Exosomes from miRNA-378-modified adipose-derived stem cells prevent glucocorticoid-induced osteonecrosis of the femoral head by enhancing angiogenesis and osteogenesis via targeting miR-378 negatively regulated suppressor of fused (Sufu)

Stem Cell Research & Therapy

Kang Liu¹  Zilong Geng²  Dong Li²  Lihong Fan²  Kai Nan²  Yuankai Zhang²  Xin Zhang²  Donglong Shang²  Zhaopu Jing²  Yan Zhao² 

[1] Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 710004, Xi’an, Shaanxi Province, People’s Republic of China;Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, 710004, Xi’an, Shaanxi Province, People’s Republic of China;

关键词: miR-378;    Exosomes;    ASCs;    ONFH;    Sufu;    Shh signaling;   

DOI  :  10.1186/s13287-021-02390-x

来源: Springer

【 摘 要 】

BackgroundLocal ischemia and defective osteogenesis are implicated in the progression of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Recent studies have revealed that exosomes released from adipose-derived stem cells (ASCs) play important roles in ONFH therapy. The present study aimed to investigate whether exosomes derived from miR-378-overexpressing ASCs (miR-378-ASCs-Exos) could promote angiogenesis and osteogenesis in GC-induced ONFH.MethodsIn vitro, we investigated the osteogenic potential of miR-378-ASCs-Exos on bone marrow stromal cells (BMSCs) by alkaline phosphatase staining and western blotting. The angiogenic effects of miR-378-ASCs-Exos on human umbilical vein endothelial cells (HUVECs) were examined by evaluating their proliferation, migration, and tube-forming analyses. We identified the underlying mechanisms of miR-378 in osteogenic and angiogenic regulation. In addition, an ONFH rat model was established to explore the effects of miR-378-ASCs-Exos through histological and immunohistochemical staining and micro-CT in vivo.ResultsAdministration of miR-378-ASCs-Exos improved the osteogenic and angiogenic potentials of BMSCs and HUVECs. miR-378 negatively regulated the suppressor of fused (Sufu) and activated Sonic Hedgehog (Shh) signaling pathway, and recombinant Sufu protein reduced the effects triggered by miR-378-ASCs-Exos. In vivo experiments indicated that miR-378-ASCs-Exos markedly accelerated bone regeneration and angiogenesis, which inhibited the progression of ONFH.ConclusionOur study indicated that miR-378-ASCs-Exos enhances osteogenesis and angiogenesis by targeting Sufu to upregulate the Shh signaling pathway, thereby attenuating GC-induced ONFH development.

【 授权许可】

CC BY