Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
J Cell Physiol. 2019 Aug;234(10):17382-17391. doi: 10.1002/jcp.28360. Epub 2019 Feb 26.
Heterotopic ossification is common in tendon healing after trauma, but the detailed mechanisms remain unknown. Tendon-derived stem cells (TDSCs) are a type of progenitor cell found in the tendon niche, and their incorrect differentiation after trauma may lead to tendon calcification. The expression of hepatocyte growth factor (HGF) presents drastic fluctuations in serum/tissue after trauma and was found to activate quiescent stellate cells and contribute to wound healing; however, its potential role in TDSCs remains elusive. In this study, TDSCs isolated from rats were cultured in media containing HGF with or without a signaling inhibitor, and the proliferation, migration, and differentiation ability of TDSCs were measured to determine the role and mechanism of HGF in TDSCs. We showed that HGF promotes TDSC proliferation and migration but inhibits TDSC osteogenic differentiation ability. HGF activated-HGF/c-Met, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling, which was positively correlated with TDSCs proliferation and migration but negatively related to TDSC osteogenic differentiation ability. The phosphorylation of Smad1/5/8 was also negatively related to HGF/c-Met, MAPK/ERK1/2, and PI3K/AKT signaling, which demonstrated that the inhibition of osteogenic differentiation was dependent on BMP/Smad1/5/8 signaling. Overall, we showed that HGF could promote TDSCs proliferation and migration and inhibit osteogenic differentiation in vitro, suggesting a potential role for HGF as a cytokine treatment of tendon trauma.
异位骨化在创伤后肌腱愈合中很常见，但详细的机制尚不清楚。肌腱源性干细胞（TDSCs）是一种存在于肌腱龛中的祖细胞，它们在创伤后的不正确分化可能导致肌腱钙化。肝细胞生长因子（HGF）在创伤后血清/组织中的表达呈现出剧烈波动，被发现可激活静止的星状细胞并有助于伤口愈合；然而，其在 TDSCs 中的潜在作用仍不清楚。在这项研究中，从大鼠中分离出的 TDSCs 在含有 HGF 的培养基中进行培养，有或没有信号抑制剂，并测量 TDSCs 的增殖、迁移和分化能力，以确定 HGF 在 TDSCs 中的作用和机制。我们表明，HGF 促进 TDSC 的增殖和迁移，但抑制 TDSC 的成骨分化能力。HGF 激活 HGF/c-Met、丝裂原活化蛋白激酶（MAPK）/细胞外信号调节蛋白激酶 1 和 2（ERK1/2）和磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）信号通路，这与 TDSC 的增殖和迁移呈正相关，但与 TDSC 的成骨分化能力呈负相关。Smad1/5/8 的磷酸化也与 HGF/c-Met、MAPK/ERK1/2 和 PI3K/AKT 信号通路呈负相关，这表明成骨分化的抑制依赖于 BMP/Smad1/5/8 信号通路。总体而言，我们表明 HGF 可在体外促进 TDSCs 的增殖、迁移和抑制成骨分化，提示 HGF 作为一种细胞因子治疗肌腱创伤的潜力。
