Skin regeneration is enabled in the absence of fibroblast inflammatory priming

In adult mammals, skin wound healing has evolved to favor rapid repair through the formation of fibrotic scar. These dermal scars are dysfunctional and may lead to chronic disfigurement and disability, yet the biologic mechanisms that drive fibrosis and prevent tissue regeneration remain unknown. Here, we report that reindeer (<i>R</i><i>angifer tarandus</i>) antler velvet exhibits regenerative wound healing, whereas identical full-thickness injury in dorsal back skin of the same animal forms fibrotic scar. This regenerative capacity is retained even following ectopic transplantation of velvet to a scar-forming site, demonstrating that this latent regenerative capacity is innate to velvet cells and independent of local factors derived from the growing antler. Single cell RNA-sequencing of uninjured skin revealed a marked divergence in resting fibroblast transcriptional states and immunomodulatory function. Uninjured velvet fibroblast shared a striking resemblance with human fetal fibroblasts whereas uninjured back skin fibroblasts exhibited an overrepresentation of pro-inflammatory genes resembling adult human fibroblasts. Identical skin injury resulted in site-specific fibroblast polarization; back fibroblasts exacerbated the inflammatory response, whereas velvet fibroblasts adopted an immunosuppressive state and reverted back to a regeneration-competent ground state. Consequently, velvet wounds exhibited an accelerated adoption of anti-inflammatory immune states and an expedited resolution of immune response. This study demonstrates reindeer as a novel comparative mammalian model to study both adult skin regeneration (velvet) and scar formation (back skin) within the same animal. Our study underscores the importance of fibroblast heterogeneity in shaping local immune cell functions that ultimately polarize wound healing outcomes. Purposeful, acute modulation of fibroblast-mediated immune signaling represents an important therapeutic avenue to mitigate scar and improve wound healing.在成年哺乳动物中，皮肤伤口愈合已演化出通过纤维化瘢痕（fibrotic scar）形成以实现快速修复的策略。此类真皮瘢痕功能异常，可能引发慢性畸形与残疾，但驱动纤维化并阻碍组织再生的生物学机制仍未明确。本研究发现，驯鹿（*Rangifer tarandus*）的鹿茸绒膜展现出再生性伤口愈合，而同一动物背部皮肤的全层皮肤损伤（full-thickness injury）则会形成纤维化瘢痕。即使将鹿茸绒膜进行异位移植（ectopic transplantation）至瘢痕形成部位，其再生能力仍得以保留，这表明这种潜在的再生能力是绒膜细胞固有的，且不依赖于生长中的鹿茸所产生的局部因子。对未受损皮肤的单细胞RNA测序（single cell RNA-sequencing）显示，静息成纤维细胞的转录状态与免疫调节功能存在显著差异。未受损的鹿茸绒膜成纤维细胞与人类胎儿成纤维细胞具有惊人的相似性，而未受损的背部皮肤成纤维细胞则高表达促炎基因，其特征与成年人类成纤维细胞类似。相同的皮肤损伤会导致成纤维细胞发生位点特异性极化：背部成纤维细胞会加剧炎症反应，而鹿茸绒膜成纤维细胞则会呈现免疫抑制状态，并恢复至具备再生能力的基础状态。因此，鹿茸绒膜的伤口会更快地转向抗炎免疫状态，并加速免疫反应的消退。本研究证明，驯鹿可作为一种新型的比较哺乳动物模型，在同一动物体内同时研究成年皮肤再生（鹿茸绒膜）与瘢痕形成（背部皮肤）。我们的研究强调了成纤维细胞异质性在塑造局部免疫细胞功能中的重要性，而后者最终决定了伤口愈合的结局。有针对性地急性调控成纤维细胞介导的免疫信号通路，或是减轻瘢痕形成、改善伤口愈合的重要治疗方向。