Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China.
Int J Mol Sci. 2018 Mar 5;19(3):734. doi: 10.3390/ijms19030734.
Absence of effective therapeutic methods for avascular necrosis of femoral head (ANFH) is still perplexing the world's medical community. Bone marrow mesenchymal stem cells (BMSCs) adoptive cell therapy combined with core decompression is a promising modality, which is highly dependent on the cellular activities of BMSCs. Hepatocyte growth factor (HGF) is a survival factor for BMSCs, yet the underlying mechanism is not fully elucidated. In this study, the effects of multiplicity of infections (MOIs) of recombinant adenovirus carrying HGF gene (rAd-HGF) on human BMSC proliferation and osteogenic differentiation were systemically examined. Infection of rAd-HGF produced secretory HGF and promoted hBMSC proliferation in a MOI-dependent manner, while the osteogenesis was also strengthened as indicated by enhanced calcium nodule formation with the strongest effects achieved at MOI = 250. Blocking the activities of c-MET or its downstream signaling pathways, WNT, ERK1/2, and PI3K/AKT led to differential consequents. Specifically, blockage of the WNT pathway significantly promoted osteogenic differentiation, which also showed additive effects when combined application with rAd-HGF. Our data demonstrated the pro-osteogenic effects of optimized MOIs of rAd-HGF, while inhibition of WNT pathway or activation of PI3K/AKT pathway may act as candidate adjuvant modalities for promoting osteogenic differentiation in rAd-HGF-modified hBMSC treatment on ANFH.
股骨头缺血性坏死（ANFH）缺乏有效的治疗方法，仍然困扰着世界医学界。骨髓间充质干细胞（BMSCs）过继细胞疗法联合核心减压是一种很有前途的方法，它高度依赖于 BMSCs 的细胞活性。肝细胞生长因子（HGF）是 BMSCs 的生存因子，但作用机制尚未完全阐明。在这项研究中，系统地研究了携带 HGF 基因的重组腺病毒（rAd-HGF）的多重感染（MOIs）对人 BMSC 增殖和成骨分化的影响。rAd-HGF 的感染产生了分泌型 HGF，并以 MOI 依赖性方式促进 hBMSC 的增殖，同时成骨也得到了增强，表现为钙结节形成增强，MOI = 250 时效果最强。阻断 c-MET 或其下游信号通路 WNT、ERK1/2 和 PI3K/AKT 的活性会导致不同的后果。具体而言，阻断 WNT 通路显著促进成骨分化，当与 rAd-HGF 联合应用时也表现出相加作用。我们的数据表明，rAd-HGF 的优化 MOIs 具有促成骨作用，而抑制 WNT 通路或激活 PI3K/AKT 通路可能成为促进 rAd-HGF 修饰的 hBMSC 治疗 ANFH 中成骨分化的候选辅助方式。
