LncRNA H19 mediates BMP9-induced angiogenesis in mesenchymal stem cells by promoting the p53-Notch1 angiogenic signaling axis

作     者：Chengcheng Du Qiang Cheng Piao Zhao Claire Wang Zhenglin Zhu Xiangdong Wu Shengqiang Gao Bowen Chen Jing Zou Wei Huang Junyi Liao Chengcheng Du;Qiang Cheng;Piao Zhao;Claire Wang;Zhenglin Zhu;Xiangdong Wu;Shengqiang Gao;Bowen Chen;Jing Zou;Wei Huang;Junyi Liao

作者机构：Department of Orthopedic SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Orthopedic Laboratory of Chongqing Medical UniversityChongqing 400016China Molecular Oncology LaboratoryDepartment of Orthopedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Computational and Applied MathematicsRice UniversityHoustonTX 77005USA Department of Orthopedic SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China 

出 版 物：《Genes & Diseases》 (基因与疾病（英文）)

年 卷 期：2023年第10卷第3期

页      面：1040-1054页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China,PRC(No.#82002312 and#81972069) This project was also supported by Science and Technology Research Program of Chongqing Education Commission,PRC(No.#KJQN202100431 and#KJZD-M202100401) Candidate of Tip-Top Talent of the First Affiliated Hospital of Chongqing Medical University,PRC(No.BJRC2021-04) Natural Science Foundation of Chongqing Science and Technology Commission,PRC(No.#cstc2018jcyjAX0088) 

主　　题：Angiogenesis BMP9 Bone tissue engineering LncRNA H19 Mesenchymal stem cells 

摘      要：BMP9 mediated osteogenic differentiation mechanisms of MSCs were widely explored, however, mechanisms of BMP9-induced angiogenesis still need to be clarified. We previously characterized that Notch1 promoted BMP9-induced osteogenesis–angiogenesis coupling process in mesenchymal stem cells (MSCs). Here, we explored the underlying mechanisms of lncRNA H19 (H19) mediated regulation of BMP9-induced angiogenesis through activating Notch1 signaling. We demonstrated that basal expression level of H19 was high in MSCs, and silencing H19 attenuates BMP9-induced osteogenesis and angiogenesis of MSCs both in vitro and in vivo. Meanwhile, we identified that BMP9-induced production of CD31+ cells was indispensable for BMP9-induced bone formation, and silencing H19 dramatically blocked BMP9-induced production of CD31^(+) cells. In addition, we found that down-regulation of H19 inhibited BMP9 mediated blood vessel formation and followed subsequent bone formation in vivo. Mechanistically, we clarified that H19 promoted p53 phosphorylation by direct interacting and phosphorylating binding, and phosphorylated p53 potentiated Notch1 expression and activation of Notch1 targeting genes by binding on the promoter area of Notch1 gene. These findings suggested that H19 regulated BMP9-induced angiogenesis of MSCs by promoting the p53-Notch1 angiogenic signaling axis.