ECM-Focused Proteomic Analysis of Ear Punch Regeneration in Acomys cahirinus

While significant acute injury leads to a functionally deficient fibrotic scar in mammals, the spiny mouse Acomys cahirinus has evolved scar-free regeneration of severely damaged tissue. Extracellular matrix (ECM) composition is a critical regulator of wound repair, and previous studies have suggested that alterations in its expression may be responsible for the differences in regenerative capacity observed between Mus musculus and A. cahirinus, yet analysis of this critical tissue component has been limited in previous studies by its insolubility. Here, we utilize a two-step ECM-optimized extraction to perform proteomic analysis of tissue composition during wound repair after full-thickness ear punches in A. cahirinus and M. musculus from weeks 1 to 4 postinjury. We observe changes in various ECM proteins implicated in wound regeneration and fibrosis, including collagens, provisional matrix, coagulation proteins, and matricryptic signaling domains. We additionally report differences in cross-linking enzyme activity and ECM protein solubility between species. Furthermore, we observed rapid and sustained increases in pro-regenerative macrophage markers in Acomys but not in Mus. Together, these findings indicate that ECM differences contribute to the pro-regenerative restoration of functional tissue seen in Acomys and implicate potential targets for future therapies to attenuate scar formation in other mammals.