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Striae distensae are common disfiguring cutaneous lesions but lack effective treatments because of an incomplete understanding of their pathophysiology. Dermal fibroblasts likely play an important role. The authors investigate the cellular-molecular features distinguishing fibroblasts from human striae distensae and normal skin. The authors also develop a mouse model of striae distensae.Human striae distensae and normal skin samples were compared for tensile strength and histologic structure. Fibroblasts from striae distensae and normal skin were isolated by fluorescence-activated cell sorting for gene expression analysis. Immunofluorescence staining and fluorescence-activated cell sorting were used to confirm gene expression data at the protein level. A mouse model of striae distensae formation was created by administering corticosteroids and mechanically loading the dorsal skin.Human striae distensae exhibited reduced tensile strength, more disordered collagen fibers, and epidermal atrophy compared to human normal skin. There were 296 up-regulated genes in striae distensae fibroblasts, including the profibrotic lineage and surface marker CD26. Up-regulated genes were involved in profibrotic and mechanoresponsive signaling pathways (TGFβ and FAK-PI3-AKT-signaling). In contrast, 571 genes were down-regulated, including CD74 and genes of the AMPK pathway. Increased CD26 and decreased CD74 expression was confirmed by fluorescence-activated cell sorting and immunofluorescence. Similar cutaneous histologic and gene expression changes were induced in hypercortisolemic mice by mechanically loading the dorsal skin.Fibroblasts from human striae distensae exhibit increased profibrotic and decreased antifibrotic signaling. CD26 and CD74 are promising surface markers that may be targeted therapeutically. The authors' mouse model of striae distensae can be used as a platform to test the efficacy of potential therapeutic agents.Striae distensae are common disfiguring cutaneous lesions whose etiology remains elusive, which has hindered development of effective treatment strategies. Dermal fibroblasts likely play an important role. The authors sought to elucidate the key cellular-molecular pathways distinguishing fibroblasts in striae distensae from those in normal skin.

Purpose: Contracture is a long-term complication of radiotherapy (RT) that results from pathologic fibrosis of soft tissue in the radiation field. Fat grafting can regenerate fibrotic soft tissue by decreasing collagen density and reorganizing collagen fiber networks. Fibroblasts are the predominant cell involved in extracellular matrix (ECM) synthesis, and dermal fibroblasts possess distinct embryonic origins. We recently identified a profibrotic fibroblast in the mouse ventral dermis marked by embryonic expression of paired related homeobox 1 (Prrx1). Here we sought to investigate how fat grafting alters Prrx1-positive subpopulation distribution as well as functional contractures. Methods: Adult Prrx-1Cre;R26mTmG reporter mice (n=9) underwent whole body lethal irradiation with 9 Gy for hematopoietic depletion. Mice were immediately reconstituted with 2 million nucleated bone-derived cells from donor NSG (NOD.CB17-Prkdcsscid/J) mice via retro-orbital sinus injection. The success of reconstitution and immunodepletion was assessed by fluorescence-activated cell sorting (FACS) analysis of peripheral blood. After 4 weeks, 30 Gy was delivered to the right hindlimb in five fractionated doses to generate limb contracture. The irradiated, contracted limb was then grafted with 200 μl fresh human lipoaspirate and limb extension was measured over the subsequent 8 weeks, at which point skin was harvested for assessment of fibroblast subtypes for FACS and immunofluorescence. A group of mice with radiation-induced groin contracture did not undergo fat grafting and served as the control group. Results: FACS analysis indicated successful immunodepletion and engraftment by 3 weeks post bone marrow transplantation. At one month following groin irradiation, mice had developed significant right hind limb contracture with significantly reduced limb extension (****p≤0.0001). Histologically this was paralleled by thickening of the dermis, and substantial expansion of the fibrogenic Prrx-1-positive fibroblast subpopulation. While human fat graft volume retention was reduced over 8 weeks following implantation, this was associated with significantly improved in limb extension. The skin overlying the grafted fat showed reduced collagen density, as indicated by trichrome staining, as well as a reduction in the fibrogenic Prrx-1-positive fibroblast subpopulation by immunofluorescence imaging, as compared to the control mice. Conclusion: Here we show that fat grafting improves the extensibility of irradiated and contracted hind limbs and reverses radiation-induced skin fibrosis by both reducing the collagen content and by altering the composition of dermal fibroblast subpopulations. Specifically, fat grafting results in a depletion of the Prrx-1-positive fibroblast subpopulation. Further elucidating how this profibrotic fibroblast subpopulation is involved in ventral surface soft tissue fibrosis will facilitate development of novel strategies to treat/prevent debilitating late side-effect of radiotherapy.