Polycomb Protein BMI1 Regulates Osteogenic Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells Downstream of GSK3

Becker, Matthias; Potapenko, Tamara; Niklaus, Andrea L.; Ho, Anthony D.; Müller, Albrecht

doi:10.1089/scd.2015.0277

Cited by 7 publications

(6 citation statements)

References 74 publications

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“…It has recently been shown that in vitro overexpression of BMI1 enhanced osteogenesis of human adipose tissue‐derived MSCs, whereas knockdown of BMI1 reduced their osteogenic differentiation . Our previous study showed that Bmi1 deficiency reduced osteogenesis of BM‐MSCs with downregulation of osteogenic gene expression .…”

Section: Discussionmentioning

confidence: 93%

“…Recently, study showed that the upregulation of BMI1 induced by hypoxic‐cultures stimulated the proliferation of human umbilical cord blood‐MSCs, whereas knockdown of BMI1 in hypoxic cells inhibited their proliferation . in vitro study also showed that overexpression of BMI1 resulted in osteogenic priming of human adipose tissue‐derived MSCs under nondifferentiating conditions and enhanced osteogenesis upon differentiation, whereas knockdown of BMI1 reduced their osteogenic differentiation . However, it is unknown whether overexpression of Bmi1 in MSCs in vivo affects the proliferation and differentiation of MSCs.…”

Section: Introductionmentioning

confidence: 99%

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Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress

Chen

Zhang

et al. 2019

Stem Cells

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We previously demonstrated that Bmi1 deficiency leads to osteoporosis phenotype by inhibiting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs), but it is unclear whether overexpression of Bmi1 in MSCs stimulates skeletal development and rescues Bmi1 deficiency‐induced osteoporosis. To answer this question, we constructed transgenic mice (Bmi1Tg) that overexpressed Bmi1 driven by the Prx1 gene and analyzed their skeletal phenotype differences with that of wild‐type littermates. We then hybridized Bmi1Tg to Bmi1−/− mice to generate Bmi1−/− mice overexpressing Bmi1 in MSCs and compared their skeletal phenotypes with those of Bmi1−/− and wild‐type mice using imaging, histopathological, immunohistochemical, histomorphometric, cellular, and molecular methods. Bmi1Tg mice exhibited enhanced bone growth and osteoblast formation, including the augmentation of bone size, cortical and trabecular volume, number of osteoblasts, alkaline phosphatase (ALP)‐positive and type I collagen‐positive areas, number of total colony forming unit fibroblasts (CFU‐f) and ALP+ CFU‐f, and osteogenic gene expression levels. Consistently, MSC overexpressing Bmi1 in the Bmi1−/− background not only largely reversed Bmi1 systemic deficiency‐induced skeletal growth retardation and osteoporosis, but also partially reversed Bmi1 deficiency‐induced systemic growth retardation and premature aging. To further explore the mechanism of action of MSCs overexpressing Bmi1 in antiosteoporosis and antiaging, we examined changes in oxidative stress and expression levels of p16 and p19. Our results showed that overexpression of Bmi1 in MSCs inhibited oxidative stress and downregulated p16 and p19. Taken together, the results of this study indicate that overexpression of Bmi1 in MSCs exerts antiaging and antiosteoporosis effects by inactivating p16/p19 signaling and inhibiting oxidative stress. stem cells 2019;37:1200–1211

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress

Chen

Zhang

et al. 2019

Stem Cells

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“…BMI1 expression also increases during osteogenic differentiation of human adipose derived stem cells (hASCs) in vitro. Overexpression of BMI1 enhanced osteogenic differentiation of hASCs and increased BMP2 and WNT11 expression . BMI1 knockout mice have skeletal growth retardation, with decreased trabecular bone volume and bone mineral density .…”

Section: Epigenetic Targeting As Treatment Of Mmbdmentioning

confidence: 95%

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

2019

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Multiple myeloma (MM) bone disease is characterized by the development of osteolytic lesions, which cause severe complications affecting the morbidity, mortality, and treatment of myeloma patients. Myeloma tumors seeded within the bone microenvironment promote hyperactivation of osteoclasts and suppression of osteoblast differentiation. Because of this prolonged suppression of bone marrow stromal cells’ (BMSCs) differentiation into functioning osteoblasts, bone lesions in patients persist even in the absence of active disease. Current antiresorptive therapy provides insufficient bone anabolic effects to reliably repair MM lesions. It has become widely accepted that myeloma‐exposed BMSCs have an altered phenotype with pro‐inflammatory, immune‐modulatory, anti‐osteogenic, and pro‐adipogenic properties. In this review, we focus on the role of epigenetic‐based modalities in the establishment and maintenance of myeloma‐induced suppression of osteogenic commitment of BMSCs. We will focus on recent studies demonstrating the involvement of chromatin‐modifying enzymes in transcriptional repression of osteogenic genes in MM‐BMSCs. We will further address the epigenetic plasticity in the differentiation commitment of osteoprogenitor cells and assess the involvement of chromatin modifiers in MSC‐lineage switching from osteogenic to adipogenic in the context of the inflammatory myeloma microenvironment. Lastly, we will discuss the potential of employing small molecule epigenetic inhibitors currently used in the MM research as therapeutics and bone anabolic agents in the prevention or repair of osteolytic lesions in MM. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…5 Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, Beijing, China. 6 NMPA Key Laboratory for Dental Materials, Beijing, China. 7 Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China.…”

Section: Acknowledgementsmentioning

confidence: 99%

“…As we know, human adipose-derived stem cells (hASCs) have multilineage differentiation potentials and good application prospects for bone regeneration [1][2][3] because of their abundant sources and easy access for clinical uses [4]. Though plenty of signaling pathways, such as Wnt/β-catenin signal [5], glycogen synthase kinase 3 signal [6], bone morphogenetic protein (BMP) signal [7][8][9], NOTCH signal [10,11], and extracellular regulated protein kinases signal [7,12,13] have been demonstrated to dominate osteoblastic differentiation of hASCs, considerable research is still necessary to reveal intricate interactions between various signals and make further advances in hASC-based cell therapy.…”

Section: Introductionmentioning

confidence: 99%

A NOTCH1/LSD1/BMP2 co-regulatory network mediated by miR-137 negatively regulates osteogenesis of human adipose-derived stem cells

Fan

Wang

et al. 2021

Stem Cell Res Ther

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Background MicroRNAs have been recognized as critical regulators for the osteoblastic lineage differentiation of human adipose-derived stem cells (hASCs). Previously, we have displayed that silencing of miR-137 enhances the osteoblastic differentiation potential of hASCs partly through the coordination of lysine-specific histone demethylase 1 (LSD1), bone morphogenetic protein 2 (BMP2), and mothers against decapentaplegic homolog 4 (SMAD4). However, still numerous molecules involved in the osteogenic regulation of miR-137 remain unknown. This study aimed to further elucidate the epigenetic mechanisms of miR-137 on the osteogenic differentiation of hASCs. Methods Dual-luciferase reporter assay was performed to validate the binding to the 3′ untranslated region (3′ UTR) of NOTCH1 by miR-137. To further identify the role of NOTCH1 in miR-137-modulated osteogenesis, tangeretin (an inhibitor of NOTCH1) was applied to treat hASCs which were transfected with miR-137 knockdown lentiviruses, then together with negative control (NC), miR-137 overexpression and miR-137 knockdown groups, the osteogenic capacity and possible downstream signals were examined. Interrelationships between signaling pathways of NOTCH1-hairy and enhancer of split 1 (HES1), LSD1 and BMP2-SMADs were thoroughly investigated with separate knockdown of NOTCH1, LSD1, BMP2, and HES1. Results We confirmed that miR-137 directly targeted the 3′ UTR of NOTCH1 while positively regulated HES1. Tangeretin reversed the effects of miR-137 knockdown on osteogenic promotion and downstream genes expression. After knocking down NOTCH1 or BMP2 individually, we found that these two signals formed a positive feedback loop as well as activated LSD1 and HES1. In addition, LSD1 knockdown induced NOTCH1 expression while suppressed HES1. Conclusions Collectively, we proposed a NOTCH1/LSD1/BMP2 co-regulatory signaling network to elucidate the modulation of miR-137 on the osteoblastic differentiation of hASCs, thus providing mechanism-based rationale for miRNA-targeted therapy of bone defect.

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Polycomb Protein BMI1 Regulates Osteogenic Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells Downstream of GSK3

Cited by 7 publications

References 74 publications

Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress

Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

A NOTCH1/LSD1/BMP2 co-regulatory network mediated by miR-137 negatively regulates osteogenesis of human adipose-derived stem cells

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