Schwann Cells in Development, Regeneration, and Therapeutic Applications: Insights From the Sciatic Nerve Model

The sciatic nerve is the largest nerve in the human body and is frequently affected by lesions, causing pain and even loss of sensitivity. The sciatic nerve injury model provides a robust platform to study the degeneration-regeneration process. In this context, Schwann cells (SC) are central regulators of peripheral nervous system (PNS) development, homeostasis, and regeneration. During development, SC arise from neural crest-derived precursors and undergo tightly regulated lineage progression, culminating in myelinating and non-myelinating phenotypes. This process is orchestrated by coordinated transcriptional, signaling, and epigenetic mechanisms that control radial sorting, differentiation, and myelination. Following nerve injury, SC exhibit remarkable plasticity, reprogramming into a specialized repair phenotype that promotes axonal regeneration through debris clearance, trophic support, immune modulation, and the formation of Büngner bands. This work aims to summarize the known history of the plasticity and functions of SC during nerve development and regeneration. It also aims to highlight the most recent advances regarding the molecular networks underlying SC plasticity, as well as epigenetic regulators that enable dynamic transitions between cellular states. This work also describes the factors compromising nerve regeneration and functional recovery, and summarizes the emerging therapeutic strategies aimed to overcome these limitations by enhancing SC plasticity, modulating the injury microenvironment, and developing alternative cell sources, including stem cell-derived Schwann-like cells. A deeper understanding of SC heterogeneity, lineage dynamics, and regenerative mechanisms will be essential for advancing translational strategies. Collectively, this review underscores the pivotal role of SC in nerve regeneration and highlights innovative approaches to harness their therapeutic potential.