Striae Distensae Are Rich In Mechanoresponsive And Cd26-positive Human Dermal Fibroblasts And Exhibit Increased Profibrotic Signaling
Mimi R. Borrelli, MBBS, MS, Dominic Henn, MD, Shamik Mascharak, BS, Ledibabari M. Ngaage, MD, Michelle Griffin, MD, PhD, Ashraf Patel, BS, Rahim Nazerali, MD, Gordon Lee, MD, Michael Januszyk, MD, PhD, Derrick C. Wan, MD, Michael T. Longaker, MD, MA, Hermann P. Lorenz, MD.
Stanford, menlo park, CA, USA.
PURPOSE: Striae distensae (‘stretch marks’) are common disfiguring cutaneous lesions found in a variety of clinical situations. Despite their prevalence, the etiology of striae distensae remains elusive, and this has significantly hindered development of effective treatment strategies. Human dermal fibroblasts (HDF) are the principal cell of the dermis and likely play an important role. We sought to elucidate the key cellular and molecular pathways distinguishing HDF in striae distensae and normal skin.
METHODS: Striae distensae and normal skin samples were isolated from abdominoplasty specimens removed in surgical procedures (n=15 Skin tensile strength was assessed, and histological structure was compared using Hematoxylin and Eosin, Trichrome, and Picrosirius Red staining together with a novel computational assessment of collagen fiber networks. HDF were also isolated by flow cytometry using a negative and positive gating strategy (CD45-CD235a-CD31-CD90+LIVE single dermal cells) for analysis of gene expression using mRNA microarrays (Fig.1A&B). Immunofluorescence staining and flow cytometry were used for confirmation of gene expression data at the protein level.
RESULTS: The skin of striae distensae had absent rete ridges, epidermal atrophy, and a more disorganized pattern of collagen fiber bundles upon histological analysis (Fig.1C). There was clear delineation in collagen fibers from striae distensae and normal skin with the most divergence in the collagen fibers of the reticular dermis between skin types (Fig.1D). The striae distensae also exhibited reduced tensile strength compared to normal skin samples (Fig.1Ei-ii). Microarray analysis revealed 296 up-regulated and 174 down-regulated genes in HDF isolated from striae distensae compared to normal skin (Fig.1Fi-ii). Of the differentially expressed surface markers, CD26 was significantly upregulate in HDF from striae distensae compared to normal skin (Fig.1Fiv). Gene ontology analysis confirmed that key profibrotic signaling pathways were significantly up-regulated in striae distensae including focal adhesion, TGFβ, and FAK-PI3-AKT pathways. In contrast, the anti-fibrotic macrophage migration inhibitory factor receptor, CD74, and the AMPK pathway were significantly down-regulated in striae distensae (Fig.1Fiii-iv). Increased expression of CD26 and decreased expression of CD74 in striae distensae compared to normal skin was confirmed by flow cytometry and immunofluorescence staining of fresh abdominoplasty skin samples (Fig. 1G).
CONCLUSION: Our data start to elucidate the mechanisms mediating the formation of striae distensae and indicate that fibroblasts from striae exhibit increased pro-fibrotic and decreased anti-fibrotic signaling pathways. CD26 is a known marker of fibrogenic fibroblasts in mice and we show here its expression is increased in striae. CD74 is a known anti-fibrotic surface receptor. The significant up-regulation of CD26 and down-regulation of CD74 at the mRNA and protein level highlight these surface markers as promising targets for development of effective treatment strategies of striae distensae.
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