Distinct fibroblast lineages determine dermal architecture in skin development and repair

Abstract

Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibers of the extracellular matrix (ECM)1. Even within a single tissue fibroblasts exhibit remarkable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle (APM), which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesise the bulk of the fibrillar ECM, and the pre-adipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialisation. Epidermal beta-catenin activation stimulates expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECM-rich scar tissue that lacks hair follicles2-4. They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease.

Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells

“…Lrig1 and Dlk1 are expressed in the upper and lower dermis, respectively, during skin development. Those different populations have different hair follicle-regenerative abilities during reconstitution (32). In the present study, RNA-seq data showed that Dlk1 expression was quickly lost at day 1, and Lrig1 was decreased but was maintained at a certain level during culture, indicating that the dermal cells of the reconstituted skin originated from the upper dermis (SI Appendix, Fig.…”

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease

“…It is generally believed that positional skin identity is regulated by epithelial (keratinocytes) and mesenchymal (fibroblasts) interactions. 1e5 Indeed, three-dimensional skin equivalent models and transplantation experiments show that epidermal stratification during the keratinocyte differentiation program is remarkably disrupted in the absence of fibroblasts, 2,4,5 demonstrating that epidermal development and homeostasis are regulated by extrinsic factors released by fibroblasts. Such interactions have been further clarified through an analysis of the differential localization of epidermal keratins in distinct epidermal layers and body sites.…”

PDGFA regulation of dermal adipocyte stem cells

“…During wound healing, defects in adipogenesis can abrogate fibroblast recruitment into wound beds, leading to defects in extracellular matrix deposition and tissue repair (3). Migration of adipocyte precursors into the wounded area might also contribute to the mesenchymal repopulation of the wounded site (4) and in wounds where hair follicle neogenesis is observed fully functional adipocyte precursors are present (5). These findings highlight the breadth of the role of adipose tissue in the skin.…”