Identification and isolation of a dermal lineage with intrinsic fibrogenic potential

Abstract

Dermal fibroblasts represent a heterogeneous population of cells with diverse features that remain largely undefined. We reveal the presence of at least two fibroblast lineages in murine dorsal skin. Lineage tracing and transplantation assays demonstrate that a single fibroblast lineage is responsible for the bulk of connective tissue deposition during embryonic development, cutaneous wound healing, radiation fibrosis, and cancer stroma formation. Lineage-specific cell ablation leads to diminished connective tissue deposition in wounds and reduces melanoma growth. Using flow cytometry, we identify CD26/DPP4 as a surface marker that allows isolation of this lineage. Small molecule–based inhibition of CD26/DPP4 enzymatic activity during wound healing results in diminished cutaneous scarring. Identification and isolation of these lineages hold promise for translational medicine aimed at in vivo modulation of fibrogenic behavior.

Cellular and Molecular Mechanism of Dermal Fibrosis Following Burn Injury, and Exploration of Therapeutic Approaches

“…Decorin up-regulates more apoptosis genes in SF, but down-regulates their expression in DF [13][14][15]. Superficial and deep dermal fibroblasts have different behaviors in wound healing and hypertrophic scarring, which is supported by the study recently published in Science [16].…”

Unifying mechanism for different fibrotic diseases

“…Systemic induction of c-Jun in hematopoietic precursors caused rapid apoptosis; induction in the liver caused a pronounced hepatosteatosis. This unique c-Jun responsiveness seems to be shared among fibroblasts of many different tissues although fibroblasts are considered highly heterogeneous and tissue-specific (23). The fibrogenic response in multiple tissues and organs also contrasts with previously developed fibrosis models, suggesting that induction of c-Jun could be a common molecular mechanism across different human fibrotic conditions.…”

Lgr6 marks nail stem cells and is required for digit tip regeneration

“…Dermal fibroblast properties and function can vary with their embryonic source and/or anatomical location. For example, En1-derived dermal fibroblasts were recently found to be responsible for the bulk of connective tissue deposition and fibrosis during mouse dorsal cutaneous wound healing (39). Importantly, ablation or small molecule inhibition of the En1-derived cell type, in favor of another dermal fibroblast population(s), led to significant reduction in scar formation without compromising the integrity of the skin.…”