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1
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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.
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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.
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2
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Wang J, Jian K, Yang Q, Gu C, Sheng J, Zhou Y, Yin H, Zhang Z, Hua K, Zhang C. Retarding human adipose-derived MSCs senescence and promoting tendon repair using cell sheet engineering with a histone methyltransferase inhibitor. Sci Rep 2025; 15:6198. [PMID: 39979391 PMCID: PMC11842574 DOI: 10.1038/s41598-025-89234-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/04/2025] [Indexed: 02/22/2025] Open
Abstract
Mesenchymal stem cell (MSC) holds immense potential as candidates for cell therapy in the treatment of tendon injuries due to their remarkable ability for multiple cell differentiation. However, the proliferative and differentiation capacity of MSCs has been limited by cellular senescence during the process of expanding culture. Therefore, in this study, our aim was to maintain the beneficial properties of MSCs. We found that SETD7, a histone methyltransferase, was upregulated during ex vivo expansion of human adipose-derived mesenchymal stem cells (hAD-MSCs). Pharmacological inhibition of SETD7 with PFI-2 in hAD-MSCs cultures delayed their senescence, as evident by the diminished expression of senescent-associated genes and the maintenance of their proliferation and differentiation capacity. Upon transplantation, cell sheets derived from hAD-MSCs expanded with PFI-2 were better able to accelerate tendon repair. Therefore, the present findings reveal that SETD7 is an important target to improve the expansion of hAD-MSCs by delaying senescence, which is importance for the development of efficient stem cell-based therapeutic approaches.
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Affiliation(s)
- Junjuan Wang
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Ke Jian
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, 410082, China
| | - Qing Yang
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, 410082, China
| | - Chunyi Gu
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Jiajun Sheng
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Yan Zhou
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Hantian Yin
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Zhihan Zhang
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Kouzhen Hua
- Department of Anatomy, School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 311300, China.
| | - Can Zhang
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, 410082, China.
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3
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Balaraman AK, Afzal M, Moglad E, Babu MA, Priya GP, Bansal P, Rajotiya S, Kondapavuluri BK, Kazmi I, Alzarea SI, Goyal K, Ali H. The interplay of p16INK4a and non-coding RNAs: bridging cellular senescence, aging, and cancer. Biogerontology 2025; 26:50. [PMID: 39907830 DOI: 10.1007/s10522-025-10194-2] [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: 12/24/2024] [Accepted: 01/23/2025] [Indexed: 02/06/2025]
Abstract
p16INK4a is a crucial tumor suppressor and regulator of cellular senescence, forming a molecular bridge between aging and cancer. Dysregulated p16INK4a expression is linked to both premature aging and cancer progression, where non-coding RNAs (ncRNAs) such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and small interfering RNAs (siRNAs) play key roles in modulating its function. These ncRNAs interact with p16INK4a through complex post-transcriptional and epigenetic mechanisms, influencing pathways critical to senescence and tumor suppression. In this review, we explore ncRNAs, including ANRIL, MIR31HG, UCA1, MALAT1, miR-24, miR-30, and miR-141, which collectively regulate p16INK4a expression, promoting or inhibiting pathways associated with cancer and aging. ANRIL and MIR31HG modulate p16INK4a silencing via interactions with polycomb repressive complexes (PRC), while miRNAs such as miR-24 and miR-30 target p16INK4a to influence cellular proliferation and senescence. This regulatory interplay underscores the therapeutic potential of ncRNA-targeted strategies to restore p16INK4a function. We summarize recent studies supporting that ncRNAs that control p16INK4a may be diagnostic biomarkers and therapeutic targets for age-related diseases and cancer.
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Affiliation(s)
- Ashok Kumar Balaraman
- Research and Enterprise, University of Cyberjaya, Persiaran Bestari, Cyber 11, 63000, Cyberjaya, Selangor, Malaysia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, 21442, Jeddah, Saudi Arabia
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al Kharj, Saudi Arabia
| | - M Arockia Babu
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - G Padma Priya
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Pooja Bansal
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Sumit Rajotiya
- NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan, India
| | - Benod Kumar Kondapavuluri
- Department of General Surgery, Consultant Head and Neck Surgical Oncology, Dr.D.Y.Patil Medical College, Hospital and Research Centre, Pimpri, Pune, India
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Al-Jouf, Saudi Arabia
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to Be University), Clement Town, Dehradun, 248002, India.
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
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4
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Roato I, Visca M, Mussano F. Suppressing the Aging Phenotype of Mesenchymal Stromal Cells: Are We Ready for Clinical Translation? Biomedicines 2024; 12:2811. [PMID: 39767719 PMCID: PMC11673080 DOI: 10.3390/biomedicines12122811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are involved in the maintenance and regeneration of a large variety of tissues due to their stemness and multi-lineage differentiation capability. Harnessing these advantageous features, a flurry of clinical trials have focused on MSCs to treat different pathologies, but only few protocols have received regulatory approval so far. Among the various causes hindering MSCs' efficacy is the emergence of cellular senescence, which has been correlated with specific characteristics, such as morphological and epigenetic alterations, DNA damage, ROS production, mitochondrial dysfunction, telomere shortening, non-coding RNAs, loss of proteostasis, and a peculiar senescence-associated secretory phenotype. Several strategies have been investigated for delaying or even hopefully reverting the onset of senescence, as assessed by the senescent phenotype of MSCs. Here, the authors reviewed the most updated literature on the potential causes of senescence, with a particular emphasis on the current and future therapeutic approaches aimed at reverting senescence and/or extending the functional lifespan of stem cells.
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Affiliation(s)
- Ilaria Roato
- Department of Surgical Sciences, CIR-Dental School, University of Turin, 10126 Turin, Italy; (M.V.); (F.M.)
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5
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Chen X, Yu T, Li S, Fang H. Inhibition of bromodomain regulates cellular senescence in pancreatic adenocarcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2024; 17:360-370. [PMID: 39544715 PMCID: PMC11558316 DOI: 10.62347/bknq9812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/23/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators that promote the transcription of genes in the chromatin region associated with acetylated histones. Small molecule BET inhibitor JQ1 suppresses the biologic function of BET proteins in a variety of tumors and inhibits their proliferation. METHODS We investigated the effect of JQ1 in the treatment of pancreatic cancer. In addition, we evaluated the expression level of BRD4 protein in pancreatic cancer tissues using the Gene Expression Profiling Interactive Analysis (GEPIA) and the Human protein Altas databases and analyzed the correlation between BRD4 and the clinicopathologic features and immune checkpoints of pancreatic adenocarcinoma using UALACN and TIMER databases. RESULTS JQ1 significantly inhibited the proliferation of pancreatic adenocarcinoma (PAAD) cells and induced cell senescence but had little effect on Senescence-associated secretory phenotype (SASP). Interestingly, JQ1 inhibited the epithelial-mesenchymal transition (EMT) and Wnt signaling pathways. CONCLUSIONS These results provide a theoretical basis for new targets in the treatment of pancreatic cancer.
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Affiliation(s)
- Xiang Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Tao Yu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Shu Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Hongcai Fang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
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Wang J, Zhang M, Wang H. Emerging Landscape of Mesenchymal Stem Cell Senescence Mechanisms and Implications on Therapeutic Strategies. ACS Pharmacol Transl Sci 2024; 7:2306-2325. [PMID: 39144566 PMCID: PMC11320744 DOI: 10.1021/acsptsci.4c00284] [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: 05/15/2024] [Revised: 07/05/2024] [Accepted: 07/09/2024] [Indexed: 08/16/2024]
Abstract
Mesenchymal stem cells (MSCs) hold significant promise for regenerative medicine and tissue engineering due to their unique multipotent differentiation ability and immunomodulatory properties. MSC therapy is widely discussed and utilized in clinical treatment. However, during both in vitro expansion and in vivo transplantation, MSCs are prone to senescence, an irreversible growth arrest characterized by morphological, gene expression, and functional changes in genomic regulation. The microenvironment surrounding MSCs plays a crucial role in modulating their senescence phenotype, influenced by factors such as hypoxia, inflammation, and aging status. Numerous strategies targeting MSC senescence have been developed, including senolytics and senomorphic agents, antioxidant and exosome therapies, mitochondrial transfer, and niche modulation. Novel approaches addressing replicative senescence have also emerged. This paper comprehensively reviews the current molecular manifestations of MSC senescence, addresses the environmental impact on senescence, and highlights potential therapeutic strategies to mitigate senescence in MSC-based therapies. These insights aim to enhance the efficacy and understanding of MSC therapies.
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Affiliation(s)
- Jing Wang
- Department
of Cellular and Molecular Medicine, University
of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Muqing Zhang
- Institute
of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21215, United States
| | - Hu Wang
- Institute
of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21215, United States
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Huo S, Tang X, Chen W, Gan D, Guo H, Yao Q, Liao R, Huang T, Wu J, Yang J, Xiao G, Han X. Epigenetic regulations of cellular senescence in osteoporosis. Ageing Res Rev 2024; 99:102235. [PMID: 38367814 DOI: 10.1016/j.arr.2024.102235] [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: 09/18/2023] [Revised: 01/27/2024] [Accepted: 02/13/2024] [Indexed: 02/19/2024]
Abstract
Osteoporosis (OP) is a prevalent age-related disease that is characterized by a decrease in bone mineral density (BMD) and systemic bone microarchitectural disorders. With age, senescent cells accumulate and exhibit the senescence-associated secretory phenotype (SASP) in bone tissue, leading to the imbalance of bone homeostasis, osteopenia, changes in trabecular bone structure, and increased bone fragility. Cellular senescence in the bone microenvironment involves osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells (BMSCs), whose effects on bone homeostasis are regulated by epigenetics. Therefore, the epigenetic regulatory mechanisms of cellular senescence have received considerable attention as potential targets for preventing and treating osteoporosis. In this paper, we systematically review the mechanisms of aging-associated epigenetic regulation in osteoporosis, emphasizing the impact of epigenetics on cellular senescence, and summarize three current methods of targeting cellular senescence, which is helpful better to understand the pathogenic mechanisms of cellular senescence in osteoporosis and provides strategies for the development of epigenetic drugs for the treatment of osteoporosis.
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Affiliation(s)
- Shaochuan Huo
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen 518000, China; Shenzhen Research Institute of Guangzhou University of Traditional Medicine (Futian), Shenzhen 518000, China
| | - Xinzheng Tang
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen 518000, China; Shenzhen Research Institute of Guangzhou University of Traditional Medicine (Futian), Shenzhen 518000, China
| | - Weijian Chen
- Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Donghao Gan
- Department of Biochemistry, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, China
| | - Hai Guo
- Liuzhou Traditional Chinese Medicine Hospital (Liuzhou Zhuang Medical Hospital), Liuzhou 545001, China
| | - Qing Yao
- Department of Biochemistry, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, China
| | - Rongdong Liao
- Department of Orthopaedics, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Tingting Huang
- Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Junxian Wu
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen 518000, China
| | - Junxing Yang
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen 518000, China; Shenzhen Research Institute of Guangzhou University of Traditional Medicine (Futian), Shenzhen 518000, China.
| | - Guozhi Xiao
- Department of Biochemistry, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, China.
| | - Xia Han
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen 518000, China; Shenzhen Research Institute of Guangzhou University of Traditional Medicine (Futian), Shenzhen 518000, China.
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8
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Zhang Q, Hu J, Li DL, Qiu JG, Jiang BH, Zhang CY. Construction of single-molecule counting-based biosensors for DNA-modifying enzymes: A review. Anal Chim Acta 2024; 1298:342395. [PMID: 38462345 DOI: 10.1016/j.aca.2024.342395] [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: 12/10/2023] [Revised: 02/18/2024] [Accepted: 02/19/2024] [Indexed: 03/12/2024]
Abstract
DNA-modifying enzymes act as critical regulators in a wide range of genetic functions (e.g., DNA damage & repair, DNA replication), and their aberrant expression may interfere with regular genetic functions and induce various malignant diseases including cancers. DNA-modifying enzymes have emerged as the potential biomarkers in early diagnosis of diseases and new therapeutic targets in genomic research. Consequently, the development of highly specific and sensitive biosensors for the detection of DNA-modifying enzymes is of great importance for basic biomedical research, disease diagnosis, and drug discovery. Single-molecule fluorescence detection has been widely implemented in the field of molecular diagnosis due to its simplicity, high sensitivity, visualization capability, and low sample consumption. In this paper, we summarize the recent advances in single-molecule counting-based biosensors for DNA-modifying enzyme (i.e, alkaline phosphatase, DNA methyltransferase, DNA glycosylase, flap endonuclease 1, and telomerase) assays in the past four years (2019 - 2023). We highlight the principles and applications of these biosensors, and give new insight into the future challenges and perspectives in the development of single-molecule counting-based biosensors.
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Affiliation(s)
- Qian Zhang
- Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China; College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan, 250014, China
| | - Juan Hu
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China
| | - Dong-Ling Li
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China
| | - Jian-Ge Qiu
- Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Bing-Hua Jiang
- Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Chun-Yang Zhang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China.
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Ibragimova M, Kussainova A, Aripova A, Bersimbaev R, Bulgakova O. The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation. Cells 2024; 13:550. [PMID: 38534394 PMCID: PMC10969416 DOI: 10.3390/cells13060550] [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: 02/20/2024] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 03/28/2024] Open
Abstract
This review discusses the relationship between cellular senescence and radiation exposure. Given the wide range of ionizing radiation sources encountered by people in professional and medical spheres, as well as the influence of natural background radiation, the question of the effect of radiation on biological processes, particularly on aging processes, remains highly relevant. The parallel relationship between natural and radiation-induced cellular senescence reveals the common aspects underlying these processes. Based on recent scientific data, the key points of the effects of ionizing radiation on cellular processes associated with aging, such as genome instability, mitochondrial dysfunction, altered expression of miRNAs, epigenetic profile, and manifestation of the senescence-associated secretory phenotype (SASP), are discussed. Unraveling the molecular mechanisms of cellular senescence can make a valuable contribution to the understanding of the molecular genetic basis of age-associated diseases in the context of environmental exposure.
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Affiliation(s)
- Milana Ibragimova
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
| | - Assiya Kussainova
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
- Department of Health Sciences, University of Genova, Via Pastore 1, 16132 Genoa, Italy
| | - Akmaral Aripova
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
| | - Rakhmetkazhi Bersimbaev
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
| | - Olga Bulgakova
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
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10
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Luo L, An X, Xiao Y, Sun X, Li S, Wang Y, Sun W, Yu D. Mitochondrial-related microRNAs and their roles in cellular senescence. Front Physiol 2024; 14:1279548. [PMID: 38250662 PMCID: PMC10796628 DOI: 10.3389/fphys.2023.1279548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 12/13/2023] [Indexed: 01/23/2024] Open
Abstract
Aging is a natural aspect of mammalian life. Although cellular mortality is inevitable, various diseases can hasten the aging process, resulting in abnormal or premature senescence. As cells age, they experience distinctive morphological and biochemical shifts, compromising their functions. Research has illuminated that cellular senescence coincides with significant alterations in the microRNA (miRNA) expression profile. Notably, a subset of aging-associated miRNAs, originally encoded by nuclear DNA, relocate to mitochondria, manifesting a mitochondria-specific presence. Additionally, mitochondria themselves house miRNAs encoded by mitochondrial DNA (mtDNA). These mitochondria-residing miRNAs, collectively referred to as mitochondrial miRNAs (mitomiRs), have been shown to influence mtDNA transcription and protein synthesis, thereby impacting mitochondrial functionality and cellular behavior. Recent studies suggest that mitomiRs serve as critical sensors for cellular senescence, exerting control over mitochondrial homeostasis and influencing metabolic reprogramming, redox equilibrium, apoptosis, mitophagy, and calcium homeostasis-all processes intimately connected to senescence. This review synthesizes current findings on mitomiRs, their mitochondrial targets, and functions, while also exploring their involvement in cellular aging. Our goal is to shed light on the potential molecular mechanisms by which mitomiRs contribute to the aging process.
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Affiliation(s)
- Ling Luo
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xingna An
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yinghui Xiao
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiguang Sun
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Sijie Li
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yingzhao Wang
- Department of Neurology, Qianwei Hospital of Jilin Province, Changchun, Jilin, China
| | - Weixia Sun
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Dehai Yu
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
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11
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Rasouli M, Naeimzadeh Y, Hashemi N, Hosseinzadeh S. Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging. Curr Stem Cell Res Ther 2024; 19:15-32. [PMID: 36642876 DOI: 10.2174/1574888x18666230113144016] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023]
Abstract
Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Sun Q, Bai R, Chen S, Zhuang Z, Deng J, Xin T, Zhang Y, Li Q, Han B. Lysine demethylase 3A promotes chondrogenic differentiation of aged human dental pulp stem cells. J Dent Sci 2024; 19:86-91. [PMID: 38303882 PMCID: PMC10829671 DOI: 10.1016/j.jds.2023.05.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/23/2023] [Indexed: 02/03/2024] Open
Abstract
BACKGROUND/PURPOSE Aging severely impairs the beneficial effects of human dental pulp stem cells (hDPSCs) on cartilage regeneration. Lysine demethylase 3A (KDM3A) is involved in regulating mesenchymal stem cells (MSCs) senescence and bone aging. In this study, we investigated the role of KDM3A in hDPSCs aging and whether KDM3A could rejuvenate aged hDPSCs to enhance their chondrogenic differentiation capacity. MATERIALS AND METHODS The cellular aging of hDPSCs was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. Protein levels were determined using Western blot analysis. KDM3A was overexpressed in aged hDPSCs by lentivirus infection. Quantitative reverse-transcription polymerase chain reaction (RT-qPCR) were used to determine the mRNA levels of stemness markers. Toluidine blue staining was used to evaluate the effect of KDM3A overexpression on the chondrogenic differentiation of aged hDPSCs. RESULTS hDPSCs at passage 12 or treated with etoposide exhibited augmented cellular senescence as evidenced by increased SA-β-gal activity. KDM3A was significantly increased during senescence of hDPSCs. Overexpression of KDM3A did not affect the stemness properties but significantly promoted the chondrogenic differentiation of aged hDPSCs. CONCLUSION Our findings indicate that KDM3A plays an important role in the maintenance of the chondrogenic differentiation capacity of aged hDPSCs and suggest that therapies targeting KDM3A may be a novel strategy to rejuvenate aged hDPSCs.
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Affiliation(s)
- Qiannan Sun
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Rushui Bai
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Si Chen
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Zimeng Zhuang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Jie Deng
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Tianyi Xin
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yunfan Zhang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Qian Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Bing Han
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
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13
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Mazzella M, Walker K, Cormier C, Kapanowski M, Ishmakej A, Saifee A, Govind Y, Chaudhry GR. Regulation of self-renewal and senescence in primitive mesenchymal stem cells by Wnt and TGFβ signaling. Stem Cell Res Ther 2023; 14:305. [PMID: 37880755 PMCID: PMC10601332 DOI: 10.1186/s13287-023-03533-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 10/11/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND The therapeutic application of multipotent mesenchymal stem cells (MSCs) encounters significant challenges, primarily stemming from their inadequate growth and limited self-renewal capabilities. Additionally, as MSCs are propagated, their ability to self-renew declines, and the exact cellular and molecular changes responsible for this are poorly understood. This study aims to uncover the complex molecular mechanisms that govern the self-renewal of primitive (p) MSCs. METHODS We grew pMSCs using two types of medium, fetal bovine serum (FM) and xeno-free (XM), at both low passage (LP, P3) and high passage (HP, P20). To evaluate LP and HP pMSCs, we examined their physical characteristics, cell surface markers, growth rate, colony-forming ability, BrdU assays for proliferation, telomerase activity, and potential to differentiate into three lineages. Moreover, we conducted RNA-seq to analyze their transcriptome and MNase-seq analysis to investigate nucleosome occupancies. RESULTS When grown in FM, pMSCs underwent changes in their cellular morphology, becoming larger and elongated. This was accompanied by a decrease in the expression of CD90 and CD49f, as well as a reduction in CFE, proliferation rate, and telomerase activity. In addition, these cells showed an increased tendency to differentiate into the adipogenic lineage. However, when grown in XM, pMSCs maintained their self-renewal capacity and ability to differentiate into multiple lineages while preserving their fibroblastoid morphology. Transcriptomic analysis showed an upregulation of genes associated with self-renewal, cell cycle regulation, and DNA replication in XM-cultured pMSCs, while senescence-related genes were upregulated in FM-cultured cells. Further analysis demonstrated differential nucleosomal occupancies in self-renewal and senescence-related genes for pMSCs grown in XM and FM, respectively. These findings were confirmed by qRT-PCR analysis, which revealed alterations in the expression of genes related to self-renewal, cell cycle regulation, DNA replication, differentiation, and senescence. To understand the underlying mechanisms, we investigated the involvement of Wnt and TGFβ signaling pathways by modulating them with agonists and antagonists. This experimental manipulation led to the upregulation and downregulation of self-renewal genes in pMSCs, providing further insights into the signaling pathways governing the self-renewal and senescence of pMSCs. CONCLUSION Our study shows that the self-renewal potential of pMSCs is associated with the Wnt pathway, while senescence is linked to TGFβ.
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Affiliation(s)
- Matteo Mazzella
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Keegan Walker
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Christina Cormier
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Michael Kapanowski
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Albi Ishmakej
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Azeem Saifee
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Yashvardhan Govind
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - G Rasul Chaudhry
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA.
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14
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Petrashen AP, Verdesca AD, Kreiling JA, Sedivy JM. Regulation of the somatotropic axis by MYC-mediated miRNA repression. Front Cell Dev Biol 2023; 11:1269860. [PMID: 37908640 PMCID: PMC10615138 DOI: 10.3389/fcell.2023.1269860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/26/2023] [Indexed: 11/02/2023] Open
Abstract
The transcription factor MYC is overexpressed in many human cancers and has a significant causal role in tumor incidence and progression. In contrast, Myc +/- heterozygous mice, which have decreased MYC expression, exhibit a 10-20% increase in lifespan and a decreased incidence or progression of several age-related diseases. Myc heterozygous mice were also reported to have decreased mTOR and IGF1 signaling, two pathways whose reduced activity is associated with longevity in diverse species. Given MYC's downstream role in these pathways, the downregulation of mTOR and IGF1 signaling in Myc heterozygotes suggests the presence of feedback loops within this regulatory network. In this communication we provide further evidence that the reduction of Myc expression in Myc +/- heterozygous mice provokes a female-specific decrease in circulating IGF1 as well as a reduction of IGF1 protein in the liver. In particular, reduced Myc expression led to upregulation of miRNAs that target the Igf1 transcript, thereby inhibiting its translation and leading to decreased IGF1 protein levels. Using Argonaute (AGO)-CLIP-sequencing we found enrichment of AGO binding in the Igf1 transcript at the target sites of let-7, miR-122, and miR-29 in female, but not male Myc heterozygotes. Upregulation of the liver-specific miR-122 in primary hepatocytes in culture and in vivo in mice resulted in significant downregulation of IGF1 protein, but not mRNA. Reduced levels of IGF1 increased GH production in the pituitary through a well-documented negative-feedback relationship. In line with this, we found that IGF1 levels in bone (where miR-122 is not expressed) were unchanged, consistent with the decreased incidence of osteoporosis in female Myc heterozygotes, despite decreased circulating IGF1.
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Affiliation(s)
| | | | | | - John M. Sedivy
- Center on the Biology of Aging, Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, United States
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15
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Ortiz GGR, Mohammadi Y, Nazari A, Ataeinaeini M, Kazemi P, Yasamineh S, Al-Naqeeb BZT, Zaidan HK, Gholizadeh O. A state-of-the-art review on the MicroRNAs roles in hematopoietic stem cell aging and longevity. Cell Commun Signal 2023; 21:85. [PMID: 37095512 PMCID: PMC10123996 DOI: 10.1186/s12964-023-01117-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 03/25/2023] [Indexed: 04/26/2023] Open
Abstract
Aging is a biological process determined through time-related cellular and functional impairments, leading to a decreased standard of living for the organism. Recently, there has been an unprecedented advance in the aging investigation, especially the detection that the rate of senescence is at least somewhat regulated via evolutionarily preserved genetic pathways and biological processes. Hematopoietic stem cells (HSCs) maintain blood generation over the whole lifetime of an organism. The senescence process influences many of the natural features of HSC, leading to a decline in their capabilities, independently of their microenvironment. New studies show that HSCs are sensitive to age-dependent stress and gradually lose their self-renewal and regeneration potential with senescence. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally inhibit translation or stimulate target mRNA cleavage of target transcripts via the sequence-particular connection. MiRNAs control various biological pathways and processes, such as senescence. Several miRNAs are differentially expressed in senescence, producing concern about their use as moderators of the senescence process. MiRNAs play an important role in the control of HSCs and can also modulate processes associated with tissue senescence in specific cell types. In this review, we display the contribution of age-dependent alterations, including DNA damage, epigenetic landscape, metabolism, and extrinsic factors, which affect HSCs function during aging. In addition, we investigate the particular miRNAs regulating HSCs senescence and age-associated diseases. Video Abstract.
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Affiliation(s)
- Geovanny Genaro Reivan Ortiz
- Laboratory of Basic Psychology, Behavioral Analysis and Programmatic Development (PAD-LAB), Catholic University of Cuenca, Cuenca, Ecuador
| | - Yasaman Mohammadi
- Faculty of Dentistry, Islamic Azad University, Shiraz Branch, Shiraz, Iran
| | - Ahmad Nazari
- Tehran University of Medical Sciences, Tehran, Iran
| | | | - Parisa Kazemi
- Faculty of Dentistry, Ilam University of Medical Sciences, Ilam, Iran
| | - Saman Yasamineh
- Stem Cell Research Center at, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Haider Kamil Zaidan
- Department of Medical Laboratories Techniques, Al-Mustaqbal University College, Hillah, Babylon, Iraq
| | - Omid Gholizadeh
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran.
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16
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Mazzella M, Walker K, Cormier C, Kapanowski M, Ishmakej A, Saifee A, Govind Y, Chaudhry GR. WNT and VEGF/PDGF signaling regulate self-renewal in primitive mesenchymal stem cells. RESEARCH SQUARE 2023:rs.3.rs-2512048. [PMID: 37090660 PMCID: PMC10120760 DOI: 10.21203/rs.3.rs-2512048/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
Background Therapeutic use of multipotent mesenchymal stem cells (MSCs) is hampered due to poor growth and limited self-renewal potential. The self-renewal potential of MSCs is also affected during propagation and changes are poorly understood. This study investigated the molecular mechanism involved in the self-renewal of primitive (p) MSCs. Methods pMSCs were cultured to low passage (LP), P3, and high passage (HP), P20, in fetal bovine serum medium (FM) and xeno-free medium (XM). The characteristics of LP and HP pMSCs were evaluated for morphology, expression of cell surface markers, doubling time (DT), colony forming efficiency (CFE), proliferation by BrdU assay, telomerase activity and trilineage differentiation. We then examined transcriptome and nucleosome occupancies using RNA-seq and MNase-seq, respectively analyses. Results pMSCs grown in FM gradually changed morphology to large elongated cells and showed a significant reduction in the expression of CD90 and CD49f, CFE, proliferation, and telomerase activity. In addition, cells had a greater propensity to differentiate into the adipogenic lineage. In contrast, pMSCs grown in XM maintained small fibroblastoid morphology, self-renewal, and differentiation potential. Transcriptomic analysis showed upregulation of genes involved in self-renewal, cell cycle, and DNA replication in XM-grown pMSCs. Whereas senescence genes were upregulated in cells in FM. MNase-seq analysis revealed less nucleosomal occupancies in self-renewal genes and senescence genes in pMSCs grown in XM and FM, respectively. The expression of selected genes associated with self-renewal, cell cycle, DNA replication, differentiation, and senescence was confirmed by qRT-PCR. These results led us to propose signaling pathways involved in the self-renewal and senescence of pMSCs. Conclusion We conclude that the self-renewal potential of pMSCs is controlled by WNT and VEGF/PDGF, but TGFβ and PI3K signaling induce senescence.
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17
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Recent advance in nucleic acid amplification-integrated methods for DNA methyltransferase assay. Trends Analyt Chem 2023. [DOI: 10.1016/j.trac.2023.116998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
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18
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Bose R, Spulber S, Ceccatelli S. The Threat Posed by Environmental Contaminants on Neurodevelopment: What Can We Learn from Neural Stem Cells? Int J Mol Sci 2023; 24:4338. [PMID: 36901772 PMCID: PMC10002364 DOI: 10.3390/ijms24054338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 02/03/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Exposure to chemicals may pose a greater risk to vulnerable groups, including pregnant women, fetuses, and children, that may lead to diseases linked to the toxicants' target organs. Among chemical contaminants, methylmercury (MeHg), present in aquatic food, is one of the most harmful to the developing nervous system depending on time and level of exposure. Moreover, certain man-made PFAS, such as PFOS and PFOA, used in commercial and industrial products including liquid repellants for paper, packaging, textile, leather, and carpets, are developmental neurotoxicants. There is vast knowledge about the detrimental neurotoxic effects induced by high levels of exposure to these chemicals. Less is known about the consequences that low-level exposures may have on neurodevelopment, although an increasing number of studies link neurotoxic chemical exposures to neurodevelopmental disorders. Still, the mechanisms of toxicity are not identified. Here we review in vitro mechanistic studies using neural stem cells (NSCs) from rodents and humans to dissect the cellular and molecular processes changed by exposure to environmentally relevant levels of MeHg or PFOS/PFOA. All studies show that even low concentrations dysregulate critical neurodevelopmental steps supporting the idea that neurotoxic chemicals may play a role in the onset of neurodevelopmental disorders.
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Affiliation(s)
| | | | - Sandra Ceccatelli
- Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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19
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Dumasia NP, Khanna AP, Pethe PS. Retinoic acid signaling is critical for generation of pancreatic progenitors from human embryonic stem cells. Growth Factors 2023; 41:8-19. [PMID: 36373834 DOI: 10.1080/08977194.2022.2144284] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022]
Abstract
Retinoic acid (RA) is essential for gut endoderm development and has been extensively used for in vitro pancreatic differentiation from human pluripotent stem cells. However, the gene regulatory network triggered by RA signaling remains poorly addressed. Also, whether RA signals control histone modifiers such as the Polycomb group proteins during pancreatic specification remains to be explored. Here, we assess the role of RA on pancreas-specific genes during the differentiation of human embryonic stem cells (hESCs). We demonstrate that RA helps cells exit the definitive endoderm stage and proceed toward a pancreatic fate. Inhibition of the RA pathway using the pharmacological inhibitor LE135 impairs the induction of pancreatic endoderm (PE) markers FOXA2, HNF4α, HNF1β, HHEX, and PDX1. We further determine that RA signals alter the expression of epigenetic-associated genes BMI1 and RING1B in the hESC-derived pancreatic progenitors. These findings broaden our understanding of the mechanisms that drive early PE specification.
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Affiliation(s)
- Niloufer P Dumasia
- Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to-be) University, Mumbai, India
| | - Aparna P Khanna
- Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to-be) University, Mumbai, India
- Centre for Computational Biology & Translational Research, Amity Institute of Biotechnology (AIB), Amity University, Mumbai, India
| | - Prasad S Pethe
- Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis International University, Lavale, Pune, India
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20
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Abstract
Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age-onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence-associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age-related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355-4386, 2023.
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Affiliation(s)
- Robert J Pignolo
- Department of Medicine, Divisions of Geriatric Medicine and Gerontology, Endocrinology, and Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.,The Department of Physiology and Biomedical Engineering, and the Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
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21
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Sekelova T, Danisovic L, Cehakova M. Rejuvenation of Senescent Mesenchymal Stem Cells to Prevent Age-Related Changes in Synovial Joints. Cell Transplant 2023; 32:9636897231200065. [PMID: 37766590 PMCID: PMC10540599 DOI: 10.1177/09636897231200065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/13/2023] [Accepted: 08/24/2023] [Indexed: 09/29/2023] Open
Abstract
Mesenchymal/medicinal stem/signaling cells (MSCs), well known for regenerative potential, have been involved in hundreds of clinical trials. Even if equipped with reparative properties, aging significantly decreases their biological activity, representing a major challenge for MSC-based therapies. Age-related joint diseases, such as osteoarthritis, are associated with the accumulation of senescent cells, including synovial MSCs. An impaired ability of MSCs to self-renew and differentiate is one of the main contributors to the human aging process. Moreover, senescent MSCs (sMSCs) are characterized by the senescence-messaging secretome (SMS), which is typically manifested by the release of molecules with an adverse effect. Many factors, from genetic and metabolic pathways to environmental stressors, participate in the regulation of the senescent phenotype of MSCs. To better understand cellular senescence in MSCs, this review discusses the characteristics of sMSCs, their role in cartilage and synovial joint aging, and current rejuvenation approaches to delay/reverse age-related pathological changes, providing evidence from in vivo experiments as well.
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Affiliation(s)
- Tatiana Sekelova
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Lubos Danisovic
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Michaela Cehakova
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
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22
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Zhang Q, Zhang X, Ma F, Zhang CY. Advances in quantum dot-based biosensors for DNA-modifying enzymes assay. Coord Chem Rev 2022. [DOI: 10.1016/j.ccr.2022.214674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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23
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Ruiz-Aparicio PF, Vernot JP. Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities. J Pers Med 2022; 12:jpm12050716. [PMID: 35629139 PMCID: PMC9147878 DOI: 10.3390/jpm12050716] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/20/2022] [Accepted: 04/27/2022] [Indexed: 12/17/2022] Open
Abstract
Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.
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Affiliation(s)
- Paola Fernanda Ruiz-Aparicio
- Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia;
| | - Jean-Paul Vernot
- Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia;
- Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia
- Correspondence:
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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.
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25
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Arora D, Robey PG. Recent updates on the biological basis of heterogeneity in bone marrow stromal cells/skeletal stem cells. BIOMATERIALS TRANSLATIONAL 2022; 3:3-16. [PMID: 35837340 PMCID: PMC9255791 DOI: 10.12336/biomatertransl.2022.01.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/17/2022] [Accepted: 03/20/2022] [Indexed: 11/15/2022]
Abstract
Based on studies over the last several decades, the self-renewing skeletal lineages derived from bone marrow stroma could be an ideal source for skeletal tissue engineering. However, the markers for osteogenic precursors; i.e., bone marrowderived skeletal stem cells (SSCs), in association with other cells of the marrow stroma (bone marrow stromal cells, BMSCs) and their heterogeneous nature both in vivo and in vitro remain to be clarified. This review aims to highlight: i) the importance of distinguishing BMSCs/SSCs from other "mesenchymal stem/stromal cells", and ii) factors that are responsible for their heterogeneity, and how these factors impact on the differentiation potential of SSCs towards bone. The prospective role of SSC enrichment, their expansion and its impact on SSC phenotype is explored. Emphasis has also been given to emerging single cell RNA sequencing approaches in scrutinizing the unique population of SSCs within the BMSC population, along with their committed progeny. Understanding the factors involved in heterogeneity may help researchers to improvise their strategies to isolate, characterize and adopt best culture practices and source identification to develop standard operating protocols for developing reproducible stem cells grafts. However, more scientific understanding of the molecular basis of heterogeneity is warranted that may be obtained from the robust high-throughput functional transcriptomics of single cells or clonal populations.
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Affiliation(s)
- Deepika Arora
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
- Biosystems and Biomaterials Division, National Institute of Standards and Technology, Department of Commerce, Gaithersburg, MD, USA
- Department of Biotechnology, School of Biological Engineering & Life Sciences, Shobhit Institute of Engineering & Technology (Deemed-to-be-University), Meerut, India
| | - Pamela Gehron Robey
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
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Spinelli R, Florese P, Parrillo L, Zatterale F, Longo M, D’Esposito V, Desiderio A, Nerstedt A, Gustafson B, Formisano P, Miele C, Raciti GA, Napoli R, Smith U, Beguinot F. ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first-degree relatives of type 2 diabetics. Aging Cell 2022; 21:e13557. [PMID: 35146866 PMCID: PMC8920444 DOI: 10.1111/acel.13557] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/16/2021] [Accepted: 01/09/2022] [Indexed: 12/18/2022] Open
Abstract
Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age-related subcutaneous adipose tissue (SAT) dysfunction, and increases risk of type 2 diabetes (T2D). First-degree relatives of T2D individuals (FDR) feature restricted adipogenesis, reflecting the detrimental effects of APC senescence earlier in life and rendering FDR more vulnerable to T2D. Epigenetics may contribute to these abnormalities but the underlying mechanisms remain unclear. In previous methylome comparison in APC from FDR and individuals with no diabetes familiarity (CTRL), ZMAT3 emerged as one of the top-ranked senescence-related genes featuring hypomethylation in FDR and associated with T2D risk. Here, we investigated whether and how DNA methylation changes at ZMAT3 promote early APC senescence. APC from FDR individuals revealed increases in multiple senescence markers compared to CTRL. Senescence in these cells was accompanied by ZMAT3 hypomethylation, which caused ZMAT3 upregulation. Demethylation at this gene in CTRL APC led to increased ZMAT3 expression and premature senescence, which were reverted by ZMAT3 siRNA. Furthermore, ZMAT3 overexpression in APC determined senescence and activation of the p53/p21 pathway, as observed in FDR APC. Adipogenesis was also inhibited in ZMAT3-overexpressing APC. In FDR APC, rescue of ZMAT3 methylation through senolytic exposure simultaneously downregulated ZMAT3 expression and improved adipogenesis. Interestingly, in human SAT, aging and T2D were associated with significantly increased expression of both ZMAT3 and the P53 senescence marker. Thus, DNA hypomethylation causes ZMAT3 upregulation in FDR APC accompanied by acquisition of the senescence phenotype and impaired adipogenesis, which may contribute to FDR predisposition for T2D.
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Affiliation(s)
- Rosa Spinelli
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Pasqualina Florese
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Luca Parrillo
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Federica Zatterale
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Michele Longo
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Vittoria D’Esposito
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Antonella Desiderio
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Annika Nerstedt
- Lundberg Laboratory for Diabetes ResearchDepartment of Molecular and Clinical MedicineSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Birgit Gustafson
- Lundberg Laboratory for Diabetes ResearchDepartment of Molecular and Clinical MedicineSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Pietro Formisano
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Claudia Miele
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Gregory Alexander Raciti
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
| | - Raffaele Napoli
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
| | - Ulf Smith
- Lundberg Laboratory for Diabetes ResearchDepartment of Molecular and Clinical MedicineSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Francesco Beguinot
- Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
- URT Genomics of DiabetesInstitute of Experimental Endocrinology and OncologyNational Research CouncilNaplesItaly
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27
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Jiang D, Sun W, Wu T, Zou M, Vasamsetti SB, Zhang X, Zhao Y, Phillippi JA, Sawalha AH, Tavakoli S, Dutta P, Florentin J, Chan SY, Tollison TS, Di Wu, Cui J, Huntress I, Peng X, Finkel T, Li G. Post-GWAS functional analysis identifies CUX1 as a regulator of p16 INK4a and cellular senescence. NATURE AGING 2022; 2:140-154. [PMID: 37117763 PMCID: PMC10154215 DOI: 10.1038/s43587-022-00177-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 12/21/2021] [Indexed: 04/30/2023]
Abstract
Accumulation of senescent cells with age is an important driver of aging and age-related diseases. However, the mechanisms and signaling pathways that regulate senescence remain elusive. In this report, we performed post-genome-wide association studies (GWAS) functional studies on the CDKN2A/B locus, a locus known to be associated with multiple age-related diseases and overall human lifespan. We demonstrate that transcription factor CUX1 (Cut-Like Homeobox 1) specifically binds to an atherosclerosis-associated functional single-nucleotide polymorphism (fSNP) (rs1537371) within the locus and regulates the CDKN2A/B-encoded proteins p14ARF, p15INK4b and p16INK4a and the antisense noncoding RNA in the CDK4 (INK4) locus (ANRIL) in endothelial cells (ECs). Endothelial CUX1 expression correlates with telomeric length and is induced by both DNA-damaging agents and oxidative stress. Moreover, induction of CUX1 expression triggers both replicative and stress-induced senescence via activation of p16INK4a expression. Thus, our studies identify CUX1 as a regulator of p16INK4a-dependent endothelial senescence and a potential therapeutic target for atherosclerosis and other age-related diseases.
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Affiliation(s)
- Danli Jiang
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Wei Sun
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ting Wu
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Meijuan Zou
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Sathish Babu Vasamsetti
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Xiaoyu Zhang
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yihan Zhao
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Julie A Phillippi
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amr H Sawalha
- Departments of Pediatrics Medicine, and Immunology & Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sina Tavakoli
- Departments of Radiology and Medicine, University of Pittsburgh, UPMC Presbyterian Hospital, Pittsburg, PA, USA
| | - Partha Dutta
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Jonathan Florentin
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Stephen Y Chan
- Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Tammy S Tollison
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA
| | - Di Wu
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Oral and Craniofacial Health Sciences, Adam School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jing Cui
- Department of Medicine, Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, MA, USA
| | - Ian Huntress
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA
- Bioinformatics Graduate Program, North Carolina State University, Raleigh, NC, USA
| | - Xinxia Peng
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA
| | - Toren Finkel
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Gang Li
- Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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Weng Z, Wang Y, Ouchi T, Liu H, Qiao X, Wu C, Zhao Z, Li L, Li B. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:356-371. [PMID: 35485439 PMCID: PMC9052415 DOI: 10.1093/stcltm/szac004] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/19/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
| | | | - Takehito Ouchi
- Department of Physiology, Tokyo Dental College, Tokyo, Japan
| | - Hanghang Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Xianghe Qiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Bo Li
- Corresponding author: Bo Li, DDS, PhD, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section of Ren Min Nan Rd. Chengdu, Sichuan 610041, People’s Republic of China.
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Chao CC, Shen PW, Tzeng TY, Kung HJ, Tsai TF, Wong YH. Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging. Biomedicines 2021; 9:1635. [PMID: 34829864 PMCID: PMC8615703 DOI: 10.3390/biomedicines9111635] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 12/21/2022] Open
Abstract
With an increased life expectancy among humans, aging has recently emerged as a major focus in biomedical research. The lack of in vitro aging models-especially for neurological disorders, where access to human brain tissues is limited-has hampered the progress in studies on human brain aging and various age-associated neurodegenerative diseases at the cellular and molecular level. In this review, we provide an overview of age-related changes in the transcriptome, in signaling pathways, and in relation to epigenetic factors that occur in senescent neurons. Moreover, we explore the current cell models used to study neuronal aging in vitro, including immortalized cell lines, primary neuronal culture, neurons directly converted from fibroblasts (Fib-iNs), and iPSC-derived neurons (iPSC-iNs); we also discuss the advantages and limitations of these models. In addition, the key phenotypes associated with cellular senescence that have been observed by these models are compared. Finally, we focus on the potential of combining human iPSC-iNs with genome editing technology in order to further our understanding of brain aging and neurodegenerative diseases, and discuss the future directions and challenges in the field.
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Affiliation(s)
- Chuan-Chuan Chao
- Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-C.C.); (T.-F.T.)
- Department of Neurology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Po-Wen Shen
- Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112, Taiwan;
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
| | - Tsai-Yu Tzeng
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Hsing-Jien Kung
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan;
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA 95817, USA
| | - Ting-Fen Tsai
- Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-C.C.); (T.-F.T.)
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan;
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Yu-Hui Wong
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
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30
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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.
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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.)
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31
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Sibley LA, Broda N, Gross WR, Menezes AF, Embry RB, Swaroop VT, Chambers HG, Schipma MJ, Lieber RL, Domenighetti AA. Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury. FASEB J 2021; 35:e21928. [PMID: 34559924 DOI: 10.1096/fj.202100649r] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 08/11/2021] [Accepted: 08/31/2021] [Indexed: 12/26/2022]
Abstract
Limb contractures are a debilitating and progressive consequence of a wide range of upper motor neuron injuries that affect skeletal muscle function. One type of perinatal brain injury causes cerebral palsy (CP), which affects a child's ability to move and is often painful. While several rehabilitation therapies are used to treat contractures, their long-term effectiveness is marginal since such therapies do not change muscle biological properties. Therefore, new therapies based on a biological understanding of contracture development are needed. Here, we show that myoblast progenitors from contractured muscle in children with CP are hyperproliferative. This phenotype is associated with DNA hypermethylation and specific gene expression patterns that favor cell proliferation over quiescence. Treatment of CP myoblasts with 5-azacytidine, a DNA hypomethylating agent, reduced this epigenetic imprint to TD levels, promoting exit from mitosis and molecular mechanisms of cellular quiescence. Together with previous studies demonstrating reduction in myoblast differentiation, this suggests a mechanism of contracture formation that is due to epigenetic modifications that alter the myogenic program of muscle-generating stem cells. We suggest that normalization of DNA methylation levels could rescue myogenesis and promote regulated muscle growth in muscle contracture and thus may represent a new nonsurgical approach to treating this devastating neuromuscular condition.
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Affiliation(s)
| | | | | | | | - Ryan B Embry
- NUseq Core, Northwestern University, Chicago, Illinois, USA
| | - Vineeta T Swaroop
- Shirley Ryan AbilityLab, Chicago, Illinois, USA.,Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Henry G Chambers
- Rady Children's Hospital and Health Center, San Diego, California, USA
| | - Matthew J Schipma
- Rady Children's Hospital and Health Center, San Diego, California, USA
| | - Richard L Lieber
- Shirley Ryan AbilityLab, Chicago, Illinois, USA.,Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, Illinois, USA.,Hines VA Medical Center, Maywood, Illinois, USA
| | - Andrea A Domenighetti
- Shirley Ryan AbilityLab, Chicago, Illinois, USA.,Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, Illinois, USA
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32
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Florkowska A, Meszka I, Nowacka J, Granica M, Jablonska Z, Zawada M, Truszkowski L, Ciemerych MA, Grabowska I. PAX7 Balances the Cell Cycle Progression via Regulating Expression of Dnmt3b and Apobec2 in Differentiating PSCs. Cells 2021; 10:2205. [PMID: 34571854 PMCID: PMC8472244 DOI: 10.3390/cells10092205] [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] [Received: 06/30/2021] [Revised: 08/04/2021] [Accepted: 08/23/2021] [Indexed: 12/03/2022] Open
Abstract
PAX7 transcription factor plays a crucial role in embryonic myogenesis and in adult muscles in which it secures proper function of satellite cells, including regulation of their self renewal. PAX7 downregulation is necessary for the myogenic differentiation of satellite cells induced after muscle damage, what is prerequisite step for regeneration. Using differentiating pluripotent stem cells we documented that the absence of functional PAX7 facilitates proliferation. Such action is executed by the modulation of the expression of two proteins involved in the DNA methylation, i.e., Dnmt3b and Apobec2. Increase in Dnmt3b expression led to the downregulation of the CDK inhibitors and facilitated cell cycle progression. Changes in Apobec2 expression, on the other hand, differently impacted proliferation/differentiation balance, depending on the experimental model used.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Iwona Grabowska
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland; (A.F.); (I.M.); (J.N.); (M.G.); (Z.J.); (M.Z.); (L.T.); (M.A.C.)
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33
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Purkait S, Patra S, Mitra S, Behera MM, Panigrahi MK, Kumar P, Kar M, Hallur V, Chandra Samal S. Elevated Expression of DNA Methyltransferases and Enhancer of Zeste Homolog 2 in Helicobacter pylori - Gastritis and Gastric Carcinoma. Dig Dis 2021; 40:156-167. [PMID: 33895728 DOI: 10.1159/000516478] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 04/08/2021] [Indexed: 02/02/2023]
Abstract
AIM The aim of this study was to study the role of key epigenetic regulators pertaining to DNA methylation and histone-modification systems in Helicobacter pylori (HP)-associated gastritis and gastric carcinogenesis. METHODS The expression of DNA methyltransferase (DNMT-1, 3A, and 3B) and the catalytic subunit of polycomb repressive complex-2 (enhancer of zeste homolog 2 [EZH2]) in gastric carcinomas (n = 104), mucosa adjacent to carcinoma (n = 104), HP-associated gastritis (n = 95), and histologically normal mucosa (n = 31) was assessed by immunohistochemistry and qRT-PCR. RESULTS The expression of all 3 DNMTs and EZH2 was significantly higher in HP-associated gastritis and carcinoma cases than in those with adjacent and normal mucosa. The expression of DNMT-1 and 3B was maximum in HP-associated gastritis. DNMT-3A showed higher expression in carcinoma-adjacent mucosa than in normal mucosa. Interestingly, the expression of EZH2 was higher in cases of HP-associated gastritis with metaplasia than in those without metaplasia and also in cases of intestinal type of adenocarcinoma. Significant positive correlation of EZH2 was identified with DNMT-1, DNMT-3A, and DNMT-3B. However, none of these markers was associated with survival outcome. CONCLUSION This study establishes an important role of the key epigenetic regulators in the pathogenesis of both HP-associated gastritis and gastric carcinoma. Higher expression of all the epigenetic markers in the gastritis and their persistence in the carcinoma point toward their implications in HP-driven gastric carcinogenesis. Further, an inter-relation between the 2 arms of epigenetics, namely, DNA methylation and histone-modification in the pathogenesis of gastric carcinoma, is also documented. Given the reversibility of epigenetic phenomenon, these molecules may be of important therapeutic use.
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Affiliation(s)
- Suvendu Purkait
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Susama Patra
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Suvradeep Mitra
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Minakshi M Behera
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Manas Kumar Panigrahi
- Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Pankaj Kumar
- Department of General Surgery, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Madhabananda Kar
- Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Vinaykumar Hallur
- Department of Microbiology, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Subash Chandra Samal
- Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, India
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Pignolo RJ, Law SF, Chandra A. Bone Aging, Cellular Senescence, and Osteoporosis. JBMR Plus 2021; 5:e10488. [PMID: 33869998 PMCID: PMC8046105 DOI: 10.1002/jbm4.10488] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/17/2021] [Indexed: 12/15/2022] Open
Abstract
Changes in aging bone that lead to osteoporosis are mediated at multiple levels, including hormonal alterations, skeletal unloading, and accumulation of senescent cells. This pathological interplay is superimposed upon medical conditions, potentially bone-wasting medications, modifiable and unmodifiable personal risk factors, and genetic predisposition that accelerate bone loss with aging. In this study, the focus is on bone hemostasis and its dysregulation with aging. The major physiological changes with aging in bone and the role of cellular senescence in contributing to age-related osteoporosis are summarized. The aspects of bone aging are reviewed including remodeling deficits, uncoupling phenomena, inducers of cellular senescence related to bone aging, roles of the senescence-associated secretory phenotype, radiation-induced bone loss as a model for bone aging, and the accumulation of senescent cells in the bone microenvironment as a predominant mechanism for age-related osteoporosis. The study also addresses the rationale and potential for therapeutic interventions based on the clearance of senescent cells or suppression of the senescence-associated secretory phenotype. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Robert J Pignolo
- Department of MedicineMayo ClinicRochesterMNUSA
- Department of Physiology and Biomedical EngineeringMayo ClinicRochesterMNUSA
| | - Susan F Law
- Department of MedicineMayo ClinicRochesterMNUSA
| | - Abhishek Chandra
- Department of MedicineMayo ClinicRochesterMNUSA
- Department of Physiology and Biomedical EngineeringMayo ClinicRochesterMNUSA
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35
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Soni P, Ghufran MS, Olakkaran S, Puttaswamygowda GH, Duddukuri GR, Kanade SR. Epigenetic alterations induced by aflatoxin B 1: An in vitro and in vivo approach with emphasis on enhancer of zeste homologue-2/p21 axis. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 762:143175. [PMID: 33131875 DOI: 10.1016/j.scitotenv.2020.143175] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/21/2020] [Accepted: 10/14/2020] [Indexed: 06/11/2023]
Abstract
The potent environmental toxicant aflatoxin B1 (AFB1), is a group I carcinogen reported to induce the expression of many cancer associated proteins. Epigenetic alterations such as DNA methylation and histone modifications play vital role in AFB1-mediated carcinogenesis. These epigenetic modifications may result in the recruitment of specific proteins and transcription factors to the promoter region and regulate gene expression. Here we show that AFB1, at lower concentrations (100 and 1000 nM) induced proliferation in L-132 and HaCaT cells with activation of the Akt pathway, which ultimately steered abnormal proliferation and transmission of survival signals. We demonstrated a significant reduction in the expression of p21 with a remarkable increase in the expression of cyclin D1 that correlated with increased methylation of CpG dinucleotides in p21 proximal promoter, while cyclin D1 promoter remained unmethylated. The chromatin immunoprecipitation results revealed the enrichment of DNMT3a and H3K27me3 repressive marks on the p21 proximal promoter where EZH2 mediated H3K27me3 mark enhanced the binding of DNMT3a at the promoter and further contributed to the transcriptional inactivation. The overall study provided the novel information on the impact of AFB1 on p21 inactivation via EZH2 and promoter methylation which is known to be a vital process in proliferation. Furthermore, AFB1 induced the expression of EZH2 analogue protein E(z), cyclin D1 analogue cyclin D and decreased the expression of p21 analogue Dacapo in Drosophila melanogaster. Interestingly, the aggressiveness in their expression upon re-exposure in successive generations suggested first hand perspectives on multigenerational epigenetic memory.
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Affiliation(s)
- Priyanka Soni
- Department of Biochemistry and Molecular Biology, School of Biological Sciences, Central University of Kerala, Tejaswini Hills, Periye, Kasargod 671316, Kerala, India
| | - Md Sajid Ghufran
- Department of Biochemistry and Molecular Biology, School of Biological Sciences, Central University of Kerala, Tejaswini Hills, Periye, Kasargod 671316, Kerala, India
| | - Shilpa Olakkaran
- Department of Zoology, School of Biological Sciences, Central University of Kerala, Tejaswini Hills, Periye, Kasargod 671316, Kerala, India
| | | | - Govinda Rao Duddukuri
- Department of Biochemistry and Molecular Biology, School of Biological Sciences, Central University of Kerala, Tejaswini Hills, Periye, Kasargod 671316, Kerala, India
| | - Santosh R Kanade
- Department of Plant Science, School of Life Science, University of Hyderabad, Prof. C. R. Rao Road Gachibowli, Hyderabad 500046, India.
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36
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Pluquet O, Abbadie C. Cellular senescence and tumor promotion: Role of the Unfolded Protein Response. Adv Cancer Res 2021; 150:285-334. [PMID: 33858599 DOI: 10.1016/bs.acr.2021.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Senescence is a cellular state which can be viewed as a stress response phenotype implicated in various physiological and pathological processes, including cancer. Therefore, it is of fundamental importance to understand why and how a cell acquires and maintains a senescent phenotype. Direct evidence has pointed to the homeostasis of the endoplasmic reticulum whose control appears strikingly affected during senescence. The endoplasmic reticulum is one of the sensing organelles that transduce signals between different pathways in order to adapt a functional proteome upon intrinsic or extrinsic challenges. One of these signaling pathways is the Unfolded Protein Response (UPR), which has been shown to be activated during senescence. Its exact contribution to senescence onset, maintenance, and escape, however, is still poorly understood. In this article, we review the mechanisms through which the UPR contributes to the appearance and maintenance of characteristic senescent features. We also discuss whether the perturbation of the endoplasmic reticulum proteostasis or accumulation of misfolded proteins could be possible causes of senescence, and-as a consequence-to what extent the UPR components could be considered as therapeutic targets allowing for the elimination of senescent cells or altering their secretome to prevent neoplastic transformation.
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Affiliation(s)
- Olivier Pluquet
- Univ Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.
| | - Corinne Abbadie
- Univ Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
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37
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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.
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38
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Grajeda Y, Arias N, Barrios A, Pervin S, Singh R. Aging-induced stem cell dysfunction: Molecular mechanisms and potential therapeutic avenues. STEM CELLS AND AGING 2021:203-222. [DOI: 10.1016/b978-0-12-820071-1.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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39
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Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers. Cancers (Basel) 2020; 13:cancers13010068. [PMID: 33383723 PMCID: PMC7794884 DOI: 10.3390/cancers13010068] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/16/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary As for many other cancers, the risk of developing hematologic malignancies increases considerably as people age. In recent years, a growing number of studies have highlighted the influence of the aging microenvironment on hematopoiesis and tumor progression. Mesenchymal stromal cells are a major player in intercellular communication inside the bone marrow microenvironment involved in hematopoiesis support. With aging, their functions may be altered, leading to hematopoiesis disturbances which can lead to hematologic cancers. A good understanding of the mechanisms involved in mesenchymal stem cell aging and the consequences on hematopoiesis and tumor progression is therefore necessary for a better comprehension of hematologic malignancies and for the development of therapeutic approaches. Abstract Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.
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40
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Ijomone OM, Ijomone OK, Iroegbu JD, Ifenatuoha CW, Olung NF, Aschner M. Epigenetic influence of environmentally neurotoxic metals. Neurotoxicology 2020; 81:51-65. [PMID: 32882300 PMCID: PMC7708394 DOI: 10.1016/j.neuro.2020.08.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 08/25/2020] [Accepted: 08/25/2020] [Indexed: 02/08/2023]
Abstract
Continuous globalization and industrialization have ensured metals are an increasing aspect of daily life. Their usefulness in manufacturing has made them vital to national commerce, security and global economy. However, excess exposure to metals, particularly as a result of environmental contamination or occupational exposures, has been detrimental to overall health. Excess exposure to several metals is considered environmental risk in the aetiology of several neurological and neurodegenerative diseases. Metal-induced neurotoxicity has been a major health concern globally with intensive research to unravel the mechanisms associated with it. Recently, greater focus has been directed at epigenetics to better characterize the underlying mechanisms of metal-induced neurotoxicity. Epigenetic changes are those modifications on the DNA that can turn genes on or off without altering the DNA sequence. This review discusses how epigenetic changes such as DNA methylation, post translational histone modification and noncoding RNA-mediated gene silencing mediate the neurotoxic effects of several metals, focusing on manganese, arsenic, nickel, cadmium, lead, and mercury.
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Affiliation(s)
- Omamuyovwi M Ijomone
- The Neuro- Lab, Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria.
| | - Olayemi K Ijomone
- The Neuro- Lab, Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria; Department of Anatomy, University of Medical Sciences, Ondo, Nigeria
| | - Joy D Iroegbu
- The Neuro- Lab, Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
| | - Chibuzor W Ifenatuoha
- The Neuro- Lab, Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
| | - Nzube F Olung
- The Neuro- Lab, Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
| | - Michael Aschner
- Departments of Molecular Pharmacology and Neurosciences, Albert Einstein College of Medicine, NY, USA.
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41
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Hodjat M, Khan F, Saadat KA. Epigenetic alterations in aging tooth and the reprogramming potential. Ageing Res Rev 2020; 63:101140. [PMID: 32795505 DOI: 10.1016/j.arr.2020.101140] [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] [Received: 03/15/2020] [Revised: 07/27/2020] [Accepted: 08/04/2020] [Indexed: 02/07/2023]
Abstract
Tooth compartments and associated supportive tissues exhibit significant alterations during aging, leading to their impaired functioning. Aging not only affects the structure and function of dental tissue but also reduces its capacity to maintain physiological homeostasis and the healing process. Decreased cementocyte viability; diminished regenerative potential of stem cells residing in the pulp, alveolar bone and periodontal ligament; and impaired osteogenic and odontogenic differentiation capacity of progenitor cells are among the cellular impacts associated with oral aging. Various physiological and pathological phenomena are regulated by the epigenome, and hence, changes in epigenetic markers due to external stimuli have been reported in aging oral tissues and are considered a possible molecular mechanism underlying dental aging. The role of nutri-epigenetics in aging has emerged as an attractive research area. Thus far, various nutrients and bioactive compounds have been identified to have a modulatory effect on the epigenetic machinery, showing a promising response in dental aging. The human microbiota is another key player in aging and can be a target for anti-aging interventions in dental tissue. Considering the reversible characteristics of epigenetic markers and the potential for environmental factors to manipulate the epigenome, to minimize the deteriorative effects of aging, it is important to evaluate the linkage between external stimuli and their effects in terms of age-related epigenetic modifications.
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42
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Spinelli R, Parrillo L, Longo M, Florese P, Desiderio A, Zatterale F, Miele C, Raciti GA, Beguinot F. Molecular basis of ageing in chronic metabolic diseases. J Endocrinol Invest 2020; 43:1373-1389. [PMID: 32358737 PMCID: PMC7481162 DOI: 10.1007/s40618-020-01255-z] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023]
Abstract
AIM Over the last decades, the shift in age distribution towards older ages and the progressive ageing which has occurred in most populations have been paralleled by a global epidemic of obesity and its related metabolic disorders, primarily, type 2 diabetes (T2D). Dysfunction of the adipose tissue (AT) is widely recognized as a significant hallmark of the ageing process that, in turn, results in systemic metabolic alterations. These include insulin resistance, accumulation of ectopic lipids and chronic inflammation, which are responsible for an elevated risk of obesity and T2D onset associated to ageing. On the other hand, obesity and T2D, the paradigms of AT dysfunction, share many physiological characteristics with the ageing process, such as an increased burden of senescent cells and epigenetic alterations. Thus, these chronic metabolic disorders may represent a state of accelerated ageing. MATERIALS AND METHODS A more precise explanation of the fundamental ageing mechanisms that occur in AT and a deeper understanding of their role in the interplay between accelerated ageing and AT dysfunction can be a fundamental leap towards novel therapies that address the causes, not just the symptoms, of obesity and T2D, utilizing strategies that target either senescent cells or DNA methylation. RESULTS In this review, we summarize the current knowledge of the pathways that lead to AT dysfunction in the chronological ageing process as well as the pathophysiology of obesity and T2D, emphasizing the critical role of cellular senescence and DNA methylation. CONCLUSION Finally, we highlight the need for further research focused on targeting these mechanisms.
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Affiliation(s)
- R Spinelli
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy
| | - L Parrillo
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy
| | - M Longo
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy
| | - P Florese
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy
| | - A Desiderio
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy
| | - F Zatterale
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy
| | - C Miele
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy
| | - G Alexander Raciti
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy
| | - F Beguinot
- Department of Translation Medicine, Federico II University of Naples, 80131, Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131, Naples, Italy.
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43
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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.
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44
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Sharma S, Bhonde R. Genetic and epigenetic stability of stem cells: Epigenetic modifiers modulate the fate of mesenchymal stem cells. Genomics 2020; 112:3615-3623. [DOI: 10.1016/j.ygeno.2020.04.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/08/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022]
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45
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The Premature Senescence in Breast Cancer Treatment Strategy. Cancers (Basel) 2020; 12:cancers12071815. [PMID: 32640718 PMCID: PMC7408867 DOI: 10.3390/cancers12071815] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/19/2020] [Accepted: 06/30/2020] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence is a permanent blockade of cell proliferation. In response to therapy-induced stress, cancer cells undergo apoptosis or premature senescence. In apoptosis-resistant cancer cells or at lower doses of anticancer drugs, therapy-induced stress leads to premature senescence. The role of this senescence in cancer treatment is discussable. First of all, the senescent cells lose the ability to proliferate, migrate, and invade. In addition, the senescent cells secrete a set of proteins (inflammatory cytokines, chemokines, growth factors) known as the senescence-associated secretory phenotype (SASP), which influences non-senescent normal cells and non-senescent cancer cells in the tumor microenvironment and triggers tumor promotion and recurrence. Recently, many studies have examined senescence induction through breast cancer therapy and potentially using this phenomenon to treat this cancer. This review summarizes the recent in vitro, in vivo, and clinical studies investigating senescence in breast cancer treatments. Senescence inductors, senolytics, as well as their action mechanism are discussed herein. Potential SASP-modulating treatment strategies are also described.
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46
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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.
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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
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47
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Liu Q, Li Q, Zhu S, Yi Y, Cao Q. B lymphoma Moloney murine leukemia virus insertion region 1: An oncogenic mediator in prostate cancer. Asian J Androl 2020; 21:224-232. [PMID: 29862993 PMCID: PMC6498728 DOI: 10.4103/aja.aja_38_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.
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Affiliation(s)
- Qipeng Liu
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Xiangya School of Medicine, Central South University, Changsha 410008, China
| | - Qiaqia Li
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Xiangya School of Medicine, Central South University, Changsha 410008, China
| | - Sen Zhu
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Yang Yi
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China.,Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qi Cao
- Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.,Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA.,Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA
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48
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Symmank J, Bayer C, Reichard J, Pensold D, Zimmer-Bensch G. Neuronal Lhx1 expression is regulated by DNMT1-dependent modulation of histone marks. Epigenetics 2020; 15:1259-1274. [PMID: 32441560 PMCID: PMC7595593 DOI: 10.1080/15592294.2020.1767372] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Apart from the conventional view of repressive promoter methylation, the DNA methyltransferase 1 (DNMT1) was recently described to modulate gene expression through a variety of interactions with diverse epigenetic key players. We here investigated the DNMT1-dependent transcriptional control of the homeobox transcription factor LHX1, which we previously identified as an important regulator in cortical interneuron development. We found that LHX1 expression in embryonic interneurons originating in the embryonic pre-optic area (POA) is regulated by non-canonic DNMT1 function. Analysis of histone methylation and acetylation revealed that both epigenetic modifications seem to be implicated in the control of Lhx1 gene activity and that DNMT1 contributes to their proper establishment. This study sheds further light on the regulatory network of cortical interneuron development including the complex interplay of epigenetic mechanisms.
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Affiliation(s)
- Judit Symmank
- Institute for Human Genetics, Am Klinikum 1, University Hospital Jena , Jena, Germany.,Polyclinic for Orthodontics, Leutragraben 3, University Hospital Jena , Jena, Germany
| | - Cathrin Bayer
- Institute for Human Genetics, Am Klinikum 1, University Hospital Jena , Jena, Germany.,Department of Functional Epigenetics in the Animal Model, Institute for Biology II, Worringerweg 3, RWTH Aachen University , Aachen, Germany
| | - Julia Reichard
- Institute for Human Genetics, Am Klinikum 1, University Hospital Jena , Jena, Germany.,Department of Functional Epigenetics in the Animal Model, Institute for Biology II, Worringerweg 3, RWTH Aachen University , Aachen, Germany.,Research Training Group 2416 MultiSenses, MultiScales, RWTH Aachen University , Aachen, Germany
| | - Daniel Pensold
- Institute for Human Genetics, Am Klinikum 1, University Hospital Jena , Jena, Germany.,Department of Functional Epigenetics in the Animal Model, Institute for Biology II, Worringerweg 3, RWTH Aachen University , Aachen, Germany
| | - Geraldine Zimmer-Bensch
- Institute for Human Genetics, Am Klinikum 1, University Hospital Jena , Jena, Germany.,Polyclinic for Orthodontics, Leutragraben 3, University Hospital Jena , Jena, Germany.,Department of Functional Epigenetics in the Animal Model, Institute for Biology II, Worringerweg 3, RWTH Aachen University , Aachen, Germany
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49
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The DNMT1/miR-34a/FOXM1 Axis Contributes to Stemness of Liver Cancer Cells. JOURNAL OF ONCOLOGY 2020; 2020:8978930. [PMID: 32308683 PMCID: PMC7142390 DOI: 10.1155/2020/8978930] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/08/2020] [Accepted: 02/18/2020] [Indexed: 12/11/2022]
Abstract
Background Whether DNA methyltransferase 1 (DNMT1)/miR-34a/FoxM1 signaling promotes the stemness of liver cancer stem cells (LCSCs) remains unclear. This study aimed to assess whether methylation-based silencing of miR-34a by DNMT1 contributes to stemness features via FoxM1 upregulation in LCSCs. Methods The CD133+ subgroup of MHCC97H cells sorted by MACS was used as LCSCs. DNMT1, BMI1, SOX2, and OCT4 mRNA levels, and miR-34a amounts were determined by qRT-PCR. DNMT1, CD44, and FoxM1 proteins were analyzed by immunoblot. Sphere and colony formation abilities were detected by respective assays. CD133+ cell percentages were assessed by flow cytometry. In vivo oncogenicity was evaluated using a tumor xenograft model in mice. The effects of DNMT1/miR-34a signaling on the stemness of LCSCs were examined by knockdown or overexpression of DNMT1 and/or transfection of miR-34a mimic or inhibitor using lentivirus-delivery systems. FoxM1 association with miR-34a was detected by a reporter assay. Results We here showed that LCSCs exhibited elevated DNMT1 activity and expression, lower miR-34a expression with higher promoter methylation, and stronger stemness, compared with the parental liver cancer cells. DNMT1 knockdown repressed DNMT1, increased miR-34a amounts by promoter demethylation, and reduced stemness in LCSCs, whereas DNMT1 overexpression had the opposite effects in liver cancer cells. Transfection with miR-34a mimic repressed the stemness of LCSCs, while miR-34a inhibitor significantly downregulated miR-34a and enhanced stemness, without affecting DNMT1 in liver cancer cells. MiR-34a mimic rescued the effects of DNMT1 overexpression on the stemness of LCSCs, without affecting DNMT1 expression. Finally, FOXM1 was identified as a direct target by miR-34a in LCSCs. Conclusions We revealed that aberrant activation of DNMT1 causes miR-34a promoter methylation and suppression, leading to FoxM1 upregulation by disinhibition and promotion of LCSC stemness. These findings suggest that blockage of DNMT1/miR-34a-mediated FOXM1 upregulation might suppress liver cancer by targeting LCSCs.
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Somasundaram L, Levy S, Hussein AM, Ehnes DD, Mathieu J, Ruohola-Baker H. Epigenetic metabolites license stem cell states. Curr Top Dev Biol 2020; 138:209-240. [PMID: 32220298 DOI: 10.1016/bs.ctdb.2020.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
It has become clear during recent years that stem cells undergo metabolic remodeling during their activation process. While these metabolic switches take place in pluripotency as well as adult stem cell populations, the rules that govern the switch are not clear. In this review, we summarize some of the transitions in adult and pluripotent cell types and will propose that the key function in this process is the generation of epigenetic metabolites that govern critical epigenetic modifications, and therefore stem cell states.
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Affiliation(s)
- Logeshwaran Somasundaram
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Shiri Levy
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Abdiasis M Hussein
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Devon D Ehnes
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Julie Mathieu
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States; Department of Comparative Medicine, University of Washington, Seattle, WA, United States
| | - Hannele Ruohola-Baker
- Department of Biochemistry, University of Washington, Seattle, WA, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States.
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