Type III Collagen Regulates Matrix Architecture and Mechanosensing during Wound Healing

Postnatal cutaneous wound healing is characterized by development of a collagen-rich scar lacking the architecture and functional integrity of unwounded tissue. Directing cell behaviors to efficiently heal wounds while minimizing scar formation remains a major wound management goal. In this study, we demonstrate type III collagen (COL3) as a critical regulator of re-epithelialization and scar formation during healing of COL3-enriched, regenerative (Acomys), scar-permissive (CD-1 Mus and wild-type Col3^B6/B6 mice) and COL3-deficient, scar-promoting (Col3^F/F, a murine conditional knockdown model) cutaneous wound models. We define a scar-permissive fibrillar collagen architecture signature characterized by elongated and anisotropically aligned collagen fibers that is dose-dependently suppressed by COL3. Furthermore, loss of COL3 alters how cells interpret their microenvironment-their mechanoperception-such that COL3-deficient cells display mechanically active phenotypes in the absence of increased microenvironmental stiffness through the upregulation and engagement of the profibrotic integrin α11. Further understanding COL3's role in regulating matrix architecture and mechanoresponses may inform clinical strategies that harness proregenerative mechanisms.