Comparative transcriptomic analysis of dermal wound healing reveals de novo skeletal muscle regeneration in Acomys cahirinus

The African spiny mouse, Acomys spp., is capable of scar-free dermal wound healing. Here, we have performed a comprehensive analysis of gene expression throughout wound healing following full-thickness excisional dermal wounds in both Acomys cahirinus and Mus musculus. Additionally, we provide an annotated, de novo transcriptome assembly of A. cahirinus skin and skin wounds. Using a novel computational comparative RNA-Seq approach along with pathway and co-expression analyses, we identify enrichment of regeneration associated genes as well as upregulation of genes directly related to muscle development or function. Our RT-qPCR data reveals induction of the myogenic regulatory factors, as well as upregulation of embryonic myosin, starting between days 14 and 18 post-wounding in A. cahirinus. In contrast, the myogenic regulatory factors remain downregulated, embryonic myosin is only modestly upregulated, and no new muscle fibers of the panniculus carnosus are generated in M. musculus wounds. Additionally, we show that Col6a1, a key component of the satellite cell niche, is upregulated in A. cahirinus compared to M. musculus. Our data also demonstrate that the macrophage profile and inflammatory response is different between species, with A. cahirinus expressing significantly higher levels of Il10. We also demonstrate differential expression of the upstream regulators Wnt7a, Wnt2 and Wnt6 during wound healing. Our analyses demonstrate that A. cahirinus is capable of de novo skeletal muscle regeneration of the panniculus carnosus following removal of the extracellular matrix. We believe this study represents the first detailed analysis of de novo skeletal muscle regeneration observed in an adult mammal.非洲刺小鼠（African spiny mouse，*Acomys* spp.）具备无瘢痕皮肤伤口愈合能力。本研究对开罗刺鼠（*Acomys cahirinus*）与小家鼠（*Mus musculus*）实施全层切除性皮肤伤口造模后，对其伤口愈合全过程进行了全面的基因表达分析。此外，本研究还提供了开罗刺鼠皮肤及伤口组织的注释版从头转录组组装（de novo transcriptome assembly）结果。本研究采用一种全新的计算比较RNA测序（RNA-Seq）分析方法，结合通路分析与共表达分析，鉴定出再生相关基因的富集现象，同时发现与肌肉发育或功能直接相关的基因出现表达上调。实时定量逆转录PCR（RT-qPCR）数据显示，在开罗刺鼠中，肌源性调节因子（myogenic regulatory factors）以及胚胎肌球蛋白（embryonic myosin）的表达在伤后14至18天开始被诱导上调。与之相反，小家鼠伤口中的肌源性调节因子仍处于下调状态，胚胎肌球蛋白仅出现轻度上调，且未生成肉膜肌（panniculus carnosus）的新生肌纤维。此外，本研究发现，作为卫星细胞生态位（satellite cell niche）关键组分的*Col6a1*基因，在开罗刺鼠中的表达水平显著高于小家鼠。本研究数据还表明，两个物种的巨噬细胞表型与炎症反应存在显著差异，开罗刺鼠的*Il10*基因表达水平显著更高。本研究同时证实，伤口愈合过程中上游调控因子*Wnt7a*、*Wnt2*与*Wnt6*的表达存在差异。本研究分析表明，在移除细胞外基质（extracellular matrix）后，开罗刺鼠能够实现肉膜肌的从头骨骼肌再生。我们认为，本研究为首个针对成年哺乳动物骨骼肌从头再生现象的系统性详细分析。