Motor neurons transplantation alleviates neurofibrogenesis during chronic degeneration by reversibly regulating Schwann cells epithelial-mesenchymal transition

A novel understanding of peripheral nerve injury is epithelial-mesenchymal transition (EMT), which characterizes the process of dedifferentiation and transformation of Schwann cells after nerve injury. Despite being regarded as an important mechanism for healing nerve injuries, long-term EMT is the primary cause of fibrosis in other tissue organs. The potential mechanism promoting neurofibrosis in the process of chronic degeneration of nerve injury and the effects of motor neurons (MNs) transplantation on neurofibrosis and repair of nerve injury were studied by transcriptome sequencing and bioinformatics analysis, which were confirmed by in vivo and in vitro experiments. Even 3 months after nerve injury, the distal nerve maintained high levels of transforming growth factor β-1 (TGFβ-1) and Snail family transcriptional repressor 2 (Snai2). The microenvironment TGFβ-1, Snai2 and endogenous TGFβ-1 formed a positive feedback loop in vivo and in vitro, which may contribute to the sustained EMT state and neurofibrogenesis in the distal injured nerve. Inhibiting TGFβ-1 and Snai2 expression and reversing EMT can be achieved by transferring MNs to distal nerves, and the removal of transplanted MNs is capable of reactivating EMT and promoting the growth of proximal axons. In conclusion, EMT persisting can be an explanation for distal neurofibrosis and a potential therapeutic target. By reversibly regulating EMT, MNs transplantation can alleviate neurofibrogenesis of distal nerve in chronic degeneration. As chronic neurodegeneration progresses, a positive feedback loop of “environmental TGFβ-1/ Snai2/ endogenous TGFβ-1” maintains epithelial mesenchymal transformation (EMT) and fibrosis at the distal end of injured nerves, where Snai2 is a key transcription factor. The strategy of transplanting and re-excising motor neurons(MNs) can reversibly regulate the positive feedback loop, thus inhibiting nerve fibrosis and promoting regeneration of axons. [Display omitted] •A long-term EMT state is maintained in the distal nerve after injury, leading to neurofibrosis.•Snai2 and TGFβ-1 formed a positive feedback loop that maintains EMT at the distal nerve.•Motor neurons transplantation suppresses persistent EMT by downregulating Snai2 expression, thereby alleviating neurofibrosis.•Excision of transplanted motor neurons can re-induce EMT at the distal nerve, which facilitates nerve regeneration.