School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Orthopedic Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, Guangdong, China.
Mol Neurobiol. 2024 Dec;61(12):10830-10844. doi: 10.1007/s12035-024-04248-8. Epub 2024 May 25.
Spinal cord injury (SCI) is a severe neurological condition that can lead to paralysis or even death. This study explored the potential benefits of bone marrow mesenchymal stem cell (BMSC) transplantation for repairing SCI. BMSCs also differentiate into astrocytes within damaged spinal cord tissues hindering the cell transplantation efficacy, therefore it is crucial to enhance their neuronal differentiation rate to facilitate spinal cord repair. Wnt5a, an upstream protein in the non-classical Wnt signaling pathway, has been implicated in stem cell migration, differentiation, and neurite formation but its role in the neuronal differentiation of BMSCs remains unclear. Thus, this study investigated the role and underlying mechanisms of Wnt5a in promoting neuronal differentiation of BMSCs both in vivo and in vitro. Wnt5a enhanced neuronal differentiation of BMSCs in vitro while reducing astrocyte differentiation. Additionally, high-throughput RNA sequencing revealed a correlation between Wnt5a and phosphoinositide 3-kinase (PI3K)/protein kinase B(AKT) signaling, which was confirmed by the use of the PI3K inhibitor LY294002 to reverse the effects of Wnt5a on BMSC neuronal differentiation. Furthermore, transplantation of Wnt5a-modified BMSCs into SCI rats effectively improved the histomorphology (Hematoxylin and eosin [H&E], Nissl and Luxol Fast Blue [LFB] staining), motor function scores (Footprint test and Basso-Beattie-Bresnahan [BBB]scores)and promoted neuron production, axonal formation, and remodeling of myelin sheaths (microtubule associated protein-2 [MAP-2], growth-associated protein 43 [GAP43], myelin basic protein [MBP]), while reducing astrocyte production (glial fibrillary acidic protein [GFAP]). Therefore, targeting the Wnt5a/PI3K/AKT pathway could enhance BMSC transplantation for SCI treatment.
脊髓损伤（SCI）是一种严重的神经系统疾病，可导致瘫痪甚至死亡。本研究探讨了骨髓间充质干细胞（BMSC）移植修复 SCI 的潜在益处。BMSCs 也会在受损的脊髓组织内分化为星形胶质细胞，从而阻碍细胞移植的疗效，因此，提高其神经元分化率以促进脊髓修复至关重要。Wnt5a 是非经典 Wnt 信号通路的上游蛋白，与干细胞迁移、分化和神经突形成有关，但它在 BMSC 神经元分化中的作用尚不清楚。因此，本研究在体内和体外研究了 Wnt5a 促进 BMSC 神经元分化的作用及其潜在机制。Wnt5a 增强了 BMSC 的体外神经元分化，同时减少了星形胶质细胞的分化。此外，高通量 RNA 测序显示 Wnt5a 与磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）信号之间存在相关性，PI3K 抑制剂 LY294002 的使用证实了这一点，该抑制剂逆转了 Wnt5a 对 BMSC 神经元分化的影响。此外，将 Wnt5a 修饰的 BMSCs 移植到 SCI 大鼠体内，有效改善了组织形态学（苏木精和伊红[H&E]、尼氏和卢索快速蓝[LFB]染色）、运动功能评分（足迹试验和巴索-比蒂-布雷森汉[BBB]评分），并促进了神经元的产生、轴突的形成和髓鞘的重塑（微管相关蛋白-2[MAP-2]、生长相关蛋白 43[GAP43]、髓鞘碱性蛋白[MBP]），同时减少了星形胶质细胞的产生（胶质纤维酸性蛋白[GFAP]）。因此，靶向 Wnt5a/PI3K/AKT 通路可能增强 BMSC 移植治疗 SCI 的效果。
