CD201+ fascia progenitors choreograph injury repair

Abstract

Optimal tissue recovery and organismal survival1 are achieved by tight spatiotemporal tuning of tissue inflammation, contraction and scar-formation. Here, we discover a multipotent fibroblast progenitor marked by CD201 expression in the fascia, the deepest connective tissue layer of the skin. Using murine skin injury models, single-cell transcriptomics, and genetic lineage tracing and ablation models, we demonstrate that CD201+ progenitors pace wound healing by generating multiple specialized cell types from proinflammatory fibroblasts to myofibroblasts in a spatiotemporally tuned sequence. We identify retinoic acid and hypoxia signaling as differentiation checkpoints that control the graduated entry of fascia progenitor into the proinflammatory and myofibroblast states. Modulating their differentiation, with retinoic acid and hypoxia-inducible factor 1-alpha, or genetically ablating this cellular lineage, impaired the graduated appearances of specialized fibroblasts and chronically delayed wound healing. The discovery of fascia progenitors, their microenvironment, and the signaling pathways that control the graduated transitions thereof provides a new roadmap to understand and clinically treat impaired wound healing.

Fibroblasts – the cellular choreographers of wound healing

“…Thus, Hif1-α was found to control the proinflammatory exit and orchestrate the appearance of (proto-)myofibroblasts. In this context, it is also worth noting that both checkpoint signals (retinoic acid and Hif1-α) chronologically and functionally preceded known (proto-)myofibroblasts inducers such as TGF-ß and YAP-TAZ ( 125 ).…”

“…Recently, Rinkevich’s group has revealed the root of cellular pathways underlying the wound healing cascade ( 125 ). In fact, the researchers identified multipotent fibroblast progenitors marked by CD201 expression in the subcutaneous fascia.…”

“…More specifically, during the initial transition of these CD201 + fascia progenitors into proinflammatory fibroblasts, retinoic acid sustained inflammation whilst preventing the conversion into myofibroblasts. In other words: retinoic acid represented a fibroblast differentiation checkpoint, regulating the entry from the fascia progenitor into the pro-inflammatory state ( 125 ).…”

“…Accordingly, fine-tuning of myofibroblast activity by accurately manipulating the gatekeeping function of Hif1-α could prevent excessive scar formation/contraction without compromising the necessary proinflammatory wound state. The fact that CD201+ fibroblast differentiation from naïve fascia progenitor cells through the inflammatory state to myofibroblasts has also been conserved in human keloid and psoriatic bioinformatics datasets renders clinical-practical leveraging of these basic science findings in the management of impaired wound healing and skin diseases all the more auspicious ( 125 ).…”

Life of Pi: Exploring functions of Pi16+ fibroblasts

“…14 Notably, fibroblasts with a Pi16+ phenotype were also found away from blood vessels, instead associated with the reticular interstitium, 15 a band of fluid-filled space enmeshed with fibrous collagen found within and across tissues including skin and subcutaneous adipose. 6,16 These shared niches may either suggest a conserved function across tissues or may be the driving force in maintaining transcriptional similarity across tissues. 2.…”