, limits the large-scale applications of MSCs in regenerative medicine. Growing evidence implies that epigenetic mechanisms are a critical regulator of the differentiation programs for cell fate and are subject to changes during aging. Thus, we here review epigenetic dysregulations that contribute to MSC aging and osteoporosis. Comprehending detailed epigenetic mechanisms could provide us with a novel horizon for dissecting MSC-related pathogenesis and further optimizing MSC-mediated regenerative therapies.
Collapse
|
44
|
Systemic Administration of Rejuvenated Adipose-Derived Mesenchymal Stem Cells Improves Liver Metabolism in Equine Metabolic Syndrome (EMS)- New Approach in Veterinary Regenerative Medicine. Stem Cell Rev Rep 2020; 15:842-850. [PMID: 31620992 PMCID: PMC6925066 DOI: 10.1007/s12015-019-09913-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Equine metabolic syndrome (EMS) is characterized by adiposity, insulin dysregulation and increased risk for laminitis. Increased levels of specific liver enzymes in the peripheral blood are typical findings in horses diagnosed with EMS. Current management of EMS is based on caloric restriction and increased physical activity. However, new potential treatment options are arising such as the transplantation of autologous adipose stem cells (ASC). However, cytophysiological properties of ASC derived from EMS horses are impaired which strongly limits their therapeutic potential. We hypothesized, that in vitro pharmacotherapy of those cells with 5-azacytidine (AZA) and resveratrol (RES) before their clinical application can reverse the aged phenotype of those cells and improve clinical outcome of autologous therapy. A 9 year old Dutch Warmblood Horse used for driving, was presented with severe obesity, insulin resistance. After EMS diagnosis, the animal received three intravenous injections of autologous, AZA/RES treated ASCs at weekly intervals. The therapeutic effect was assessed by the analysis of liver specific enzymes in the blood. ASC-transplantation reduced levels of glutamate dehydrogenase (GLDH), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH) and aspartate transaminase (AST). This case report demonstrates the therapeutic potential of this intervention for EMS as well as apt utility of autologous, rejuvenated ASC injections.
Collapse
|
45
|
Changes in Stemness Properties, Differentiation Potential, Oxidative Stress, Senescence and Mitochondrial Function in Wharton's Jelly Stem Cells of Umbilical Cords of Mothers with Gestational Diabetes Mellitus. Stem Cell Rev Rep 2020; 15:415-426. [PMID: 30645713 DOI: 10.1007/s12015-019-9872-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gestational diabetes mellitus (GDM) has been associated with an increased risk of maternal and neonatal morbidity. The Wharton's jelly (WJ) of the umbilical cord (UC) is a useful indicator of the deleterious effects of hyperglycemia on fetal tissues as it represents the fetus embryologically, physiologically and genetically. We studied WJ mesenchymal stem cells (hWJSCs) from UC from mothers without GDM (Normal; n = 3); insulin-controlled GDM mothers (GDMi; n = 3) and diet-controlled GDM mothers (GDMd; n = 3)]. Cell proliferation, stemness markers, telomerase, osteogenic and chondrogenic differentiation, antioxidant enzymes and gene expression for mitochondrial function (ND2, TFAM, PGC1α, and NDUFB9) were significantly lower in GDMi-hWJSCs and GDMd-hWJSCs compared to normal hWJSCs (P < 0.05). On the other hand, cell cycle inhibitors (p16, p21, p27) and p53 were remarkably up-regulated in GDMi-hWJSCs and GDMd-hWJSCs compared to normal hWJSCs. The results from this study confirmed that maternal hyperglycemia even though managed with insulin or diet, induced changes in the properties of the WJ and its cells. These changes may also be observed in fetal tissues and if true, prevention of the onset of gestational diabetes should be a priority over management. Generation of tissues that simulate those of the fetus such as pancreatic and cardiovascular cells from GDM-hWJSCs by direct differentiation or via induced pluripotent stem cell reprogramming provide possible platforms to evaluate the effects of glucose on specific fetal organ.
Collapse
|
46
|
Epigenetic Clock: DNA Methylation in Aging. Stem Cells Int 2020; 2020:1047896. [PMID: 32724310 PMCID: PMC7366189 DOI: 10.1155/2020/1047896] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/11/2020] [Accepted: 06/20/2020] [Indexed: 02/07/2023] Open
Abstract
Aging, which is accompanied by decreased organ function and increased disease incidence, limits human lifespan and has attracted investigators for thousands of years. In recent decades, with the rapid development of biology, scientists have shown that epigenetic modifications, especially DNA methylation, are key regulators involved in this process. Regular fluctuations in global DNA methylation levels have been shown to accurately estimate biological age and disease prognosis. In this review, we discuss recent findings regarding the relationship between variations in DNA methylation level patterns and aging. In addition, we introduce the known mechanisms by which DNA methylation regulators affect aging and related diseases. As more studies uncover the mechanisms by which DNA methylation regulates aging, antiaging interventions and treatments for related diseases may be developed that enable human life extension.
Collapse
|
47
|
Tansriratanawong K, Tabei I, Ishikawa H, Ohyama A, Toyomura J, Sato S. Characterization and comparative DNA methylation profiling of four adipogenic genes in adipose-derived stem cells and dedifferentiated fat cells from aging subjects. Hum Cell 2020; 33:974-989. [PMID: 32495194 PMCID: PMC7505878 DOI: 10.1007/s13577-020-00379-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 05/14/2020] [Indexed: 12/20/2022]
Abstract
Adipose-derived stem cells (ASCs) and dedifferentiated fat (DFAT) cells are alternative cell sources in tissue engineering and regeneration because they are easily obtained and exhibit multilineage differentiation. However, aging may attenuate their regenerative potential and metabolic functions. Reports characterizing DFAT cells derived from aging donors are rare, and comparisons of DNA methylation profiles between aging ASCs and DFAT cells are poorly understood. Therefore, this study aimed to characterize DFAT cells relative to ASCs derived from aging subjects and compare the DNA methylation profiles of four adipogenic genes in these cells. ASCs and DFAT cells from aging donors exhibited characteristics similar to those of stem cells, including colony formation, proliferation, and multilineage differentiation abilities. However, compared with ASCs, DFAT cells exhibited increased proliferation, smooth muscle actin alpha (SMA-α) expression and decreased cellular senescence. DNA methylation profiling of ASCs and DFAT cells by combined bisulfite restriction analysis (COBRA) demonstrated hypermethylation patterns in three potent adipogenic genes—peroxisome proliferator-activated receptor gamma 2 (PPARγ2), fatty acid-binding protein 4 (FABP4), and lipoprotein lipase (LPL)—but hypomethylation of CCAAT/enhancer binding protein alpha (C/EBPα) in the aging group. Statistically significant differences were observed between the aging group and the young group. Epigenetic regulation maintains the stability of ASCs and DFAT cells in an age-dependent manner. Our findings suggested that although the DNA methylation patterns of three adipogenic genes correlated with hypermethylation and aging, ASCs and DFAT cells exhibited cellular stability and several stem cell characteristics, offering further opportunities for personalized regeneration and energy maintenance by adipogenesis during aging.
Collapse
Affiliation(s)
- Kallapat Tansriratanawong
- Department of Oral Medicine and Periodontology, Faculty of Dentistry, Mahidol University, 6 Yothi Street Rajthevi, Bangkok, 10400, Thailand.
| | - Isao Tabei
- Department of Surgery, Jikei University School of Medicine, Tokyo, 105-0003, Japan
| | - Hiroshi Ishikawa
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Akihiro Ohyama
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Junko Toyomura
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Soh Sato
- Department of Periodontology, Nippon Dental University, Niigata, 951-1500, Japan
| |
Collapse
|
48
|
Zhou X, Hong Y, Zhang H, Li X. Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges. Front Cell Dev Biol 2020; 8:364. [PMID: 32582691 PMCID: PMC7283395 DOI: 10.3389/fcell.2020.00364] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 04/23/2020] [Indexed: 12/14/2022] Open
Abstract
Over the past decades, mesenchymal stem cell (MSC)-based therapy has been intensively investigated and shown promising results in the treatment of various diseases due to their easy isolation, multiple lineage differentiation potential and immunomodulatory effects. To date, hundreds of phase I and II clinical trials using MSCs have been completed and many are ongoing. Accumulating evidence has shown that transplanted allogeneic MSCs lose their beneficial effects due to immunorejection. Nevertheless, the function of autologous MSCs is adversely affected by age, a process termed senescence, thus limiting their therapeutic potential. Despite great advances in knowledge, the potential mechanisms underlying MSC senescence are not entirely clear. Understanding the molecular mechanisms that contribute to MSC senescence is crucial when exploring novel strategies to rejuvenate senescent MSCs. In this review, we aim to provide an overview of the biological features of senescent MSCs and the recent progress made regarding the underlying mechanisms including epigenetic changes, autophagy, mitochondrial dysfunction and telomere shortening. We also summarize the current approaches to rejuvenate senescent MSCs including gene modification and pretreatment strategies. Collectively, rejuvenation of senescent MSCs is a promising strategy to enhance the efficacy of autologous MSC-based therapy, especially in elderly patients.
Collapse
Affiliation(s)
- Xueke Zhou
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China
| | - Yimei Hong
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hao Zhang
- School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Xin Li
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China
| |
Collapse
|
49
|
Xin TY, Yu TT, Yang RL. DNA methylation and demethylation link the properties of mesenchymal stem cells: Regeneration and immunomodulation. World J Stem Cells 2020; 12:351-358. [PMID: 32547683 PMCID: PMC7280864 DOI: 10.4252/wjsc.v12.i5.351] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 03/27/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a heterogeneous population that can be isolated from various tissues, including bone marrow, adipose tissue, umbilical cord blood, and craniofacial tissue. MSCs have attracted increasingly more attention over the years due to their regenerative capacity and function in immunomodulation. The foundation of tissue regeneration is the potential of cells to differentiate into multiple cell lineages and give rise to multiple tissue types. In addition,the immunoregulatory function of MSCs has provided insights into therapeutic treatments for immune-mediated diseases. DNA methylation and demethylation are important epigenetic mechanisms that have been shown to modulate embryonic stem cell maintenance, proliferation, differentiation and apoptosis by activating or suppressing a number of genes. In most studies, DNA hypermethylation is associated with gene suppression, while hypomethylation or demethylation is associated with gene activation. The dynamic balance of DNA methylation and demethylation is required for normal mammalian development and inhibits the onset of abnormal phenotypes. However, the exact role of DNA methylation and demethylation in MSC-based tissue regeneration and immunomodulation requires further investigation. In this review, we discuss how DNA methylation and demethylation function in multi-lineage cell differentiation and immunomodulation of MSCs based on previously published work. Furthermore, we discuss the implications of the role of DNA methylation and demethylation in MSCs for the treatment of metabolic or immune-related diseases.
Collapse
Affiliation(s)
- Tian-Yi Xin
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
| | - Ting-Ting Yu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
| | - Rui-Li Yang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China.
| |
Collapse
|
50
|
Pepin ME, Infante T, Benincasa G, Schiano C, Miceli M, Ceccarelli S, Megiorni F, Anastasiadou E, Della Valle G, Fatone G, Faenza M, Docimo L, Nicoletti GF, Marchese C, Wende AR, Napoli C. Differential DNA Methylation Encodes Proliferation and Senescence Programs in Human Adipose-Derived Mesenchymal Stem Cells. Front Genet 2020; 11:346. [PMID: 32351540 PMCID: PMC7174643 DOI: 10.3389/fgene.2020.00346] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/23/2020] [Indexed: 11/28/2022] Open
Abstract
Adult adipose tissue-derived mesenchymal stem cells (ASCs) constitute a vital population of multipotent cells capable of differentiating into numerous end-organ phenotypes. However, scientific and translational endeavors to harness the regenerative potential of ASCs are currently limited by an incomplete understanding of the mechanisms that determine cell-lineage commitment and stemness. In the current study, we used reduced representation bisulfite sequencing (RRBS) analysis to identify epigenetic gene targets and cellular processes that are responsive to 5′-azacitidine (5′-AZA). We describe specific changes to DNA methylation of ASCs, uncovering pathways likely associated with the enhancement of their proliferative capacity. We identified 4,797 differentially methylated regions (FDR < 0.05) associated with 3,625 genes, of which 1,584 DMRs annotated to the promoter region. Gene set enrichment of differentially methylated promoters identified “phagocytosis,” “type 2 diabetes,” and “metabolic pathways” as disproportionately hypomethylated, whereas “adipocyte differentiation” was the most-enriched pathway among hyper-methylated gene promoters. Weighted coexpression network analysis of DMRs identified clusters associated with cellular proliferation and other developmental programs. Furthermore, the ELK4 binding site was disproportionately hyper-methylated within the promoters of genes associated with AKT signaling. Overall, this study offers numerous preliminary insights into the epigenetic landscape that influences the regenerative capacity of human ASCs.
Collapse
Affiliation(s)
- Mark E Pepin
- Department of Pathology, Division of Molecular & Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Teresa Infante
- Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giuditta Benincasa
- Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Concetta Schiano
- Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | - Simona Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesca Megiorni
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Eleni Anastasiadou
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Giovanni Della Valle
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy
| | - Gerardo Fatone
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy
| | - Mario Faenza
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, Plastic Surgery Unit, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ludovico Docimo
- Clinical Department of Internal Medicine and Specialistics, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giovanni F Nicoletti
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, Plastic Surgery Unit, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Adam R Wende
- Department of Pathology, Division of Molecular & Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Claudio Napoli
- IRCCS SDN, Naples, Italy.,Clinical Department of Internal Medicine and Specialistics, University of Campania Luigi Vanvitelli, Naples, Italy
| |
Collapse
|