Partial Reprogramming in Senescent Schwann Cells Enhances Peripheral Nerve Regeneration via Restoration of Stress Granule Homeostasis

Abstract Partial reprogramming (pulsed expression of reprogramming transcription factors) ameliorates multiple tissue functions in aged mice; however, its impact on peripheral nerve regeneration remains largely unexplored. In this study, the temporal dynamics of Schwann cells following sciatic nerve injury in young and aged rats are systematically examined using single‐cell transcriptomics to identify a Runx2 + cell population highly enriched with stress granules as transitional homeostatic cells during Schwann cell differentiation. It is found that pathological accumulation of this cluster during axonal regeneration constitutes a critical contributing factor to impaired neural repair in aging. Intriguingly, partial reprogramming enhances axonal regeneration and attenuates senescence‐associated phenotypes and functional deficits in aged Schwann cells, demonstrating that partial reprogramming promotes peripheral nerve regeneration through Schwann cell rejuvenation. Mechanistically, aged Schwann cells exhibit a stress granule homeostatic imbalance, characterized by compromised formation and impaired degradation, which is effectively reset by partial reprogramming. Importantly, this homeostatic resetting ameliorated the pathological aggregation of Runx2 + Schwann cells during nerve repair in aged rats. The findings reveal that dysregulated stress granule homeostasis drives the pathological accumulation of Runx2 + Schwann cells, representing a key mechanism underlying age‐related axonal regeneration deficits in peripheral nerve repair. This study establishes that partial reprogramming can restore this critical cellular homeostasis and enhance peripheral nerve regeneration during aging.