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During fetal development, mammalian back-skin undergoes a natural transition in response to injury, from scarless regeneration to skin scarring. Here, we characterize dermal morphogenesis and follow two distinct embryonic fibroblast lineages, based on their history of expression of the engrailed 1 gene. We use single-cell fate-mapping, live three dimensional confocal imaging and in silico analysis coupled with immunolabelling to reveal unanticipated structural and regional complexity and dynamics within the dermis. We show that dermal development and regeneration are driven by engrailed 1-history-naive fibroblasts, whose numbers subsequently decline. Conversely, engrailed 1-history-positive fibroblasts possess scarring abilities at this early stage and their expansion later on drives scar emergence. The transition can be reversed, locally, by transplanting engrailed 1-naive cells. Thus, fibroblastic lineage replacement couples the decline of regeneration with the emergence of scarring and creates potential clinical avenues to reduce scarring.

Scars are more severe when the subcutaneous fascia beneath the dermis is injured upon surgical or traumatic wounding. Here, we present a detailed analysis of fascia cell mobilisation by using deep tissue intravital live imaging of acute surgical wounds, fibroblast lineage-specific transgenic mice, and skin-fascia explants (scar-like tissue in a dish – SCAD). We observe that injury triggers a swarming-like collective cell migration of fascia fibroblasts that progressively contracts the skin and form scars. Swarming is exclusive to fascia fibroblasts, and requires the upregulation of N-cadherin. Both swarming and N-cadherin expression are absent from fibroblasts in the upper skin layers and the oral mucosa, tissues that repair wounds with minimal scar. Impeding N-cadherin binding inhibits swarming and skin contraction, and leads to reduced scarring in SCADs and in animals. Fibroblast swarming and N-cadherin thus provide therapeutic avenues to curtail fascia mobilisation and pathological fibrotic responses across a range of medical settings.

| 147 wileyonlinelibrary.com/journal/imr 1 | INTRODUC TI ON "Stromal" cell refers to the cellular component that form and maintain the structural parts of an organ, whereas parenchymal cells perform the specific organ function. Stromal cells, such as fibroblasts, have traditionally been considered as quiescent cells that primarily function to make extracellular matrices. Relevant in the clinic, these cells contribute to excessive connective tissue formation during injury repair, cancer, and fibrosis. However, these dedicated cells, and the niches they create, also orchestrate immunological functions by influencing the differentiation, movement, and activation of immune cells. Recent genetic lineage-tracing and single-cell RNA sequencing studies highlight the diversity of stromal cell populations in tissues and revealed how eclectic stromal cells orchestrate the diversity of immunological functions.These days, fibroblasts are no longer considered as mere structural components of organs but as dynamic participants in immune processes. We discuss four major mechanisms by which fibroblasts and immune cells interact: (a) paracrine signaling via cytokine and chemokine secretion, (b) direct priming via juxtacrine interactions, and (c) behavioral modulation through extracellular matrix remodeling. Finally, and more recently described, (d) transfer or mobilization of extracellular matrix microenvironments. In the following sections, we review the impact of these four modes of interaction between distinct fibroblast populations and immune cells during homeostasis, injury repair, scarring, and disease in the mammalian skin. Finally, we discuss the origins, of these and other stromal lineages, and their

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