Abstract
ABSTRACTTissue fibrosis is the deposition of excessive extracellular matrix and can occur as part of the body's natural wound healing process upon injury, or as a consequence of diseases such as systemic sclerosis. Skin fibrosis contributes to significant morbidity due to the prevalence of injuries resulting from trauma and burn. Fibroblasts, the principal cells of the dermis, synthesize extracellular matrix to maintain the skin during homeostasis and also play a pivotal role in all stages of wound healing. Although it was previously believed that fibroblasts are homogeneous and mostly quiescent cells, it has become increasingly recognized that numerous fibroblast subtypes with unique functions and morphologies exist. This Review provides an overview of fibroblast heterogeneity in the mammalian dermis. We explain how fibroblast identity relates to their developmental origin, anatomical site and precise location within the skin tissue architecture in both human and mouse dermis. We discuss current evidence for the varied functionality of fibroblasts within the dermis and the relationships between fibroblast subtypes, and explain the current understanding of how fibroblast subpopulations may be controlled through transcriptional regulatory networks and paracrine communications. We consider how fibroblast heterogeneity can influence wound healing and fibrosis, and how insight into fibroblast heterogeneity could lead to novel therapeutic developments and targets for skin fibrosis. Finally, we contemplate how future studies should be shaped to implement knowledge of fibroblast heterogeneity into clinical practice in order to lessen the burden of skin fibrosis.
Highlights
Fibrosis is the replacement of functional connective tissue with excessive collagen-rich extracellular matrix (ECM)
Emerging evidence indicates that fibroblasts are a morphologically and functionally heterogeneous cell population. This has led to a fresh perspective on dermal fibrosis, on the critical role that fibroblast heterogeneity plays, in skin homeostasis and in pathology, such as scarring and fibrosis (Sriram et al, 2015). This Review aims to discuss the current knowledge of the role of fibroblast heterogeneity in wound healing and fibrosis
The longknown differences in the histological structure of papillary and reticular dermis has led the investigation into fibroblast heterogeneity within these two layers of the murine dermis (Driskell and Watt, 2015)
Summary
Fibrosis is the replacement of functional connective tissue with excessive collagen-rich extracellular matrix (ECM). The fibroblasts marked by embryonic expression of En1 are responsible for most of the dermal connective tissue deposition during cutaneous wound healing, radiation-induced fibrosis and cancer stroma (see Glossary, Box 1) in adult murine skin (Rinkevich et al, 2015). This fibrogenic fibroblast lineage could be identified through CD26 [ known as dipeptidyl peptidase 4 (DPP4)] expression, a finding with important translational implications because these markers could be used to target the pro-fibrotic fibroblast subpopulation in humans (Rinkevich et al, 2015). A follow-up study demonstrated that dermal regeneration is driven by En1– fibroblasts: the transition from scarring to regeneration can be reversed by transplanting En1– cells into the dorsal dermis of recipient mice, highlighting that two fibroblastic lineages govern dermal development and the shift from regeneration to scarring (Jiang et al, 2018)
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