Histological type of oncogenity and expression of cell cycle genes in tumor cells from human mesenchymal stem cells

Jiang, Runqiu; Xu, Wenrong; Zhu, Wenhe; Chen, Miao; Qian, Hui; Qiao, Chun; Yang, Huan; Xing-zhong, Wang; Chen, Yongchang

doi:10.3892/or.16.5.1021

Cited by 5 publications

(5 citation statements)

References 16 publications

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“…p16, p21, and p53 have also been demonstrated to be significantly upregulated in senescent hBM-MSCs [39]. In comparison, at the late stage of the hBM-MSC lifespan, significantly increased expression was observed in p16 but not p21 nor p53 [40]. Therefore, p16 might be the key marker for hBM-MSC senescence.…”

Section: Discussionmentioning

confidence: 99%

Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells

Shen

et al. 2019

Stem Cells International

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The application of human bone marrow mesenchymal stem cells (hBM-MSCs) in cell-based clinical therapies is hindered by the limited number of cells remaining after the initial isolation process and by cellular senescence following in vitro expansion. Understanding the process of in vitro senescence in hBM-MSCs would enable the development of strategies to maintain their vitality after cell culture. Herein, we compared the gene expression profiles of human embryonic stem cells and human BM-MSCs from donors of different ages. We first found that the expression of discoidin domain receptor 2 (DDR2) in adult donor-derived hBM-MSCs was lower than it was in the young donor-derived hBM-MSCs. Moreover, in vitro cultured late-passage hBM-MSCs showed significant downregulation of DDR2 compared to their early-passage counterparts, and siRNA inhibition of DDR2 expression recapitulated features of senescence in early-passage hBM-MSCs. Further, we found through knockdown and overexpression approaches that coactivator-associated arginine methyltransferase 1 (CARM1) regulated the expression level of DDR2 and the senescence of hBM-MSCs. Finally, chromatin immunoprecipitation analysis confirmed direct binding of CARM1 to the DDR2 promoter region with a high level of H3R17 methylation in early-passage hBM-MSCs, and inhibition of CARM1-mediated histone arginine methylation decreased DDR2 expression and led to cellular senescence. Taken together, our findings suggest that DDR2 plays a major role in regulating the in vitro senescence of hBM-MSCs and that CARM1-mediated histone H3 methylation might be the upstream regulatory mechanism controlling this function of DDR2.

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Section: Discussionmentioning

confidence: 99%

Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells

Shen

et al. 2019

Stem Cells International

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“…Bmi1‐deficient mice (Bmi1 −/− ) display defects in the hematopoietic, nervous, and skeletal systems . Previous studies showed that Bmi1 is expressed in bone marrow MSCs, and Bmi1 is used to immortalize bone marrow MSCs . We have previously showed that the bone formation defects in the Bmi1 −/− mice were not completely restored by Sirt1 overexpression.…”

Section: Introductionmentioning

confidence: 99%

Sirt1 Promotes Osteogenic Differentiation and Increases Alveolar Bone Mass via Bmi1 Activation in Mice

Wang

et al. 2019

Journal of Bone and Mineral Research

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Sirtuin 1 (Sirt1), a protein deacetylase, is a novel target for bone metabolism. To investigate whether overexpression of Sirt1 in mandibular mesenchymal stem cells (M-MSCs) increased alveolar bone mass in vivo, we generated Sirt1 transgenic mice (Sirt1 TG ), with Sirt1 gene expression driven by the Prx1 gene, which represents the mesenchymal lineage. Our results demonstrated that overexpression of Sirt1 in M-MSCs increased the alveolar bone volume in 1-month-old, 9-month-old, and 18-month-old Sirt1 TG mice compared with age-matched wild-type (WT) mice, and in ovariectomized Sirt1 TG mice compared with ovariectomized WT mice by stimulating M-MSC differentiation into osteoblasts. Treatment with resveratrol, a Sirt1 activator, increased Sirt1 binding with Bmi1 and reduced Bmi1 acetylation in a dose-dependent manner demonstrated in M-MSC cultures. Both treatment with resveratrol in M-MSC cultures and overexpressed Sirt1 in M-MSCs ex vivo cultures increased nuclear translocation of Bmi1. Furthermore, we demonstrated that deletion of Bmi1 blocked the increased alveolar bone volume in Sirt1 TG mice. The Sirt1 activator resveratrol inhibited human MSC senescence and promoted their differentiation into osteoblasts, which were associated with upregulating the expression levels of Sirt1 and nuclear translocation of Bmi1. The present results suggested that Sirt1 promotes MSC proliferation and osteogenic differentiation, inhibits MSC senescence to increase alveolar bone volume by promoting the deacetylation and nuclear translocation of Bmi1. Thus, our study elucidated the mechanism by which Sirt1 increases alveolar bone mass, and these findings are important for the clinical application of the Sirt1 activator resveratrol for the promotion of alveolar bone formation and prevention of alveolar bone loss.

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“…Bmi-1 is required for the self-renewal and postnatal maintenance of hematopoietic stem cells (HSCs) (6,7) and neural stem cells from the central nervous system and peripheral nervous system. (8,9) Previous studies have reported that Bmi-1 also is expressed in bone marrow mesenchymal stem cells (BM-MSCs), (10) and Bmi-1 has been used to immortalize BM-MSCs. (11) It is unknown, however, whether defects in endogenous Bmi-1 can alter BM-MSCs.…”

Section: Introductionmentioning

confidence: 99%

Defects in mesenchymal stem cell self-renewal and cell fate determination lead to an osteopenic phenotype in Bmi-1 null mice

Zhang

Ding

Jin

et al. 2010

Journal of Bone and Mineral Research

134

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In parathyroid hormone-related protein 1-84 ] knockin mice, expression of the polycomb protein Bmi-1 is reduced and potentially can mediate the phenotypic alterations observed. We have therefore now examined the skeletal phenotype of Bmi-1 À/À mice in vivo and also assessed the function of bone marrow mesenchymal stem cells (BM-MSCs) from Bmi-1 À/À mice ex vivo in culture.Neonatal Bmi-1 À/À mice exhibited skeletal growth retardation, with reduced chondrocyte proliferation and increased apoptosis.Osteoblast numbers; gene expression of alkaline phosphatase, type I collagen, and osteocalcin; the mineral apposition rate; trabecular bone volume; and bone mineral density all were reduced significantly; however, the number of bone marrow adipocytes and Ppar-g expression were increased. These changes were consistent with the skeletal phenotype observed in the PTHrP(1-84) knockin mouse. The efficiency of colony-forming unit fibroblast (CFU-F) formation in bone marrow cultures was decreased, and the percentage of alkaline phosphatase-positive CFU-F and Runx2 expression were reduced. In contrast, adipocyte formation and Ppar-g expression in cultures were increased, and expression of the polycomb protein sirtuin (Sirt1) was reduced. Reduced proliferation and increased apoptosis of BM-MSCs were associated with upregulation of senescence-associated tumor-suppressor genes, including p16, p19, and p27. Analysis of the skeletal phenotype in Bmi-1 À/À mice suggests that Bmi-1 functions downstream of PTHrP. Furthermore, our studies indicate that Bmi-1 maintains self-renewal of BM-MSCs by inhibiting the expression of p27, p16, and p19 and alters the cell fate of BM-MSCs by enhancing osteoblast differentiation and inhibiting adipocyte differentiation at least in part by stimulating Sirt1 expression. Bmi-1 therefore plays a critical role in promoting osteogenesis. ß

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Histological type of oncogenity and expression of cell cycle genes in tumor cells from human mesenchymal stem cells

Cited by 5 publications

References 16 publications

Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells

Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells

Sirt1 Promotes Osteogenic Differentiation and Increases Alveolar Bone Mass via Bmi1 Activation in Mice

Defects in mesenchymal stem cell self-renewal and cell fate determination lead to an osteopenic phenotype in Bmi-1 null mice

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