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Depletion of histone demethylase KDM2A inhibited cell proliferation of stem cells from apical papilla by de-repression of p15INK4B and p27Kip1 总被引:1,自引:0,他引:1
Runtao Gao Rui Dong Juan Du Ping Ma Songlin Wang Zhipeng Fan 《Molecular and cellular biochemistry》2013,379(1-2):115-122
Mesenchymal stem cells (MSCs) are a reliable resource for tissue regeneration; although, the molecular mechanisms of their differentiation and proliferation are not clearly understood, which restricts the applications of MSCs. The histone demethylase, lysine (K)-specific demethylase 2A (KDM2A), and the mammalian paralog, lysine (K)-specific demethylase 2B (KDM2B), are evolutionarily conserved and ubiquitously expressed members of the JmjC-domain-containing histone demethylase family. A previous study determined that KDM2A and KDM2B can regulate the differentiation of MSCs, and KDM2B has been implicated in cell cycle regulation by de-repressing p15INK4B (cyclin-dependent kinase inhibitor 2B). It is not known whether KDM2A is involved in the cell proliferation of MSCs. Here, we show that depletion of KDM2A by short hairpin RNAs can inhibit cell proliferation and arrest cell cycle progression at the G1/S-phase in human stem cells from apical papilla (SCAPs). The effect of KDM2A on cell proliferation was found to be mediated through de-repression of the cyclin-dependent kinase inhibitors, p15INK4B and p27Kip1 (cyclin-dependent kinase inhibitor 1B), in KDM2A knock-down SCAPs. Furthermore, chromatin immunoprecipitation assays demonstrated that silencing of KDM2A increased histone H3 Lysine 4 (H3K4) trimethylation at the p15INK4B and p27Kip1 loci and regulated its expression. Together, our results indicate that KDM2A is a H3K4 demethylase that regulates cell proliferation through p15INK4B and p27Kip1 in SCAPs. 相似文献
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Haoqing Yang Jiao Fan Yangyang Cao Runtao Gao Zhipeng Fan 《Experimental cell research》2019,374(1):221-230
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Takeshi Inagaki Satoshi Iwasaki Yoshihiro Matsumura Takeshi Kawamura Toshiya Tanaka Yohei Abe Ayumu Yamasaki Yuya Tsurutani Ayano Yoshida Yoko Chikaoka Kanako Nakamura Kenta Magoori Ryo Nakaki Timothy F. Osborne Kiyoko Fukami Hiroyuki Aburatani Tatsuhiko Kodama Juro Sakai 《The Journal of biological chemistry》2015,290(7):4163-4177
Polycomb repressive complex 1 (PRC1) plays an essential role in the epigenetic repression of gene expression during development and cellular differentiation via multiple effector mechanisms, including ubiquitination of H2A and chromatin compaction. However, whether it regulates the stepwise progression of adipogenesis is unknown. Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. Knockdown of either RING1B or SKP1 prevented FBXL10-mediated repression of 3T3-L1 preadipocyte differentiation indicating that PRC1 formation mediates the inhibitory effect of FBXL10 on adipogenesis. Using ChIP-seq, we show that FBXL10 recruits RING1B to key specific genomic loci surrounding the key cell cycle and the adipogenic genes Cdk1, Uhrf1, Pparg1, and Pparg2 to repress adipogenesis. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage. 相似文献
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KDM6A promotes chondrogenic differentiation of periodontal ligament stem cells by demethylation of SOX9 下载免费PDF全文
Pingting Wang Yanjing Li Tingting Meng Junjiang Zhang Yuanyuan Wei Zhaosong Meng Yunfeng Lin Dayong Liu Lei Sui 《Cell proliferation》2018,51(3)
Objectives
KDM6A has been demonstrated critical in the regulation of cell fates. However, whether KDM6A is involved in cartilage formation remains unclear. In this study, we investigated the role of KDM6A in chondrogenic differentiation of PDLSCs, as well as the underlying epigenetic mechanisms.Methods
KDM6A shRNA was transfected into PDLSCs by lentivirus. The chondrogenic differentiation potential of PDLSCs was assessed by Alcian blue staining. Immunofluorescence was performed to demonstrate H3K27me3 and H3K4me3 levels during chondrogenesis. SOX9, Col2a1, ACAN and miRNAs (miR‐29a, miR‐204, miR‐211) were detected by real‐time RT‐PCR. Western blot was performed to evaluate SOX9, H3K27me3 and H3K4me3.Results
The production of proteoglycans in PDLSCs was decreased after knockdown of KDM6A. Depletion of KDM6A inhibited the expression of SOX9, Col2a1, ACAN and resulted in increased H3K27me3 and decreased H3K4me3 levels. EZH2 inhibitor rescued the chondrogenic potential of PDLSCs after knockdown of KDM6A by regulating H3K27me3. Additionally, miR‐29a, miR‐204 and miR‐211 were also involved in the process of PDLSCs chondrogenesis.Conclusions
KDM6A is required in chondrogenic differentiation of PDLSCs by demethylation of H3K27me3, and EZH2 inhibitor could rescue chondrogenesis of PDLSCs after knockdown of KDM6A. It could be inferred that upregulation of KDM6A or application of EZH2 inhibitor might improve mesenchymal stem cell mediated cartilage regeneration in inflammatory tissue destruction such as osteoarthritis.8.
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Xiaoyue Yang Guannan Wang Yi Wang Jie Zhou Hairui Yuan Xiaoxia Li Ying Liu Baoli Wang 《Journal of cellular and molecular medicine》2019,23(3):2149-2162
Recent emerging evidences revealed that epigenetic methylation of histone and DNA regulates the lineage commitment of mesenchymal progenitor cells. This study was undertaken to delineate the actions of histone lysine demethylase 7A (KDM7A) on osteogenic and adipogenic differentiation. Kdm7a expression was up‐regulated in primary marrow stromal cells and established stromal ST2 line after adipogenic and osteogenic treatment. Silencing of endogenous Kdm7a in the cells blocked adipogenic differentiation whereas promoted osteogenic differentiation. Conversely, overexpression of wild‐type Kdm7a in the progenitor cells enhanced adipogenic differentiation whereas inhibited osteogenic differentiation. However, the effect of KDM7A on cell differentiation was largely attenuated when the point mutation was made that abolishes enzymatic activity of KDM7A. Mechanism investigations revealed that silencing of Kdm7a down‐regulated the expression of the CCAAT/enhancer binding protein α (C/EBPα) and secreted frizzled‐related protein 1 (Sfrp1). Chromatin immunoprecipitation (ChIP) assay revealed that KDM7A directly binds to the promoters of C/EBPα and Sfrp1 and removes the histone methylation marks H3K9me2 and H3K27me2. Furthermore, silencing of Kdm7a activated canonical Wnt signalling. Thereafter, activation of canonical Wnt signalling through silencing of Sfrp1 in ST2 attenuated the stimulation of adipogenic differentiation and inhibition of osteogenic differentiation by KDM7A. Our study suggests that KDM7A balances adipogenic and osteogenic differentiation from progenitor cells through epigenetic control of C/EBPα and canonical Wnt signalling and implicates that control of KDM7A action has an epigenetic perspective of curtailing metabolic disorders like osteoporosis. 相似文献
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Farrell E Wielopolski P Pavljasevic P van Tiel S Jahr H Verhaar J Weinans H Krestin G O'Brien FJ van Osch G Bernsen M 《Biochemical and biophysical research communications》2008,369(4):1076-1081
Successful cell therapy will depend on the ability to monitor transplanted cells. With cell labeling, it is important to demonstrate efficient long term labeling without deleterious effects on cell phenotype and differentiation capacity. We demonstrate long term (7 weeks) retention of superparamagnetic iron oxide particles (SPIO) by mesenchymal stem cells (MSCs) in vivo, detectable by MRI. In vitro, multilineage differentiation (osteogenic, chondrogenic and adipogenic) was demonstrated by histological evaluation and molecular analysis in SPIO labeled and unlabeled cells. Gene expression levels were comaparable to unlabeled controls in adipogenic and chondrogenic conditions however not in the osteogenic condition. MSCs seeded into a scaffold for 21 days and implanted subcutaneously into nude mice for 4 weeks, showed profoundly altered phenotypes in SPIO labeled samples compared to implanted unlabeled control scaffolds, indicating chondrogenic differentiation. This study demonstrates long term MSC traceability using SPIO and MRI, uninhibited multilineage MSC differentiation following SPIO labeling, though with subtle but significant phenotypical alterations. 相似文献
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Masami Kanawa Akira Igarashi Veronica Sainik Ronald Yukihito Higashi Hidemi Kurihara Masaru Sugiyama Tania Saskianti Haiou Pan Yukio Kato 《Cytotherapy》2013,15(9):1062-1072
Background aimsHuman bone marrow mesenchymal stromal cells are useful in regenerative medicine for various diseases, but it remains unclear whether the aging of donors alters the multipotency of these cells. In this study, we examined age-related changes in the chondrogenic, osteogenic and adipogenic potential of mesenchymal stromal cells from 17 donors (25–81 years old), including patients with or without systemic vascular diseases.MethodsAll stem cell lines were expanded with fibroblast growth factor-2 and then exposed to differentiation induction media. The chondrogenic potential was determined from the glycosaminoglycan content and the SOX9, collagen type 2 alpha 1 (COL2A1) and aggrecan (AGG) messenger RNA levels. The osteogenic potential was determined by monitoring the alkaline phosphatase activity and calcium content, and the adipogenic potential was determined from the glycerol-3-phosphate dehydrogenase activity and oil red O staining.ResultsSystemic vascular diseases, including arteriosclerosis obliterans and Buerger disease, did not significantly affect the trilineage differentiation potential of the cells. Under these conditions, all chondrocyte markers examined, including the SOX9 messenger RNA level, showed age-related decline, whereas none of the osteoblast or adipocyte markers showed age-dependent changes.ConclusionsThe aging of donors from young adult to elderly selectively decreased the chondrogenic potential of mesenchymal stromal cells. This information will be useful in stromal cell–based therapy for cartilage-related diseases. 相似文献
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Cristiana Leite N. Tatiana Silva Sandrine Mendes Andreia Ribeiro Joana Paes de Faria Tania Louren?o Francisco dos Santos Pedro Z. Andrade Carla M. P. Cardoso Margarida Vieira Artur Paiva Cláudia L. da Silva Joaquim M. S. Cabral Jo?o B. Relvas Mário Gr?os 《PloS one》2014,9(10)
Mesenchymal stem cells (MSCs) are viewed as safe, readily available and promising adult stem cells, which are currently used in several clinical trials. Additionally, their soluble-factor secretion and multi-lineage differentiation capacities place MSCs in the forefront of stem cell types with expected near-future clinical applications. In the present work MSCs were isolated from the umbilical cord matrix (Wharton''s jelly) of human umbilical cord samples. The cells were thoroughly characterized and confirmed as bona-fide MSCs, presenting in vitro low generation time, high proliferative and colony-forming unit-fibroblast (CFU-F) capacity, typical MSC immunophenotype and osteogenic, chondrogenic and adipogenic differentiation capacity. The cells were additionally subjected to an oligodendroglial-oriented step-wise differentiation protocol in order to test their neural- and oligodendroglial-like differentiation capacity. The results confirmed the neural-like plasticity of MSCs, and suggested that the cells presented an oligodendroglial-like phenotype throughout the differentiation protocol, in several aspects sharing characteristics common to those of bona-fide oligodendrocyte precursor cells and differentiated oligodendrocytes. 相似文献
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Zhongzheng Zhi Chenglin Zhang Jian Kang Yingjie Wang Jingdong Liu Furong Wu Guanghui Xu 《Journal of cellular physiology》2020,235(10):7173-7182
Abnormal expression of KDM6A and SOX9 is a key factor in the pathogenesis of osteoarthritis (OA). Cellular treatments of OA with articular cartilage chondrocytes (ACCs) and bone marrow mesenchymal stem cells (BMSCs) are promising, but their underlying mechanisms remain to be explored. The pellet size, weight and sulfated glycosaminoglycan/DNA content of ACCs were measured to evaluate the effect of BMSCs on the chondrogenic differentiation of SCCs. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to analyze the proliferation of ACCs cultured along or cocultured with BMSCs. Quantitative polymerase chain reaction (qPCR) was performed to evaluate the messenger RNA expression of KDM6A, SOX9, type2 collagen, and Aggrecan in ACCs and OA rats. Western blot and immunohistochemistry were performed to analyze the expression of KDM6A and SOX9 proteins. Bisulfite sequencing PCR was performed to assess the DNA methylation level of the SOX9 promoter. Flow cytometry was used to evaluate the apoptotic status of ACCs. The chondrogenic differentiation of ACCs was significantly enhanced by coculturing with BMSCs, especially under a hypoxic condition. The expression of KDM6A, SOX9, type2 collagen, and Aggrecan was remarkably elevated in ACCs cocultured with BMSCs. Also, the DNA methylation of SOX9 promoter was decreased in ACCs cocultured with BMSCs, along with notably reduced apoptosis. Moreover, ACCs cocultured with BMSCs could repair cartilage lesions and prevent the abnormal expression of KDM6A, SOX9, type2 collagen, and Aggrecan in OA rats. In this study, we cocultured ACCs with BMSCs and used them to treat OA rats. Our findings presented a mechanistic basis for explaining the therapeutic effect of BMSCs on OA treatment. 相似文献
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Luyuan Jin Yu Cao Guoxia Yu Jinsong Wang Xiao Lin Lihua Ge Juan Du Liping Wang Shu Diao Xiaomeng Lian Songlin Wang Rui Dong Zhaochen Shan 《Cellular & molecular biology letters》2017,22(1):14