Laboratory of Tissue Engineering and Stem Cell, Department of Histology and Embryology, Chongqing Medical University, Chongqing, People's Republic of China.
Mol Biol Rep. 2022 Aug;49(8):7263-7273. doi: 10.1007/s11033-022-07508-9. Epub 2022 May 20.
Oligodendrocyte precursor cells (OPCs) can proliferate and differentiate into oligodendrocytes, the only myelin-forming cells in the central nervous system. Proliferating OPCs promotes remyelination in neurodegenerative diseases. Astrocytes (ASTs) are the most widespread cells in the brain and play a beneficial role in the proliferation of OPCs. Connexin 47 (Cx47) is the main component of AST-OPC gap junctions to regulate OPC proliferation. Nonetheless, the specific mechanism remains unclear.
This study investigates the proliferation mechanism of OPCs connected to ASTs via Cx47. Cx47 siRNA significantly inhibited OPCs from entering the proliferation cycle. Transcriptome sequencing of OPCs and gene ontology enrichment analysis revealed that ASTs enhanced the exosome secretion by OPCs via Cx47. Transmission electron microscopy, Western blot, and nanoparticle tracking analysis indicated that the OPC proliferation was related to extracellular exosomes. Cx47 siRNA decreased the OPC proliferation and exosome secretion in AST-OPC cocultures. Exogenous exosome supplementation alleviated the inhibitory effect of Cx47 siRNA and significantly improved OPC proliferation. Mass spectrometry revealed that LAMB2 was abundant in exosomes. The administration of exogenous LAMB2 induced DNA replication in the S phase in OPCs by activating cyclin D1.
Collectively, ASTs induce the secretion of exosomes that carry LAMB2 by OPCs via Cx47 to upregulate cyclin D1 thereby accelerating OPC proliferation.
少突胶质前体细胞（OPCs）可以增殖并分化为少突胶质细胞，这是中枢神经系统中唯一形成髓鞘的细胞。增殖的 OPC 可促进神经退行性疾病中的髓鞘再生。星形胶质细胞（ASTs）是大脑中分布最广泛的细胞，在 OPC 的增殖中发挥有益作用。连接蛋白 47（Cx47）是 AST-OPC 缝隙连接的主要组成部分，可调节 OPC 的增殖。然而，其具体机制尚不清楚。
本研究探讨了通过 Cx47 连接的 AST 对 OPC 增殖的机制。Cx47 siRNA 显著抑制 OPC 进入增殖周期。OPC 的转录组测序和基因本体富集分析显示，AST 通过 Cx47 增强 OPC 的外泌体分泌。透射电子显微镜、Western blot 和纳米颗粒跟踪分析表明，OPC 的增殖与细胞外的外泌体有关。Cx47 siRNA 减少了 AST-OPC 共培养物中的 OPC 增殖和外泌体分泌。外源性外泌体补充缓解了 Cx47 siRNA 的抑制作用，并显著改善了 OPC 的增殖。质谱分析显示 LAMB2 在 exosomes 中含量丰富。外源性 LAMB2 的给药通过激活细胞周期蛋白 D1 诱导 OPC 中 S 期的 DNA 复制。
总之，AST 通过 OPC 中的 Cx47 诱导携带 LAMB2 的 exosomes 的分泌，从而上调细胞周期蛋白 D1，加速 OPC 的增殖。
