Endogenous network modeling reveals mechanisms of repair Schwann cell decline and potential recovery targets

Abstract Schwann cells, the principal glial cells of the peripheral nervous system, play a central role in nerve repair following injury. Upon injury, mature Schwann cells dedifferentiate into repair Schwann cells. These processes are governed by complex gene regulatory networks, yet the quantitative dynamics of these processes remain unclear. Here, using a bottom-up systems biology approach, we constructed an endogenous regulatory network model based on experimentally validated interactions, without relying on high-throughput data as input. The model captures Schwann cell dedifferentiation dynamics and reveals a potential landscape composed of stable states and intermediate transition states. Simulations recapitulate post-injury trajectories and confirm the role of c-Jun upregulation in maintaining repair capacity. Furthermore, the model predicts multiple potential therapeutic targets, including P53, JNK, and PTEN, for sustaining repair competence. We also identify intrinsic heterogeneity within repair Schwann cells and uncover key transition states that simultaneously connect repair-competent cells to both repair-deficient and apoptotic phenotypes, indicating that these intermediate states may represent critical regulatory bottlenecks and key cellular targets for improving the success of peripheral nerve regeneration. Overall, this work provides new insights into the precise regulation of Schwann cell fate and establishes a theoretical framework for regenerative medicine and clinical strategies in peripheral nerve repair. Competing Interest Statement The authors have declared no competing interest.