Hepatocyte growth factor facilitates the repair of spinal cord injuries by driving the chemotactic migration of mesenchymal stem cells through the β-catenin/TCF4/Nedd9 signaling pathway

作者：Yanan Hu, Huanhuan Chen, Min Yang, Jianwei Xu, Jinming Liu, Qisheng He, Xiaojing Xu, Zhongqing Ji, Ying Yang, Mengwen Yan, Huanxiang Zhang · 发表于：Stem Cells · 年份：2024 · DOI：10.1093/stmcls/sxae055 · 被引用次数：10 · 研究领域：Mesenchymal stem cell research、Spinal Cord Injury Research、Nerve injury and regeneration

Transplanted mesenchymal stem cells (MSCs) can significantly aid in repairing spinal cord injuries (SCIs) by migrating to and settling at the injury site. However, this process is typically inefficient, as only a small fraction of MSCs successfully reach the target lesion area. During SCI, the increased expression and secretion of hepatocyte growth factor (HGF) act as a chemoattractant that guides MSC migration. Nonetheless, the precise mechanisms by which HGF influences MSC migration are not fully understood. This study focused on unraveling the molecular pathways that drive MSC migration toward the SCI site in response to HGF. It was found that HGF can activate β-catenin signaling in MSCs by either phosphorylating LRP6, suppressing GSK3β phosphorylation through the AKT and ERK1/2 pathways, or enhancing the expression and nuclear translocation of TCF4. This activation leads to elevated Nedd9 expression, which promotes focal adhesion formation and F-actin polymerization, facilitating chemotactic migration. Transplanting MSCs during peak HGF expression in injured tissues substantially improves nerve regeneration, reduces scarring, and enhances hind limb mobility. Additionally, prolonging HGF release can further boost MSC migration and engraftment, thereby amplifying regenerative outcomes. However, inhibiting HGF/Met or interfering with β-catenin or Nedd9 signaling significantly impairs MSC engraftment, obstructing tissue repair and functional recovery. Together, these findings...