Abstract
Scars are a serious health concern for burn victims and individuals with skin conditions associated with wound healing. Here, we identify regenerative factors in neonatal murine skin that transforms adult skin to regenerate instead of only repairing wounds with a scar, without perturbing development and homeostasis. Using scRNA-seq to probe unsorted cells from regenerating, scarring, homeostatic, and developing skin, we identified neonatal papillary fibroblasts that form a transient regenerative cell type that promotes healthy skin regeneration in young skin. These fibroblasts are defined by the expression of a canonical Wnt transcription factor Lef1 and using gain- and loss of function genetic mouse models, we demonstrate that Lef1 expression in fibroblasts primes the adult skin macroenvironment to enhance skin repair, including regeneration of hair follicles with arrector pili muscles in healed wounds. Finally, we share our genomic data in an interactive, searchable companion website (https://skinregeneration.org/). Together, these data and resources provide a platform to leverage the regenerative abilities of neonatal skin to develop clinically tractable solutions that promote the regeneration of adult tissue.
Introduction
Understanding how to induce skin regeneration instead of scarring will have broad implications clinically and cosmetically (Walmsley et al., 2015b). One of the main characteristics of scars is the absence of hair follicles, indicating that their regeneration in a wound may be a critical step in achieving scar-less skin repair (Yang and Cotsarelis, 2010). Interestingly, human embryonic skin has the capacity to regenerate without scars (Lo et al., 2012). Similarly, neonatal and adult mouse skin has the capacity to regenerate small non-functional hair follicles under specific conditions (Figure 1c–d; Ito et al., 2007; Rognoni et al., 2016; Telerman et al., 2017). These insights have prompted efforts in the field to define the molecular triggers that promote hair development in skin, with the ultimate goal of devising a way to regenerate fully functional hairs in adult skin wounds as a therapeutic modality (Yang and Cotsarelis, 2010).
