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Zhou X, Liang W, Hong L, Gong S, Liu Z, Li W, Cao N, Tian Y, Xu D, Li B. Transcriptome analysis reveals the alleviating effect of Polysaccharide of Atractylodes macrocephala Koidz on thymic involution in Magang geese. Poult Sci 2025; 104:105155. [PMID: 40245540 PMCID: PMC12032336 DOI: 10.1016/j.psj.2025.105155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/03/2025] [Accepted: 04/11/2025] [Indexed: 04/19/2025] Open
Abstract
Thymic involution is one of the important causes of decreased immunity in the body. Noncoding RNAs (miRNAs and lncRNAs) play crucial roles in regulating organ growth and development. Polysaccharide of Atractylodes macrocephala Koidz (PAMK) is widely acknowledged for its anti-oxidant, anti-aging, and immune-enhancing effects. However, its potential application in preventing the age-related thymic involution of Magang geese has not been previously reported. In this study, 54 4-month-old Magang geese were randomly divided into 3 groups, the thymus and serum of 18 geese were collected aseptically after 3 days of prefeeding period, and the remaining geese were randomly divided into control and PAMK groups (3 replicates per group and 6 Magang geese per replicate). Geese in the control group were fed a basal diet, and geese in the PAMK group were fed a basal diet supplemented with 400 mg/kg PAMK. The thymus and serum were collected 1 month later. The results of thymus index measurement showed that PAMK could alleviate thymus index. Furthermore, compared with the M5-Control group, HE staining showed that PAMK made the proportion of thymus medulla increased, and the boundary between cortex and medulla was clearer. Antioxidant function and cytokine content detection showed that, compared with the M5-Control group, PAMK increased T-AOC and GSH-Px levels in thymus, increased T-AOC level and SOD activity in serum, decreased MDA content in thymus and serum, and decreased IL-1β, IL-6 and TNF-α levels. To further explore the mechanism, 3 samples from the control and PAMK groups were selected for RNA-Seq. Through transcriptome analysis and prediction, a triple regulatory ceRNA network of 9 mRNAs, 11 miRNAs and 32 lncRNAs associated with alleviating thymic involution was constructed. Moreover, these genes were respectively enriched in the PPAR, Cytokine-cytokine receptor interaction, WNT, Apelin and MAPK signaling pathways. In summary, PAMK may alleviate age-related thymic involution in Magang geese by alleviating the thymus index, increasing the antioxidant level and regulating the cytokine content, potentially via the PPAR, Cytokine-cytokine receptor interaction, WNT, Apelin, and MAPK signaling pathways.
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Affiliation(s)
- Xiang Zhou
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Weijun Liang
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Longsheng Hong
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Shuying Gong
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Zhuokun Liu
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Wanyan Li
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Nan Cao
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Yunbo Tian
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Danning Xu
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Bingxin Li
- Science & Technology Innovation Platform of Guangdong Waterfowl, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China.
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Singh B, Cui K, Eisa-Beygi S, Zhu B, Cowan DB, Shi J, Wang DZ, Liu Z, Bischoff J, Chen H. Elucidating the crosstalk between endothelial-to-mesenchymal transition (EndoMT) and endothelial autophagy in the pathogenesis of atherosclerosis. Vascul Pharmacol 2024; 155:107368. [PMID: 38548093 PMCID: PMC11303600 DOI: 10.1016/j.vph.2024.107368] [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: 01/17/2024] [Revised: 03/07/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024]
Abstract
Atherosclerosis, a chronic systemic inflammatory condition, is implicated in most cardiovascular ischemic events. The pathophysiology of atherosclerosis involves various cell types and associated processes, including endothelial cell activation, monocyte recruitment, smooth muscle cell migration, involvement of macrophages and foam cells, and instability of the extracellular matrix. The process of endothelial-to-mesenchymal transition (EndoMT) has recently emerged as a pivotal process in mediating vascular inflammation associated with atherosclerosis. This transition occurs gradually, with a significant portion of endothelial cells adopting an intermediate state, characterized by a partial loss of endothelial-specific gene expression and the acquisition of "mesenchymal" traits. Consequently, this shift disrupts endothelial cell junctions, increases vascular permeability, and exacerbates inflammation, creating a self-perpetuating cycle that drives atherosclerotic progression. While endothelial cell dysfunction initiates the development of atherosclerosis, autophagy, a cellular catabolic process designed to safeguard cells by recycling intracellular molecules, is believed to exert a significant role in plaque development. Identifying the pathological mechanisms and molecular mediators of EndoMT underpinning endothelial autophagy, may be of clinical relevance. Here, we offer new insights into the underlying biology of atherosclerosis and present potential molecular mechanisms of atherosclerotic resistance and highlight potential therapeutic targets.
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Affiliation(s)
- Bandana Singh
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Kui Cui
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Shahram Eisa-Beygi
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Bo Zhu
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Douglas B Cowan
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Jinjun Shi
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Da-Zhi Wang
- Center for Regenerative Medicine, University of South Florida Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Zhenguo Liu
- Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA
| | - Joyce Bischoff
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Hong Chen
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.
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Sendera A, Adamczyk-Grochala J, Pikuła B, Cholewa M, Banaś-Ząbczyk A. Electromagnetic field (50 Hz) enhance metabolic potential and induce adaptive/reprogramming response mediated by the increase of N6-methyladenosine RNA methylation in adipose-derived mesenchymal stem cells in vitro. Toxicol In Vitro 2024; 95:105743. [PMID: 38040129 DOI: 10.1016/j.tiv.2023.105743] [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: 04/26/2023] [Revised: 11/08/2023] [Accepted: 11/24/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND Electromagnetic fields (EMF) have an impact on numerous cellular processes. It can positively and negatively affect adipose-derived stem cells (ASCs) thus their fate through the influence of specific factors and protein secretion. EMF can be a great factor for preconditioning ASCs for regenerative medicine purposes, however, understanding the cell's biological response to its effects in vitro is essential. METHODS ASCs were exposed to the EMF (50 Hz; 1.5 mT) for 24 and 48 h, and then cell biological response was analyzed. RESULTS 24 h exposure of ASCs to EMF, significantly increased N6-methyladenosine (m6A) RNA methylation, indicating epitranscriptomic changes as an important factor in ASCs preconditioning. Furthermore, the expression of stem cell markers such as Nanog, Oct-4, Sox-2, CD44, and CD105 increased after 24 h of EMF exposure. Besides, western blot analysis showed upregulation of p21 and DNMT2/TRDMT1 protein levels compared to control cells with no differences in the p53 profile. Moreover, after 24 h of exposure to EMF, cell membrane flexibility, the metabolic potential of cells as well as the distribution, morphology, and metabolism of mitochondria were altered. CONCLUSION ASCs undergo a process of mobilization and adaptation under the EMF influence through the increased m6A RNA modifications. These conditions may "force" ASCs to redefine their stem cell fate mediated by RNA-modifying enzymes and alter their reprogramming decision of as differentiation begins.
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Affiliation(s)
- Anna Sendera
- Department of Biology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Jagoda Adamczyk-Grochala
- Department of Biotechnology, Institute of Biotechnology, College of Natural Sciences, University of Rzeszow, Rzeszow, Poland
| | - Barbara Pikuła
- Department of Biology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Marian Cholewa
- Institute of Physics, College of Natural Sciences, University of Rzeszow, Rzeszow, Poland
| | - Agnieszka Banaś-Ząbczyk
- Department of Biology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland.
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Jiang X, Li W, Ge L, Lu M. Mesenchymal Stem Cell Senescence during Aging:From Mechanisms to Rejuvenation Strategies. Aging Dis 2023; 14:1651-1676. [PMID: 37196126 PMCID: PMC10529739 DOI: 10.14336/ad.2023.0208] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/08/2023] [Indexed: 05/19/2023] Open
Abstract
In cell transplantation therapy, mesenchymal stem cells(MSCs)are ideal seed cells due to their easy acquisition and cultivation, strong regenerative capacity, multi-directional differentiation abilities, and immunomodulatory effects. Autologous MSCs are better applicable compared with allogeneic MSCs in clinical practice. The elderly are the main population for cell transplantation therapy, but as donor aging, MSCs in the tissue show aging-related changes. When the number of generations of in vitro expansion is increased, MSCs will also exhibit replicative senescence. The quantity and quality of MSCs decline during aging, which limits the efficacy of autologous MSCs transplantation therapy. In this review, we examine the changes in MSC senescence as a result of aging, discuss the progress of research on mechanisms and signalling pathways of MSC senescence, and discuss possible rejuvenation strategies of aged MSCs to combat senescence and enhance the health and therapeutic potential of MSCs.
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Affiliation(s)
- Xinchen Jiang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
| | - Wenshui Li
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
| | - Lite Ge
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, China, Changsha
| | - Ming Lu
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
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Wieder R. Awakening of Dormant Breast Cancer Cells in the Bone Marrow. Cancers (Basel) 2023; 15:cancers15113021. [PMID: 37296983 DOI: 10.3390/cancers15113021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Up to 40% of patients with breast cancer (BC) have metastatic cells in the bone marrow (BM) at the initial diagnosis of localized disease. Despite definitive systemic adjuvant therapy, these cells survive in the BM microenvironment, enter a dormant state and recur stochastically for more than 20 years. Once they begin to proliferate, recurrent macrometastases are not curable, and patients generally succumb to their disease. Many potential mechanisms for initiating recurrence have been proposed, but no definitive predictive data have been generated. This manuscript reviews the proposed mechanisms that maintain BC cell dormancy in the BM microenvironment and discusses the data supporting specific mechanisms for recurrence. It addresses the well-described mechanisms of secretory senescence, inflammation, aging, adipogenic BM conversion, autophagy, systemic effects of trauma and surgery, sympathetic signaling, transient angiogenic bursts, hypercoagulable states, osteoclast activation, and epigenetic modifications of dormant cells. This review addresses proposed approaches for either eliminating micrometastases or maintaining a dormant state.
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Affiliation(s)
- Robert Wieder
- Rutgers New Jersey Medical School and the Cancer Institute of New Jersey, 185 South Orange Avenue, MSB F671, Newark, NJ 07103, USA
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Cheng M, Yuan W, Moshaverinia A, Yu B. Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging. Cells 2023; 12:998. [PMID: 37048071 PMCID: PMC10093211 DOI: 10.3390/cells12070998] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
Advanced age is a shared risk factor for many chronic and debilitating skeletal diseases including osteoporosis and periodontitis. Mesenchymal stem cells develop various aging phenotypes including the onset of senescence, intrinsic loss of regenerative potential and exacerbation of inflammatory microenvironment via secretory factors. This review elaborates on the emerging concepts on the molecular and epigenetic mechanisms of MSC senescence, such as the accumulation of oxidative stress, DNA damage and mitochondrial dysfunction. Senescent MSCs aggravate local inflammation, disrupt bone remodeling and bone-fat balance, thereby contributing to the progression of age-related bone diseases. Various rejuvenation strategies to target senescent MSCs could present a promising paradigm to restore skeletal aging.
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Affiliation(s)
- Mingjia Cheng
- Section of Restorative Dentistry, School of Dentistry, University of California, Los Angeles, CA 90095, USA
| | - Weihao Yuan
- Section of Restorative Dentistry, School of Dentistry, University of California, Los Angeles, CA 90095, USA
| | - Alireza Moshaverinia
- Section of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA 90095, USA
| | - Bo Yu
- Section of Restorative Dentistry, School of Dentistry, University of California, Los Angeles, CA 90095, USA
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Zhu J, Chen L. LincRNA-p21 Promotes Cellular Senescence by Down-regulating the Wnt/β-catenin Pathway in MPP +-treated SH-SY5Y Cells. Comb Chem High Throughput Screen 2023; 26:2476-2486. [PMID: 37073660 PMCID: PMC10556404 DOI: 10.2174/1386207326666230417103137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 01/30/2023] [Accepted: 02/09/2023] [Indexed: 04/20/2023]
Abstract
AIM AND OBJECTIVE Long intergenic non-coding RNA-p21 (lincRNA-p21) plays a critical role in various senescence-associated physiological and pathological conditions. We aimed to explore the senescence-associated effects of lincRNA-p21 in 1-methyl-4-phenylpyridinium (MPP+) treated neuroblastoma SH-SY5Y cell line as a therapeutic target. MATERIALS AND METHODS The RNA expression levels of lincRNA-p21, p53, p16, and telomere length were examined with reverse transcription-quantitative polymerase chain reaction (RTqPCR). The Telo TAGGG™ Telomerase PCR ELISA PLUS Kit was used to determine telomerase activity. Cellular viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) assay. Western blot was performed to analyze β-catenin protein expression. Besides, oxidative stress was evaluated by Jaggregate- forming delocalized lipophilic cation, 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolocarbocyanine++ + iodide (JC‑1) stain, fluorescence spectrophotometry, colorimetric assay, and malondialdehyde (MDA) formation. RESULTS This research demonstrated that MPP+ caused a distinct increase in the expression of LincRNA- p21 in SH-SY5Y cells. MPP+ induced cellular senescence with decreasing cellular proliferation and viability, increasing expression levels of senescence-associated makers such as genes p53 and p16, accompanied by significantly decreasing telomere length and telomerase activity. At the same time, these effects were abolished by silencing lincRNA-p21 with small interfering RNA (siRNA). On the contrary, β-catenin silencing contributes to reversing anti-senescent effects caused by lincRNA-p21 silencing. Moreover, modifying lincRNA-p21 exerted an anti-senescent influence depending on decreasing oxidant stress. CONCLUSION Our study showed that in the treatment of MPP+, lincRNA-p21 might serve a role in the SH-SY5Y cell senescence by modulating the Wnt/β-catenin pathway, as well as increasing oxidant stress. Thus, trying to target lincRNA-p21 may have important therapeutic and practical implications for PD.
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Affiliation(s)
- Jianyu Zhu
- Department of Traumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China
| | - Lingli Chen
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China
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Ghafouri-Fard S, Khoshbakht T, Hussen BM, Baniahmad A, Branicki W, Taheri M, Eghbali A. Emerging Role of Non-Coding RNAs in Senescence. Front Cell Dev Biol 2022; 10:869011. [PMID: 35865636 PMCID: PMC9294638 DOI: 10.3389/fcell.2022.869011] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Senescence is defined as a gradual weakening of functional features of a living organism. Cellular senescence is a process that is principally aimed to remove undesirable cells by prompting tissue remodeling. This process is also regarded as a defense mechanism induced by cellular damage. In the course of oncogenesis, senescence can limit tumor progression. However, senescence participates in the pathoetiology of several disorders such as fibrotic disorders, vascular disorders, diabetes, renal disorders and sarcopenia. Recent studies have revealed contribution of different classes of non-coding RNAs in the cellular senescence. Long non-coding RNAs, microRNAs and circular RNAs are three classes of these transcripts whose contributions in this process have been more investigated. In the current review, we summarize the available literature on the impact of these transcripts in the cellular senescence.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospitals, Jena, Germany
- *Correspondence: Aria Baniahmad, ; Mohammad Taheri, ; Ahmad Eghbali,
| | - Wojciech Branicki
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospitals, Jena, Germany
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Aria Baniahmad, ; Mohammad Taheri, ; Ahmad Eghbali,
| | - Ahmad Eghbali
- Anesthesiology Research Center, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Aria Baniahmad, ; Mohammad Taheri, ; Ahmad Eghbali,
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Cai G, Xiao Y, Yang M, Guo Q, Su T, Liu Y, Jiang T, Li C. Long noncoding RNA Gm31629 promotes bone regeneration by maintaining bone marrow mesenchymal stem cells activity. PeerJ 2022; 10:e13475. [PMID: 35702257 PMCID: PMC9188769 DOI: 10.7717/peerj.13475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 05/01/2022] [Indexed: 01/14/2023] Open
Abstract
Background Long noncoding RNA Gm31629 can regulate hypothalamic neural stem cells (htNSCs) senescence and the aging process. However, the effect of Gm31629 on the senescence of bone marrow mesenchymal stem cells (BMSCs) and bone regeneration is unclear. In the present study, we investigated the effects of Gm31629 on the senescence of BMSCs and bone regeneration. Methods Gm31629 knockout (Gm31629-KO) and wild-type (WT) mice were used to establish a bone regeneration model. The Brdu labelling, CCK8 assay, wound healing assay, β-gal staining and osteogenic differentiation assay were used to assess the effects of Gm31629 on the functions of BMSCs. Micro-computed tomography (CT), histochemical and immunohistochemical staining were used to evaluate the ability of bone regeneration. The mimic of Gm31629, theaflavin 3-gallate, was used to investigate its role on the senescence of BMSCs and bone regeneration. Results The expression of Gm31629 reduced in BMSCs of middle-aged mice was compared with that of young mice. The deletion of Gm31629 was sufficient to drive the senescence of BMSCs, resulting in impaired bone regeneration in mice. Mechanistically, Gm31629 could interact with Y-box protein 1(YB-1) and delay its degradation, decreasing the transcription of p16INK4A of BMSCs. We also found that theaflavin 3-gallate could alleviate the senescence of BMSCs and promote bone regeneration in middle-aged mice. Conclusion These results indicated that Gm31629 played an important role on BMSCs senescence and bone regeneration and provided a therapeutic target to promote bone regeneration.
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Affiliation(s)
- Guangping Cai
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Ye Xiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Mi Yang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Qi Guo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Tian Su
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Yalin Liu
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Tiejian Jiang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Chun Li
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
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10
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MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Redox Control of Cell Senescence. Antioxidants (Basel) 2022; 11:antiox11030480. [PMID: 35326131 PMCID: PMC8944605 DOI: 10.3390/antiox11030480] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 12/18/2022] Open
Abstract
Cell senescence is critical in diverse aspects of organism life. It is involved in tissue development and homeostasis, as well as in tumor suppression. Consequently, it is tightly integrated with basic physiological processes during life. On the other hand, senescence is gradually being considered as a major contributor of organismal aging and age-related diseases. Increased oxidative stress is one of the main risk factors for cellular damages, and thus a driver of senescence. In fact, there is an intimate link between cell senescence and response to different types of cellular stress. Oxidative stress occurs when the production of reactive oxygen species/reactive nitrogen species (ROS/RNS) is not adequately detoxified by the antioxidant defense systems. Non-coding RNAs are endogenous transcripts that govern gene regulatory networks, thus impacting both physiological and pathological events. Among these molecules, microRNAs, long non-coding RNAs, and more recently circular RNAs are considered crucial mediators of almost all cellular processes, including those implicated in oxidative stress responses. Here, we will describe recent data on the link between ROS/RNS-induced senescence and the current knowledge on the role of non-coding RNAs in the senescence program.
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11
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Mi L, Hu J, Li N, Gao J, Huo R, Peng X, Zhang N, Liu Y, Zhao H, Liu R, Zhang L, Xu K. The Mechanism of Stem Cell Aging. Stem Cell Rev Rep 2022; 18:1281-1293. [PMID: 35000109 PMCID: PMC9033730 DOI: 10.1007/s12015-021-10317-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2021] [Indexed: 12/22/2022]
Abstract
Stem cells have self-renewal ability and multi-directional differentiation potential. They have tissue repair capabilities and are essential for maintaining the tissue homeostasis. The depletion of stem cells is closely related to the occurrence of body aging and aging-related diseases. Therefore, revealing the molecular mechanisms of stem cell aging will set new directions for the therapeutic application of stem cells, the study of aging mechanisms, and the prevention and treatment of aging-related diseases. This review comprehensively describes the molecular mechanisms related to stem cell aging and provides the basis for further investigations aimed at developing new anti-stem cell aging strategies and promoting the clinical application of stem cells.
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Affiliation(s)
- Liangyu Mi
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Junping Hu
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
- Department of Immunology, Shanxi Medical University, Taiyuan, 030000, Shanxi, China
| | - Na Li
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Jinfang Gao
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Rongxiu Huo
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Xinyue Peng
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Na Zhang
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Ying Liu
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Hanxi Zhao
- Silc Business School, Shanghai University, Shanghai, 200444, China
| | - Ruiling Liu
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
- Department of Immunology, Shanxi Medical University, Taiyuan, 030000, Shanxi, China
| | - Liyun Zhang
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Ke Xu
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China.
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12
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Wang S, Wang Z, Su H, Chen F, Ma M, Yu W, Ye G, Cen S, Mi R, Wu X, Deng W, Feng P, Zeng C, Shen H, Wu Y. Effects of long-term culture on the biological characteristics and RNA profiles of human bone-marrow-derived mesenchymal stem cells. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:557-574. [PMID: 34631285 PMCID: PMC8479280 DOI: 10.1016/j.omtn.2021.08.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 08/12/2021] [Indexed: 12/16/2022]
Abstract
Expansion in vitro prior to mesenchymal stem cells (MSCs) application is a necessary process. Functional and genomic stability has a crucial role in stem-cell-based therapies. However, the exact expression and co-expressed profiles of coding and non-coding RNAs in human bone marrow (BM)-MSCs in vitro aging are still lacking. In the present studies, the change of morphology, immunophenotype, and capacity of proliferation, differentiation, and immunoregulation of MSCs at passage (P) 4, P6, P8, P10, and P12 were investigated. RNA sequencing identified that 439 mRNAs, 65 long noncoding RNAs (lncRNAs), 59 microRNAs (miRNAs), and 229 circular RNAs (circRNAs) were differentially expressed (DE) in P12 compared with P4, with a similar trend in P6. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) identified several significant biological processes and pathways, including binding, ossification, and Wnt and PPAR signaling pathways. Interaction and co-expression/localization analyses were performed for DE mRNAs and lncRNAs, and several key lncRNAs, circRNAs, and important pathways like autophagy and mitophagy were identified in the competing endogenous RNA (ceRNA) network. Some key RNAs found in the bioinformatics analysis were validated. Our studies indicate that replicative senescence of MSCs is a continuous process, including widespread alterations in biological characteristics and global gene expression patterns that need to be considered before therapeutic applications of MSCs.
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Affiliation(s)
- Shan Wang
- Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Ziming Wang
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Hongjun Su
- Center for Biotherapy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
| | - Fenglei Chen
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Mengjun Ma
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Wenhui Yu
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Guiwen Ye
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
| | - Shuizhong Cen
- Department of Orthopedics, Zhujiang Hospital of Southern Medical Universuty, Guangzhou 510280, P.R. China
| | - Rujia Mi
- Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Xiaohua Wu
- Center for Biotherapy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
| | - Wen Deng
- Center for Biotherapy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
| | - Pei Feng
- Center for Biotherapy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
| | - Chenying Zeng
- Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Huiyong Shen
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China.,Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
| | - Yanfeng Wu
- Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
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13
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Tumorigenic Aspects of MSC Senescence-Implication in Cancer Development and Therapy. J Pers Med 2021; 11:jpm11111133. [PMID: 34834485 PMCID: PMC8618265 DOI: 10.3390/jpm11111133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/13/2022] Open
Abstract
As an organism ages, many physiological processes change, including the immune system. This process, called immunosenescence, characterized by abnormal activation and imbalance of innate and adaptive immunity, leads to a state of chronic low-grade systemic inflammation, termed inflammaging. Aging and inflammaging are considered to be the root of many diseases of the elderly, as infections, autoimmune and chronic inflammatory diseases, degenerative diseases, and cancer. The role of mesenchymal stromal/stem cells (MSCs) in the inflammaging process and the age-related diseases is not completely established, although numerous features of aging MSCs, including altered immunomodulatory properties, impeded MSC niche supporting functions, and senescent MSC secretory repertoire are consistent with inflammaging development. Although senescence has its physiological function and can represent a mechanism of tumor prevention, in most cases it eventually transforms into a deleterious (para-)inflammatory process that promotes tumor growth. In this review we are going through current literature, trying to explore the role of senescent MSCs in making and/or sustaining a microenvironment permissive to tumor development and to analyze the therapeutic options that could target this process.
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14
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Ghafouri-Fard S, Moghadam MHB, Shoorei H, Bahroudi Z, Taheri M, Taheriazam A. The impact of non-coding RNAs on normal stem cells. Biomed Pharmacother 2021; 142:112050. [PMID: 34426251 DOI: 10.1016/j.biopha.2021.112050] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/02/2021] [Accepted: 08/12/2021] [Indexed: 12/11/2022] Open
Abstract
Self-renewal and differentiation into diverse cells are two main characteristics of stem cells. These cells have important roles in development and homeostasis of different tissues and are supposed to facilitate tissue regeneration. Function of stem cells is regulated by dynamic interactions between external signaling, epigenetic factors, and molecules that regulate expression of genes. Among the highly appreciated regulators of function of stem cells are long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). Impact of miR-342-5p, miR-145, miR-1297, miR-204-5p, miR-132, miR-128-3p, hsa-miR-302, miR-26b-5p and miR-10a are among miRNAs that regulate function of stem cells. Among lncRNAs, AK141205, ANCR, MEG3, Pnky, H19, TINCR, HULC, EPB41L4A-AS1 and SNHG7 have important roles in the regulation of stem cells. In the current paper, we aimed at reviewing the importance of miRNAs and lncRNAs in differentiation of stem cells both in normal and diseased conditions. For this purpose, we searched PubMed/Medline and google scholar databases using "stem cell" AND "lncRNA", or "long non-coding RNA", or "microRNA" or "miRNA".
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Zahra Bahroudi
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Afshin Taheriazam
- Department of Orthopedics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran.
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15
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Iwata T, Mizuno N, Ishida S, Kajiya M, Nagahara T, Kaneda-Ikeda E, Yoshioka M, Munenaga S, Ouhara K, Fujita T, Kawaguchi H, Kurihara H. Functional Regulatory Mechanisms Underlying Bone Marrow Mesenchymal Stem Cell Senescence During Cell Passages. Cell Biochem Biophys 2021; 79:321-336. [PMID: 33559812 DOI: 10.1007/s12013-021-00969-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2021] [Indexed: 12/22/2022]
Abstract
Mesenchymal stem cell (MSC) transplantation is an effective periodontal regenerative therapy. MSCs are multipotent, have self-renewal ability, and can differentiate into periodontal cells. However, senescence is inevitable for MSCs. In vitro, cell senescence can be induced by long-term culture with/without cell passage. However, the regulatory mechanism of MSC senescence remains unclear. Undifferentiated MSC-specific transcription factors can regulate MSC function. Herein, we identified the regulatory transcription factors involved in MSC senescence and elucidated their mechanisms of action. We cultured human MSCs (hMSCs) with repetitive cell passages to induce cell senescence and evaluated the mRNA and protein expression of cell senescence-related genes. Additionally, we silenced the cell senescence-induced transcription factors, GATA binding protein 6 (GATA6) and SRY-box 11 (SOX11), and investigated senescence-related signaling pathways. With repeated passages, the number of senescent cells increased, while the cell proliferation capacity decreased; GATA6 mRNA expression was upregulated and that of SOX11 was downregulated. Repetitive cell passages decreased Wnt and bone morphogenetic protein (BMP) signaling pathway-related gene expression. Silencing of GATA6 and SOX11 regulated Wnt and BMP signaling pathway-related genes and affected cell senescence-related genes; moreover, SOX11 silencing regulated GATA6 expression. Hence, we identified them as pair of regulatory transcription factors for cell senescence in hMSCs via the Wnt and BMP signaling pathways.
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Affiliation(s)
- T Iwata
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan.
| | - N Mizuno
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
| | - S Ishida
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
| | - M Kajiya
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
| | - T Nagahara
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
| | - E Kaneda-Ikeda
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
| | - M Yoshioka
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
| | - S Munenaga
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
- Department of General Dentistry, Hiroshima University Hospital, Hiroshima, 734-8553, Japan
| | - K Ouhara
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
| | - T Fujita
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
| | - H Kawaguchi
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
- Department of General Dentistry, Hiroshima University Hospital, Hiroshima, 734-8553, Japan
| | - H Kurihara
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan
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16
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Mechanical stimulation induced osteogenic differentiation of BMSCs through TWIST/E2A/p21 axis. Biosci Rep 2021; 40:222707. [PMID: 32309849 PMCID: PMC7199451 DOI: 10.1042/bsr20193876] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/02/2020] [Accepted: 04/16/2020] [Indexed: 12/11/2022] Open
Abstract
The relationship between mechanical force and alveolar bone remodeling is an important issue in orthodontics because tooth movement is dependent on the response of bone tissue to the mechanical force induced by the appliances used. Mechanical cyclical stretch plays an essential role in the cell osteogenic differentiation involved in bone remodeling. However, the underlying mechanisms are unclear, particularly the molecular pathways regulated by mechanical stimulation. In the present study, we reported a dynamic change of p21 level in response to mechanical cyclical stretch, and shRNA-p21 in bone marrow mesenchymal stem cells (BMSCs) induced osteogenic differentiation. The mechanism was mediated through TWIST/E2A/p21 axis. These results supported the mechanical stimulation-induced osteogenic differentiation is negatively regulated by p21.
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17
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Cai J, Qi H, Yao K, Yao Y, Jing D, Liao W, Zhao Z. Non-Coding RNAs Steering the Senescence-Related Progress, Properties, and Application of Mesenchymal Stem Cells. Front Cell Dev Biol 2021; 9:650431. [PMID: 33816501 PMCID: PMC8017203 DOI: 10.3389/fcell.2021.650431] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/12/2021] [Indexed: 02/05/2023] Open
Abstract
The thirst to postpone and even reverse aging progress has never been quenched after all these decades. Unequivocally, mesenchymal stem cells (MSCs), with extraordinary abilities such as self-renewal and multi-directional differentiation, deserve the limelight in this topic. Though having several affable clinical traits, MSCs going through senescence would, on one hand, contribute to age-related diseases and, on the other hand, lead to compromised or even counterproductive therapeutical outcomes. Notably, increasing evidence suggests that non-coding RNAs (ncRNAs) could invigorate various regulatory processes. With even a slight dip or an uptick of expression, ncRNAs would make a dent in or even overturn cellular fate. Thereby, a systematic illustration of ncRNAs identified so far to steer MSCs during senescence is axiomatically an urgent need. In this review, we introduce the general properties and mechanisms of senescence and its relationship with MSCs and illustrate the ncRNAs playing a role in the cellular senescence of MSCs. It is then followed by the elucidation of ncRNAs embodied in extracellular vesicles connecting senescent MSCs with other cells and diversified processes in and beyond the skeletal system. Last, we provide a glimpse into the clinical methodologies of ncRNA-based therapies in MSC-related fields. Hopefully, the intricate relationship between senescence and MSCs will be revealed one day and our work could be a crucial stepping-stone toward that future.
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Affiliation(s)
- Jingyi Cai
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Hexu Qi
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ke Yao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yang Yao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dian Jing
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wen Liao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics, Osaka Dental University, Hirakata, Japan
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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18
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Asila A, Yang X, Kaisaer Y, Ma L. SNHG16/miR‐485‐5p/BMP7 axis modulates osteogenic differentiation of human bone marrow‐derived mesenchymal stem cells. J Gene Med 2021; 23:e3296. [PMID: 33179372 DOI: 10.1002/jgm.3296] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 11/06/2020] [Accepted: 11/06/2020] [Indexed: 01/27/2023] Open
Affiliation(s)
- Ailijiang Asila
- Department of Orthopaedics TCM Hospital of Xinjiang Xinjiang China
| | - Xinjun Yang
- Department of Orthopaedics TCM Hospital of Xinjiang Xinjiang China
| | - Yilipan Kaisaer
- Department of Orthopaedics TCM Hospital of Xinjiang Xinjiang China
| | - Lei Ma
- Department of Orthopaedics TCM Hospital of Xinjiang Xinjiang China
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19
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Xu F, Li W, Yang X, Na L, Chen L, Liu G. The Roles of Epigenetics Regulation in Bone Metabolism and Osteoporosis. Front Cell Dev Biol 2021; 8:619301. [PMID: 33569383 PMCID: PMC7868402 DOI: 10.3389/fcell.2020.619301] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/31/2020] [Indexed: 12/17/2022] Open
Abstract
Osteoporosis is a metabolic disease characterized by decreased bone mineral density and the destruction of bone microstructure, which can lead to increased bone fragility and risk of fracture. In recent years, with the deepening of the research on the pathological mechanism of osteoporosis, the research on epigenetics has made significant progress. Epigenetics refers to changes in gene expression levels that are not caused by changes in gene sequences, mainly including DNA methylation, histone modification, and non-coding RNAs (lncRNA, microRNA, and circRNA). Epigenetics play mainly a post-transcriptional regulatory role and have important functions in the biological signal regulatory network. Studies have shown that epigenetic mechanisms are closely related to osteogenic differentiation, osteogenesis, bone remodeling and other bone metabolism-related processes. Abnormal epigenetic regulation can lead to a series of bone metabolism-related diseases, such as osteoporosis. Considering the important role of epigenetic mechanisms in the regulation of bone metabolism, we mainly review the research progress on epigenetic mechanisms (DNA methylation, histone modification, and non-coding RNAs) in the osteogenic differentiation and the pathogenesis of osteoporosis to provide a new direction for the treatment of bone metabolism-related diseases.
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Affiliation(s)
- Fei Xu
- College of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
- Collaborative Innovation Center, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Wenhui Li
- Collaborative Innovation Center, Shanghai University of Medicine and Health Sciences, Shanghai, China
- College of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Xiao Yang
- Traditional Chinese Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lixin Na
- Collaborative Innovation Center, Shanghai University of Medicine and Health Sciences, Shanghai, China
- College of Public Health, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Linjun Chen
- College of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Guobin Liu
- Traditional Chinese Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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20
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Li P, Mao WW, Zhang S, Zhang L, Chen ZR, Lu ZD. Sodium hydrosulfide alleviates dexamethasone-induced cell senescence and dysfunction through targeting the miR-22/sirt1 pathway in osteoblastic MC3T3-E1 cells. Exp Ther Med 2021; 21:238. [PMID: 33603846 PMCID: PMC7851607 DOI: 10.3892/etm.2021.9669] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 09/15/2020] [Indexed: 01/30/2023] Open
Abstract
Glucocorticoid-induced osteoporosis is characterized by osteoblastic cell and microarchitecture dysfunction, as well as a loss of bone mass. Cell senescence contributes to the pathological process of osteoporosis and sodium hydrosulfide (NaHS) regulates the potent protective effects through delaying cell senescence. The aim of the present study was to investigate whether senescence could contribute to dexamethasone (Dex)-induced osteoblast impairment and to examine the effect of NaHS on Dex-induced cell senescence and damage. It was found that the levels of the senescence-associated markers, p53 and p21, were markedly increased in osteoblasts exposed to Dex. A p53 inhibitor reversed Dex-induced osteoblast injury, a process that was mitigated by NaHS administration through alleviating osteoblastic cell senescence. MicroRNA (miR)-22 blocked the impact of NaHS on Dex-induced osteoblast damage and senescence through targeting the regulation of Sirtuin 1 (sirt1) expression, as shown by the decreased cell viability and alkaline phosphatase activity, as well as an increased expression of p53 and p21. It was revealed that the sirt1 gene was the target of miR-22 in osteoblastic MC3T3-E1 cells through combining the results of dual luciferase reporter assays and reverse transcription-quantitative PCR, as well as western blot analyses. Silencing of sirt1 abolished the protective effect of NaHS against Dex-associated osteoblast senescence and injury. Taken together, the present study showed that NaHS prevents Dex-induced cell senescence and damage through targeting the miR-22/sirt1 pathway in osteoblastic MC3T3-E1 cells.
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Affiliation(s)
- Peng Li
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Wei-Wei Mao
- Clinical Skill Center of Yinchuan First People's Hospital, Yinchuan, Ningxia 750001, P.R. China
| | - Shuai Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Liang Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Zhi-Rong Chen
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Zhi-Dong Lu
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
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21
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Zhuang L, Xia W, Chen D, Ye Y, Hu T, Li S, Hou M. Exosomal LncRNA-NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p. J Nanobiotechnology 2020; 18:157. [PMID: 33129330 PMCID: PMC7603694 DOI: 10.1186/s12951-020-00716-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
Background The chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers. However, its high cardiotoxicity hampered its clinical use. Exosomes derived from stem cells showed a therapeutic effect against Dox-induced cardiomyopathy (DIC). Previous studies reported that exosomes derived from mesenchymal stem cells (MSCs) pretreated with macrophage migration inhibitory factor (MIF) (exosomeMIF) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). This study aimed to investigate the role of exosomeMIF in the treatment of DIC. Results Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF). Regulatory lncRNAs activated by MIF pretreatment were explored using genomics approaches. Fluorescence-labeled exosomes were tracked in vitro by fluorescence imaging. In vivo and in vitro, miR-221-3p mimic transfection enforced miR-221-3p overexpression, and senescence-associated β-galactosidase assay was applied to test cellular senescence. Exosomal delivering LncRNA-NEAT1 induced therapeutic effect in vivo was confirmed by echocardiography. It demonstrated that exosomesMIF recovered the cardiac function and exerted the anti-senescent effect through LncRNA–NEAT1 transfer against Dox. TargetScan and luciferase assay showed that miR-221-3p targeted the Sirt2 3′-untranslated region. Silencing LncRNA–NEAT1 in MSCs, miR-221-3p overexpression or Sirt2 silencing in cardiomyocytes decreased the exosomeMIF-induced anti-senescent effect against Dox. Conclusions The results indicated exosomeMIF serving as a promising anti-senescent effector against Dox-induced cardiotoxicity through LncRNA–NEAT1 transfer, thus inhibiting miR-221-3p and leading to Sirt2 activation. The study proposed that exosomeMIF might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy.![]()
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Affiliation(s)
- Lei Zhuang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wenzheng Xia
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Didi Chen
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China
| | - Yijia Ye
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China
| | - Tingting Hu
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China
| | - Shiting Li
- Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
| | - Meng Hou
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China.
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22
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Li Y, Zhi K, Han S, Li X, Li M, Lian W, Zhang H, Zhang X. TUG1 enhances high glucose-impaired endothelial progenitor cell function via miR-29c-3p/PDGF-BB/Wnt signaling. Stem Cell Res Ther 2020; 11:441. [PMID: 33059750 PMCID: PMC7558752 DOI: 10.1186/s13287-020-01958-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 09/28/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Diabetes is associated with the dysfunction of endothelial progenitor cells (EPCs), characterized as impaired angiogenesis, a phenomenon thought to be involved in the development of diabetic foot. lncRNA plays an essential role in microvascular dysfunction and signaling pathways in patients with diabetes. lncRNA taurine upregulated gene 1 (TUG1) participates in angiogenesis in various cells. However, the mechanisms of TUG1 activity in EPCs have not been elucidated. METHODS We isolated and then characterized EPCs from the peripheral blood of mice using immunofluorescence and flow cytometry. Western blot detected the wnt/β-catenin pathway in high glucose-treated EPCs. Bioinformatics analysis predicted a putative binding site for TUG1 on miR-29c-3p. The interactions among TUG1, platelet-derived growth factor-BB (PDGF-BB), and miR-29c-3p were analyzed by luciferase assays. In vivo, diabetic mouse ischemic limb was treated with normal saline or TUG1 overexpression lentiviruses. RESULTS We found that EPC migration, invasion, and tube formation declined after treatment with high glucose, but improved with TUG1 overexpression. Mechanically, wnt/β-catenin pathway and autophagy were involved in the function of TUG1 overexpression in high glucose-treated EPCs. Moreover, TUG1 regulates the PDGF-BB/wnt pathway and function of high glucose-treated EPCs via miR-29c-3p. In vivo, injection of TUG1 lentivirus in a diabetic mouse ischemic limb model stimulated angiogenesis. CONCLUSIONS Our findings suggest that TUG1 restores high glucose-treated EPC function by regulating miR-29c-3p/PDGF-BB/Wnt signaling.
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Affiliation(s)
- Yang Li
- Department of Interventional & Vascular Surgery, Tenth People's Hospital of Tongji University, Shanghai, 200072, China
- Institute of Interventional & Vascular Surgery, Tongji University, Shanghai, 200072, China
| | - Kangkang Zhi
- Department of Vascular and Endovascular Surgery, Changzheng Hospital, Shanghai, 200003, China
| | - Shilong Han
- Department of Interventional & Vascular Surgery, Tenth People's Hospital of Tongji University, Shanghai, 200072, China
- Institute of Interventional & Vascular Surgery, Tongji University, Shanghai, 200072, China
| | - Xue Li
- Department of Interventional & Vascular Surgery, Tenth People's Hospital of Tongji University, Shanghai, 200072, China
- Institute of Interventional & Vascular Surgery, Tongji University, Shanghai, 200072, China
| | - Maoquan Li
- Department of Interventional & Vascular Surgery, Tenth People's Hospital of Tongji University, Shanghai, 200072, China
- Institute of Interventional & Vascular Surgery, Tongji University, Shanghai, 200072, China
| | - Weishuai Lian
- Department of Interventional & Vascular Surgery, Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
- Institute of Interventional & Vascular Surgery, Tongji University, Shanghai, 200072, China.
| | - Haijun Zhang
- Department of Interventional & Vascular Surgery, Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
- Institute of Interventional & Vascular Surgery, Tongji University, Shanghai, 200072, China.
| | - Xiaoping Zhang
- Department of Interventional & Vascular Surgery, Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
- Institute of Interventional & Vascular Surgery, Tongji University, Shanghai, 200072, China.
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23
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Xu Y, Yuan H, Luo Y, Zhao YJ, Xiao JH. Ganoderic Acid D Protects Human Amniotic Mesenchymal Stem Cells against Oxidative Stress-Induced Senescence through the PERK/NRF2 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8291413. [PMID: 32774686 PMCID: PMC7407022 DOI: 10.1155/2020/8291413] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 06/19/2020] [Accepted: 06/26/2020] [Indexed: 12/19/2022]
Abstract
Aging is an important risk factor in the occurrence of many chronic diseases. Senescence and exhaustion of adult stem cells are considered as a hallmark of aging in organisms. In this study, a senescent human amniotic mesenchymal stem cell (hAMSC) model subjected to oxidative stress was established in vitro using hydrogen peroxide. We investigated the effects of ganoderic acid D (GA-D), a natural triterpenoid compound produced from Ganoderma lucidum, on hAMSC senescence. GA-D significantly inhibited β-galactosidase (a senescence-associated marker) formation, in a dose-dependent manner, with doses ranging from 0.1 μM to 10 μM, without inducing cytotoxic side-effects. Furthermore, GA-D markedly inhibited the generation of reactive oxygen species (ROS) and the expression of p21 and p16 proteins, relieved the cell cycle arrest, and enhanced telomerase activity in senescent hAMSCs. Furthermore, GA-D upregulated the expression of phosphorylated protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK), peroxidase III (PRDX3), and nuclear factor-erythroid 2-related factor (NRF2) and promoted intranuclear transfer of NRF2 in senescent cells. The PERK inhibitor GSK2656157 and/or the NRF2 inhibitor ML385 suppressed the PERK/NRF2 signaling, which was activated by GA-D. They induced a rebound for the generation of ROS and β-galactosidase-positive cells and attenuated the differentiation capacity. These findings suggest that GA-D retards hAMSC senescence through activation of the PERK/NRF2 signaling pathway and may be a promising candidate for the discovery of antiaging agents.
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Affiliation(s)
- Yan Xu
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Huichuan District, Zunyi 563003, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Huichuan District, Zunyi 563003, China
| | - Huan Yuan
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Huichuan District, Zunyi 563003, China
| | - Yi Luo
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Huichuan District, Zunyi 563003, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Huichuan District, Zunyi 563003, China
| | - Yu-Jie Zhao
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Huichuan District, Zunyi 563003, China
| | - Jian-Hui Xiao
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Huichuan District, Zunyi 563003, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Huichuan District, Zunyi 563003, China
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24
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Amirinejad R, Rezaei M, Shirvani-Farsani Z. An update on long intergenic noncoding RNA p21: a regulatory molecule with various significant functions in cancer. Cell Biosci 2020; 10:82. [PMID: 32582435 PMCID: PMC7310005 DOI: 10.1186/s13578-020-00445-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 06/15/2020] [Indexed: 12/15/2022] Open
Abstract
Long intergenic noncoding RNA p21 was mapped on the human chromosome 6p21.2. Accordingly, it was firstly described by promoting the p53-dependent apoptosis in the mouse. Also, it is a new lncRNA playing some vital roles in the cell cycle, apoptosis, cell proliferation, tumorigenesis, invasion, metastasis, and angiogenesis. In this regard, it was shown that, lincRNA-p21 regulates these biological processes involved in carcinogenesis through various signaling pathways including Notch signaling, JAK2/STAT3, and AKT/mTOR pathways. Another mechanism by that lincRNA-p21 can affect these processes is a cross-talk with different miRNAs. In vitro and in vivo studies revealed dysregulation of lincRNA-p21 in various human cancers. In addition, emerging evidence demonstrated that, lincRNA-p21 can be considered as a potential prognostic and therapeutic biomarker in cancers. Also, lincRNA-p21 enhances the response to radiotherapy for colorectal cancer. However, the molecular mechanisms of lincRNA-p21 in carcinogenesis have not been fully elucidated so far. So, this review summarizes the function of lincRNA-p21, as a tumor suppressor factor in different biological processes implicated in cancers.
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Affiliation(s)
- Roya Amirinejad
- Genetics Department, Breast Cancer Research Center, Motamed Center Institute, ACECR, Tehran, Iran
| | - Mina Rezaei
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C, Tehran, Iran
| | - Zeinab Shirvani-Farsani
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C, Tehran, Iran
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25
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Li Z, Ge X, Lu J, Bian M, Li N, Wu X, Li Y, Yan M, Yu J. MiR-141-3p regulates proliferation and senescence of stem cells from apical papilla by targeting YAP. Exp Cell Res 2019; 383:111562. [PMID: 31437458 DOI: 10.1016/j.yexcr.2019.111562] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/14/2019] [Accepted: 08/17/2019] [Indexed: 01/14/2023]
Abstract
Biological phenotypes of mesenchymal stem cells (MSCs) are regulated by a series of biochemical elements, including microRNAs, hormones and growth factors. Our previous study illustrated a significant role of miR-141-3p during the osteogenic differentiation of stem cells from apical papilla (SCAPs). Nevertheless, the functions of miR-141-3p in regulating the proliferative ability and senescence of SCAPs have not been determined. This study identified that overexpression of miR-141-3p inhibited the proliferative ability of SCAPs. Meanwhile, the senescence of SCAPs was ahead of time. Conversely, transfection of miR-141-3p inhibitor promoted the proliferative ability of SCAPs and delayed their senescence. Yes-associated protein (YAP) was predicted as the downstream target gene of miR-141-3p by online softwares (miRDB, miRTarBase, miRWalk, and TargetScan), and was further verified by dual-luciferase reporter gene assay. Additionally, knockdown of YAP inhibited the proliferation and accelerated the senescence of SCAPs. Collectively, these findings proposed a novel direction that miR-141-3p impeded proliferative ability and promoted senescence of SCAPs through post-transcriptionally downregulating YAP.
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Affiliation(s)
- Zehan Li
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China; Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China
| | - Xingyun Ge
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China; Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China
| | - Jiamin Lu
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China; Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China
| | - Minxia Bian
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China; Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China
| | - Na Li
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China; Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China
| | - Xiao Wu
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China; Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China
| | - Yuzhi Li
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China; Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China
| | - Ming Yan
- Key Laboratory of Oral Diseases of Jiangsu Province and Stomatological Institute of Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China; Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China.
| | - Jinhua Yu
- Endodontic Department, School of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, Jiangsu, 210029, China.
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26
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LncRNAs Regulatory Networks in Cellular Senescence. Int J Mol Sci 2019; 20:ijms20112615. [PMID: 31141943 PMCID: PMC6600251 DOI: 10.3390/ijms20112615] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/19/2019] [Accepted: 05/06/2019] [Indexed: 02/07/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are a class of transcripts longer than 200 nucleotides with no open reading frame. They play a key role in the regulation of cellular processes such as genome integrity, chromatin organization, gene expression, translation regulation, and signal transduction. Recent studies indicated that lncRNAs are not only dysregulated in different types of diseases but also function as direct effectors or mediators for many pathological symptoms. This review focuses on the current findings of the lncRNAs and their dysregulated signaling pathways in senescence. Different functional mechanisms of lncRNAs and their downstream signaling pathways are integrated to provide a bird’s-eye view of lncRNA networks in senescence. This review not only highlights the role of lncRNAs in cell fate decision but also discusses how several feedback loops are interconnected to execute persistent senescence response. Finally, the significance of lncRNAs in senescence-associated diseases and their therapeutic and diagnostic potentials are highlighted.
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27
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Xie ZY, Wang P, Wu YF, Shen HY. Long non-coding RNA: The functional regulator of mesenchymal stem cells. World J Stem Cells 2019; 11:167-179. [PMID: 30949295 PMCID: PMC6441937 DOI: 10.4252/wjsc.v11.i3.167] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/07/2019] [Accepted: 02/28/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a subset of multipotent stroma cells residing in various tissues of the body. Apart from supporting the hematopoietic stem cell niche, MSCs possess strong immunoregulatory ability and multiple differentiation potentials. These powerful capacities allow the extensive application of MSCs in clinical practice as an effective treatment for diseases. Therefore, illuminating the functional mechanism of MSCs will help to improve their curative effect and promote their clinical use. Long noncoding RNA (LncRNA) is a novel class of noncoding RNA longer than 200 nt. Recently, multiple studies have demonstrated that LncRNA is widely involved in growth and development through controlling the fate of cells, including MSCs. In this review, we highlight the role of LncRNA in regulating the functions of MSCs and discuss their participation in the pathogenesis of diseases and clinical use in diagnosis and treatment.
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Affiliation(s)
- Zhong-Yu Xie
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Yan-Feng Wu
- Center for Biotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong Province, China
| | - Hui-Yong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
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28
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Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5813147. [PMID: 30881594 PMCID: PMC6383393 DOI: 10.1155/2019/5813147] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 11/08/2018] [Indexed: 12/17/2022]
Abstract
Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic cellular and molecular changes in cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of cardiac aging have been the subject of intense study, the recent discovery that cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous cardiac stem cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of cell turnover and renewal, has now been replaced by a dynamic model in which cardiac cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. However, CSC aging could be a programmed cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths.
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29
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Yu JL, Li C, Che LH, Zhao YH, Guo YB. Downregulation of long noncoding RNA H19 rescues hippocampal neurons from apoptosis and oxidative stress by inhibiting IGF2 methylation in mice with streptozotocin-induced diabetes mellitus. J Cell Physiol 2018; 234:10655-10670. [PMID: 30536889 DOI: 10.1002/jcp.27746] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 10/18/2018] [Indexed: 12/22/2022]
Abstract
The diabetes mellitus (DM)-induced reduction of neurogenesis in the hippocampus is consequently accompanied by cognitive decline. The present study set out to define the critical role played by long noncoding RNA H19 (lncRNA H19) in the apoptosis of hippocampal neurons, as well as oxidative stress (OS) in streptozotocin (STZ)-induced DM mice through regulation of insulin-like growth factor 2 (IGF2) methylation. The expression of lncRNA H19 in the hippocampal neurons and surviving neurons were detected. Hippocampal neurons were cultured and transfected with oe-H19, sh-H19, oe-IGF2, or sh-IGF2, followed by detection of the expressions of IGF2 and apoptosis-related genes. Determination of the lipid peroxide and glutathione levels was conducted, while antioxidant enzyme activity was identified. The IGF2 methylation, the binding of lncRNA H19 to DNA methyltransferase, and the binding of lncRNA H19 to IGF2 promoter region were detected. DM mice exhibited high expressions of H19, as well as a decreased hippocampal neurons survival rate. Higher lncRNA H19 expression was found in DM. Upregulated lncRNA H19 significantly increased the expression of Bax and caspase-3 but decreased that of Bcl-2, thus promoting the apoptosis of hippocampal neuron. Besides, upregulation of lncRNA H19 induced OS. LncRNA H19 was observed to bind specifically to the IGF2 gene promoter region and promote IGF2 methylation by enriching DNA methyltransferase, thereby silencing IGF2 expression. Taken together, downregulated lncRNA H19 reduces IGF2 methylation and enhances its expression, thereby suppressing hippocampal neuron apoptosis and OS in STZ-induced (DM) mice.
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Affiliation(s)
- Jin-Lu Yu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Chao Li
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Li-He Che
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, China
| | - Yu-Hao Zhao
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Yun-Bao Guo
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
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30
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Li WD, Zhou DM, Sun LL, Xiao L, Liu Z, Zhou M, Wang WB, Li XQ. LncRNA WTAPP1 Promotes Migration and Angiogenesis of Endothelial Progenitor Cells via MMP1 Through MicroRNA 3120 and Akt/PI3K/Autophagy Pathways. Stem Cells 2018; 36:1863-1874. [PMID: 30171660 DOI: 10.1002/stem.2904] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 07/22/2018] [Accepted: 07/27/2018] [Indexed: 01/17/2023]
Affiliation(s)
- Wen-Dong Li
- Department of Vascular Surgery, The Affiliated Drum Tower Hospital; Nanjing University Medical School; Nanjing JiangSu People's Republic of China
| | - Dong-Ming Zhou
- Department of Hematology, The Affiliated Drum Tower Hospital; Nanjing University Medical School; Nanjing JiangSu People's Republic of China
| | - Li-Li Sun
- Department of Vascular Surgery; The Second Affiliated Hospital of Soochow University; Suzhou JiangSu People's Republic of China
| | - Lun Xiao
- Department of Vascular Surgery, The Affiliated Drum Tower Hospital; Nanjing University Medical School; Nanjing JiangSu People's Republic of China
| | - Zhao Liu
- Department of Vascular Surgery, The Affiliated Drum Tower Hospital; Nanjing University Medical School; Nanjing JiangSu People's Republic of China
| | - Min Zhou
- Department of Vascular Surgery, The Affiliated Drum Tower Hospital; Nanjing University Medical School; Nanjing JiangSu People's Republic of China
| | - Wen-Bin Wang
- Department of General Surgery; The Fourth Affiliated Hospital of Anhui Medical University; HeFei People's Republic of China
| | - Xiao-Qiang Li
- Department of Vascular Surgery, The Affiliated Drum Tower Hospital; Nanjing University Medical School; Nanjing JiangSu People's Republic of China
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31
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Xia W, Zhuang L, Hou M. Role of lincRNA‑p21 in the protective effect of macrophage inhibition factor against hypoxia/serum deprivation‑induced apoptosis in mesenchymal stem cells. Int J Mol Med 2018; 42:2175-2184. [PMID: 30015822 DOI: 10.3892/ijmm.2018.3767] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 06/28/2018] [Indexed: 01/09/2023] Open
Abstract
Stem cell transplantation is a promising clinical strategy for curing ischemic cardiomyopathy. However, its efficacy is impaired by low cell survival following transplantation, partly caused by insufficient resistance of the transplanted stem cells to severe oxidative stress at the injury site. In the current study, it was demonstrated that the small‑molecule macrophage migration inhibitory factor (MIF) enhanced the defense of bone marrow‑derived mesenchymal stem cells (MSCs) against hypoxia/serum deprivation (SD)‑induced apoptosis in vitro. MIF significantly suppressed apoptosis and caspase family activities through inhibition of long intergenic noncoding (linc) RNA‑p21 to maintain activation of the Wnt/β‑catenin signaling pathway. The regulatory loop between MIF and the lincRNA‑p21‑Wnt/β‑catenin signaling pathway was identified to be associated with the inhibition of oxidative stress. The involvement of the lincRNA‑p21‑Wnt/β‑catenin signaling pathway in the effects of MIF in MSCs by overexpression of lincRNA‑p21and silencing β‑catenin using small interfering RNA was also demonstrated, both of which abolished the anti‑apoptotic and anti‑oxidative effects of MIF in MSCs under hypoxia/SD conditions. In conclusion, MIF protected MSCs from hypoxia/SD‑induced apoptosis by interacting with lincRNA‑p21, leading to activation of the downstream Wnt/β‑catenin signaling pathway and decreased oxidative stress. Thus, treatment with MIF may have important therapeutic implications in improving MSC survival and therapeutic efficiency.
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Affiliation(s)
- Wenzheng Xia
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Lei Zhuang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Meng Hou
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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32
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Li Q, Zhu Z, Wang C, Cai L, Lu J, Wang Y, Xu J, Su Z, Zheng W, Chen X. CTRP9 ameliorates cellular senescence via PGC‑1α/AMPK signaling in mesenchymal stem cells. Int J Mol Med 2018; 42:1054-1063. [PMID: 29749459 DOI: 10.3892/ijmm.2018.3666] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 05/03/2018] [Indexed: 11/06/2022] Open
Abstract
Stroke is the second most common cause of death worldwide, and thus, it imposes great financial burdens on both individuals and society. Mesenchymal stem cell (MSC) therapy is a promising approach for ischemic brain injury. However, MSC treatment potential is progressively reduced with age, limiting their therapeutic efficacy for brain repair post‑stroke. C1q and tumor necrosis factor‑related protein 9 (CTRP9) is a novel cytoprotective cytokine with antioxidant effects, which is highly expressed in brain tissue. The present study tested the hypothesis that CTRP9 might act as an antisenescence factor to promote the rejuvenation of aged MSCs. MSCs were isolated from the bone marrow of young (8‑weeks‑old) and aged (18‑months‑old) male C57BL/6 mice. Cell proliferation was measured by Cell Counting Kit‑8 assay and cell viability was determined by MTT assay. Gene expression levels of interleukin (IL)‑6 and IL‑10 were evaluated with reverse transcription‑quantitative polymerase chain reaction, and secretion of vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, and insulin‑like growth factor were measured by ELISA. The expression levels of proteins in the peroxisome proliferator‑activated receptor γcoactivator (PGC)‑1α/AMP‑activated protein kinase (AMPK) signaling pathway were investigated with western blotting. Oxidative stress was evaluated by detecting mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity and malondialdehyde. MSCs isolated from aged mice exhibited reduced proliferation and viability, and impaired immunoregulatory and paracrine abilities, compared with MSCs from younger mice. CTRP9 had a significant antisenescence effect in aged MSCs by activating PGC‑1α/AMPK signaling and decreasing the oxidative response. Silencing either PGC‑1α or AMPK abolished the above effects of CTRP9. These results suggest that CTRP9 may have a critical role in cellular senescence by facilitating stem cell rejuvenation, and may therefore have the potential to enhance the efficacy of stem cell therapy.
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Affiliation(s)
- Qun Li
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhangzhang Zhu
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Chengde Wang
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Lin Cai
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jianglong Lu
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yongchun Wang
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jiadong Xu
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhipeng Su
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Weiming Zheng
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xianbin Chen
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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