Acellular nerve grafts supplemented with induced pluripotent stem cell-derived exosomes promote peripheral nerve reconstruction and motor function recovery

• Published in: Bioactive materials 2022-09, Vol.15, p.272-287
• Main Authors: Pan, Jianfeng, Zhao, Meng, Yi, Xiangjiao, Tao, Jianguo, Li, Shaobo, Jiang, Zengxin, Cheng, Biao, Yuan, Hengfeng, Zhang, Feng
• Format: Article
• Language: English
• Subjects: Acellular nerve grafts; Exosomes; Induced pluripotent stem cells; Motor function recovery; Peripheral nerve reconstruction
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2021.12.004

Peripheral nerve injury is a great challenge in clinical work due to the restricted repair gap and weak regrowth ability. Herein, we selected induced pluripotent stem cells (iPSCs) derived exosomes to supplement acellular nerve grafts (ANGs) with the aim of restoring long-distance peripheral nerve defects. Human fibroblasts were reprogrammed into iPSCs through non-integrating transduction of Oct3/4, Sox2, Klf4, and c-Myc. The obtained iPSCs had highly active alkaline phosphatase expression and expressed Oct4, SSEA4, Nanog, Sox2, which also differentiated into all three germ layers in vivo and differentiated into mature peripheral neurons and Schwann cells (SCs) in vitro. After isolation and biological characteristics of iPSCs-derived exosomes, we found that numerous PKH26-labeled exosomes were internalized inside SCs through endocytotic pathway and exhibited a proliferative effect on SCs that were involved in the process of axonal regeneration and remyelination. After that, we prepared ANGs via optimized chemical extracted process to bridge 15 mm long-distance peripheral nerve gaps in rats. Owing to the promotion of iPSCs-derived exosomes, satisfactory regenerative outcomes were achieved including gait behavior analysis, electrophysiological assessment, and morphological analysis of regenerated nerves. Especially, motor function was restored with comparable to those achieved with nerve autografts and there were no significant differences in the fiber diameter and area of reinnervated muscle fibers. Taken together, our combined use of iPSCs-derived exosomes with ANGs demonstrates good promise to restore long-distance peripheral nerve defects, and thus represents a cell-free strategy for future clinical applications. Acellular nerve grafts (ANGs) supplemented with iPSCs-derived exosomes were used to promote peripheral nerve repair of 15-mm gap and motor function recovery through internalization process. [Display omitted] •IPSCs-derived exosomes provide a novel cell-free strategy with the regenerative power of iPSCs.•ANGs supplemented with iPSCs-derived exosomes show enhanced peripheral repair and accelerated motor functional recovery.•IPSCs-derived exosomes provide equivalent histological morphology to autologous nerve transplantation.