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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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13287-021-02495-3.

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