肝细胞生长因子在骨髓间充质干细胞诱导脊髓损伤大鼠恢复中的作用。
The role of hepatocyte growth factor in mesenchymal stem cell-induced recovery in spinal cord injured rats.
机构信息
Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Shushan District, Hefei City, Anhui Province, China.
Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
出版信息
Stem Cell Res Ther. 2020 May 14;11(1):178. doi: 10.1186/s13287-020-01691-x.
BACKGROUND
Mesenchymal stem cells (MSCs) have become a promising treatment for spinal cord injury (SCI) due to the fact that they provide a favorable environment. Treatment using MSCs results in a better neurological functional improvement through the promotion of nerve cell regeneration and the modulation of inflammation. Many studies have highlighted that the beneficial effects of MSCs are more likely associated with their secreted factors. However, the identity of the factor that plays a key role in the MSC-induced neurological functional recovery following SCI as well as its molecular mechanism still remains unclear.
METHODS
A conditioned medium (collected from the MSCs) and hepatocyte growth factor (HGF) were used to test the effects on the differentiation of neural stem cells (NSCS) in the presence of BMP4 with or without a c-Met antibody. In SCI rats, Western blot, ELISA, immunohistochemistry, and hematoxylin-eosin staining were used to investigate the biological effects of MSC-conditioned medium and HGF on nerve cell regeneration and inflammation with or without the pre-treatment using a c-Met antibody. In addition, the possible molecular mechanism (cross-talk between HGF/c-Met and the BMP/Smad 1/5/8 signaling pathway) was also detected by Western blot both in vivo and in vitro.
RESULTS
The conditioned medium from bone marrow-derived MSCs (BMSCs) was able to promote the NSC differentiation into neurons in vitro and the neurite outgrowth in the scar boundary of SCI rats by inhibiting the BMP/Smad signaling pathway as well as reduces the secondary damage through the modulation of the inflammatory process. The supplementation of HGF showed similar biological effects to those of BMSC-CM, whereas a functional blocking of the c-Met antibody or HGF knockdown in BMSCs significantly reversed the functional improvement mediated by the BMSC-CM.
CONCLUSIONS
The MSC-associated biological effects on the recovery of SCI rats mainly depend on the secretion of HGF.
背景
间充质干细胞（MSCs）因其能提供有利环境而成为治疗脊髓损伤（SCI）的一种很有前途的方法。通过促进神经细胞再生和调节炎症，MSC 治疗可导致更好的神经功能改善。许多研究强调，MSC 的有益作用更可能与其分泌的因子有关。然而，在 SCI 后 MSC 诱导的神经功能恢复中起关键作用的因子的身份及其分子机制仍不清楚。
方法
使用条件培养基（从 MSCs 中收集）和肝细胞生长因子（HGF）在存在 BMP4 的情况下测试其对神经干细胞（NSCS）分化的影响，同时使用或不使用 c-Met 抗体。在 SCI 大鼠中，使用 Western blot、ELISA、免疫组织化学和苏木精-伊红染色来研究 MSC 条件培养基和 HGF 对神经细胞再生和炎症的生物学影响，同时使用 c-Met 抗体进行预处理。此外，通过 Western blot 还在体内和体外检测了 MSC 条件培养基和 HGF 可能的分子机制（HGF/c-Met 与 BMP/Smad 1/5/8 信号通路的串扰）。
结果
骨髓来源的 MSC（BMSCs）的条件培养基能够通过抑制 BMP/Smad 信号通路促进体外 NSC 分化为神经元，并促进 SCI 大鼠瘢痕边界的神经突生长，从而减少通过调节炎症过程产生的二次损伤。HGF 的补充表现出与 BMSC-CM 相似的生物学作用，而 BMSCs 中 c-Met 抗体的功能阻断或 HGF 的敲低则显著逆转了 BMSC-CM 介导的功能改善。
结论
MSC 对 SCI 大鼠恢复的相关生物学作用主要依赖于 HGF 的分泌。
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