Dedifferentiated Schwann cell-derived TGF-β3 is essential for the neural system to promote wound healing

Abstract

Rationale: Wound healing is among the most complicated physiological processes and requires the synchronization of various cell types with distinct roles to re-establish the condition of the original skin. Patients affected by peripheral neuropathies often experience failure to heal. Loss of Schwann cells (SCs), a crucial population of peripheral nervous system cells in skin, may contribute to chronic wounds. However, the role of SCs in wound healing are poorly understood. Methods: The activity of SCs was investigated by using a cell atlas of the wound healing process, which was generated by integrating single-cell RNA sequencing (scRNA-seq) libraries covering different states of mouse back skin. The results of in silico analysis were validated by in vitro cell culture and in vivo mouse model. Selective inhibitors and conditional RNAi by virus transfection were utilized to investigate the role of SCs in wound healing. Findings from mouse experiments were further verified in scRNA-seq analysis of diabetic patients. Results: Our in silico analysis revealed the heterogeneous cellular components of skin and the dynamic interactions of neural crest derived cells (NCs) with other cell types. We found that SCs dedifferentiated at an early stage of wound repair with upregulated Wnt signaling. We also identified dedifferentiated SC (dSC) defect in diabetic wounds in both mouse and human. Wnt inhibition at the wound site repressed SC dedifferentiation, leading to defective repair. Furthermore, dSCs derived TGF-β3, which is context-dependent, promoted the migration of fibroblasts and keratinocytes. Moreover, TGF-β3 supplementation enhanced the healing of chronic wounds in diabetic mice with impaired SCs. Conclusion: Our study thus advances the understanding of the roles of neural-derived cells in skin regeneration and suggests a potential therapeutic strategy for wound healing disorders.

Human Parathyroid Hormone Analog (3–34/29–34) promotes wound re-epithelialization through inducing keratinocyte migration and epithelial–mesenchymal transition via PTHR1-PI3K/AKT activation

“…The potential signaling activation by MY-1 in keratinocytes was then investigated. It was reported that numerous signaling pathways were involved in the re-epithelialization process, among which Wnt, TGF-β/Smads, and PI3K/AKT signaling were studied in depth [ 29 , 33 – 36 ]. For PTH and analogs, however, the potential downstream signaling pathways by which they activated keratinocytes remain unclear.…”

Diminished schwann cell repair responses play a role in delayed diabetes-associated wound healing

“…We found that, unlike that in SCs from wounded normal control mice, the expressions of p75 and c-jun, induced markers of the repair cell phenotype, were delayed in SCs at the wound site after skin injury of diabetic mice. Similarly, Pierson et al ( Ou et al, 2022 )found that the expression of p75 in SCs was delayed and attenuated in diabetic rats after sciatic nerve crush injury, which may contribute to impaired peripheral nerve regeneration. Similar to our study, Ou et al (2022) found that fewer dedifferentiated SCs recognized by Sox2 expression were observed in the mice with streptozotocin (STZ)-induced diabetes (C57-STZ) wounds than in the C57 wounds, which indicated dysfunction of SC repair responses during diabetic wound healing.…”

“…Multiple genes are reported to be unregulated, and numerous transcriptional pathways are activated during SC reprogramming. The primary players that control and regulate the repair processes include c-Jun, the mitogen-activated protein kinase (MAPK) pathways, Sonic Hedgehog (Shh), chromatin modifications, Wnt signaling, and the Raf/MEK/ERK signaling pathway ( Napoli et al, 2012 ; Nocera and Jacob, 2020 ; Ou et al, 2022 ). A crucial transcription factor in the reprogramming of the SC and the response to peripheral nerve damage is c-Jun.…”

Cell Heterogeneity and Variability in Peripheral Nerve after Injury

“…Additionally, the development-like transcriptional state of SCs is also identified in dermal regeneration. The deficiency of dedifferentiated SCs (dSCs) exists in diabetic wounds both in mice and humans, and increasing dSC activity through TGF-β3 can promote early wound healing [ 32 ]. Contrasted to normal skin, the number of SCs significantly increases in keloid as well as surrounding skins.…”