Human breast milk as a bioactive material platform enabling scarless skin regeneration via macrophage reprogramming and myofibroblast heterogeneity

Abstract

The regulation of the immune system and promotion of myofibroblast heterogeneity in wounds are crucial for developing scar-reducing treatments. Currently, no approved multifaceted drug exists that can fully inhibit fibrosis. In this study, we explore the beneficial effects of human breast milk (HBM), focusing on its ability to regulate the macrophage phenotype and function, and promote myofibroblast heterogeneity to inhibit skin scar formation. Drawing inspiration from the scarless healing observed in fetuses, we utilize HBM to treat full-thickness cutaneous wounds. Our in vitro and in vivo experiments demonstrate that HBM, applied as a spray or in combination with a thermosensitive hydrogel, significantly increases M2 macrophage recruitment by at least 33.5% and enhanced angiogenic responses by up to 98.1%, while also improving skin stiffness and elasticity. Furthermore, we observe that HBM facilitates the formation of more neogenic hair follicles by activating the insulin-like growth factor 1 (IGF1) and platelet-derived growth factor C (PDGFC) signaling pathways in macrophages. This activation subsequently triggers BMP signaling, which stimulates adipocytes and promotes myofibroblast heterogeneity, resulting in normalized wound healing. These findings suggest that HBM holds significant potential for various medical applications, including the development of vascularized tissues, the reduction of stretch marks, and the promotion of wound regeneration without scarring. This study highlights the promising role of HBM in advancing regenerative medicine and tissue engineering.