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

Stem Cell Research & Therapy

Hao Liu¹  Cong Fan²  Yuejun Wang³  Yuan Zhu³  Xiaohan Ma⁴  Yunsong Liu⁵  Longwei Lv⁶ 

[1] Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China;Department of General Dentistry II, Peking University School and Hospital of Stomatology, Beijing, China;National Center of Stomatology, Beijing, China;National Clinical Research Center for Oral Diseases, Beijing, China;National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China;Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, Beijing, China;NMPA Key Laboratory for Dental Materials, Beijing, China;Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China;Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China;Department of Prosthodontics, Beijing Stomatological Hospital Capital Medical University, Beijing, China;Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China;National Center of Stomatology, Beijing, China;National Clinical Research Center for Oral Diseases, Beijing, China;National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China;Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, Beijing, China;NMPA Key Laboratory for Dental Materials, Beijing, China;National Center of Stomatology, Beijing, China;National Clinical Research Center for Oral Diseases, Beijing, China;National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China;Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, Beijing, China;NMPA Key Laboratory for Dental Materials, Beijing, China;Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China;

关键词: MicroRNA;    Human adipose-derived stem cells;    Osteogenesis;    NOTCH1;    Signaling;   

DOI  :  10.1186/s13287-021-02495-3

来源: Springer

【 摘 要 】

BackgroundMicroRNAs 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.MethodsDual-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.ResultsWe 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.ConclusionsCollectively, 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.

【 授权许可】

CC BY