634 Single cell transcriptomics identifies a two way conversion program between dermal progenitors and adipocytes during skin development and regeneration

Abstract

Dermal white adipose tissue (dWAT) is a unique layer of adipocytes and their fibroblast precursors within the reticular dermis of the skin, and recent studies have found that dWAT plays an essential role in skin development and regeneration. However, little is known how adipocytes are developed from their dermal progenitor and how adipogenesis is controlled during skin regeneration. Here, we performed single-cell RNA-sequencing (scRNA-seq) analyses of dermal fibroblasts (dFBs) isolated from mice at various post-developmental ages. Pseudotime analyses of these dFB clusters identified a Pdgfra+CD24hiThy1loSca1lo population as developmental progenitors for preadipocytes (pAD) and this progenitor population was highly abundant in neonatal skin early in life but declined in adulthood. In contrast, a Pdgfra+Sca1hiDPP4hi adult reticular interstitial (RI) adipocyte progenitor (AP) population that developed postnatally was found in adult skin. ScRNAseq analyses were then performed on dFBs from wounded skin to determine the cell fate and role of these adult RI-APs during skin regeneration. Pseudotime analysis and immunofluorescence analysis of wounded skin showed that RI-APs rapidly infiltrated the wound center and gave rise to pAD/AD and/or myofibroblasts during early stages of wound healing, contributing to dermal regeneration. Pathway analyses revealed that this two way conversion between dermal progenitors and pAD/AD was dynamically regulated by an interplay between the WNT, TGFβ and NFKB pathways. Together, our results have identified and defined the developmental pathways that shape adipogenesis from dermal progenitors during skin development and regeneration. These results provide insights into how defective adipocyte progenitor function and adipogenesis may be associated with defective wound healing associated with aging and diabetes and/or fibrotic diseases such as keloid scarring.