Peripheral nerve injury causes Schwann cells (SCs) in the distal nerve to lose contact with the axons of proximal neurons, resulting in their transdifferentiation from a myelinating to repair phenotype (Shlomo, 2011; Martini et al., 2008; Clements et al., 2017; Arthur-Farraj et al., 2017). As a result of the repair phenotype SCs, a series of repair functions are initiated, including producing neurotrophic factors, promoting the survival of injured neurons and axon growth, triggering myelin decomposition, and recruiting macrophages for myelin phagocytosis and clearance (Jessen and Arthur-Farraj, 2019; Jessen and Mirsky, 2008; Chen et al., 2007; Jessen et al., 2015). In their study, Clements et al. showed that the transformation of SCs into a repair phenotype after peripheral nerve injury exhibits characteristics of epithelial-mesenchymal transition (EMT), and transforming growth factor β-1 (TGFβ-1) in the post-injury microenvironment triggers SCs to undergo EMT (Clements et al., 2017). During the early phase of nerve healing, TGFβ-1 promotes a series of events like the sorting of SCs and the deposition of matrix proteins. Unfortunately, due to various factors, the distal stump is unable to connect to the proximal axon in time to enter the chronic denervation state. As a result, TGFβ-1 can be continuously expressed at the distal stump, resulting in neurofibrogenesis and scar formation (Ghosh et al., 2020; Wang et al., 2018), which has become a considerable barrier to nerve regeneration (Wale and Tessa, 2013; Stone et al., 2016; Sulaiman and Gordon, 2009). Taking TGFβ-1 as the target, the application of anti-TGFβ-1 antibody can reduce scar formation. However, antibody application may inhibit the physiological function of SCs, which will negatively affect nerve regeneration (Atkins et al., 2006). Therefore, the mechanism of continuous expression of TGFβ-1 at the distal stump during chronic injury needs to be further understood in order to solve the contradiction between nerve regeneration and fibrosis without affecting regeneration.

In unilateral ureteral obstruction, Grande et al. found that TGFβ-1 induced the expression of Snai2 and activated EMT, and then the EMT state of the renal tubular epithelial cells upregulated the expression of TGFβ-1. Such a positive feedback effect maintained the EMT state of the renal epithelial cells, and therefore fibrosis developed (Grande et al., 2015). The maintenance of EMT status and the continuous expression of TGFβ-1 are considered to be critical elements of fibrosis in many tissues and organs (Su et al., 2020; Zhang et al., 2014; Katsuno and Derynck, 2021; Shu and Lovicu, 2017; Quaggin and Kapus, 2011). Due to the long healing time, in the case of skin injuries with large wounds, epithelial cells continue to secrete a large amount of matrix protein as they transform into mesenchymal cells, resulting in severe fibrosis and scarring (Shu and Lovicu, 2017). Accordingly, we speculate that during chronic peripheral nerve injury, TGFβ-1 in the microenvironment induces cells in the distal nerve to increase the expression of transcription factors related to EMT, maintaining the EMT state (Craene and Berx, 2013; David et al., 2016; Janda et al., 2002; Horiguchi et al., 2009). Consequently, mesenchymal cellssecrete TGFβ-1 to the surrounding environment, further enhancing EMT state and the expression of TGFβ-1, and inducing the progression of neurofibrosis (Su et al., 2020).

As demonstrated in our previous studies, reinnervation of axons after MNs transplantation can re-myelinate SCs at the distal stump of injured nerves, and removal of transplanted neurons can dedifferentiate SCs into repair phenotypes again, suggesting that SCs are capable of converting phenotypes repeatedly (Fang et al., 2019). Taking all these into account, we hypothesized that the conversion of SCs repair phenotype to myelination phenotype may be an internal result of EMT. Using MNs for transplantation could reverse EMT, reduce TGFβ-1 expression, and alleviate fibrosis. Upon removal of transplanted MNs, the distal stump of injured nerve initiated EMT and upregulated the expression of TGFβ-1 again. By using this strategy, the expression of TGFβ-1 will be precisely regulated, that is, the EMT state and TGFβ-1 expression of the distal nerve will be modified by transplanting or removing MNs according to clinical needs.

By tracking the EMT status at the distal stump of injured nerve in the process of chronic degeneration, this study aims to expand the understanding of neurofibrosis and find new therapeutic targets and methods.