PECAM1+/Sca1+/CD38+ Vascular Cells Transform into Myofibroblast-Like Cells in Skin Wound Repair

Abstract

Skin injury induces the formation of new blood vessels by activating the vasculature in order to restore tissue homeostasis. Vascular cells may also differentiate into matrix-secreting contractile myofibroblasts to promote wound closure. Here, we characterize a PECAM1+/Sca1+ vascular cell population in mouse skin, which is highly enriched in wounds at the peak of neoangiogenesis and myofibroblast formation. These cells express endothelial and perivascular markers and present the receptor CD38 on their surface. PECAM1+/Sca1+/CD38+ cells proliferate upon wounding and could give rise to α-SMA+ myofibroblast-like cells. CD38 stimulation in immunodeficient mice reduced the wound size at the peak of neoangiogenesis and myofibroblast formation. In humans a corresponding cell population was identified, which was enriched in sprouting vessels of basal cell carcinoma biopsies. The results indicate that PECAM1+/Sca1+/CD38+ vascular cells could proliferate and differentiate into myofibroblast-like cells in wound repair. Moreover, CD38 signaling modulates PECAM1+/Sca1+/CD38+ cell activation in the healing process implying CD38 as a target for anti-angiogenic therapies in human basal cell carcinoma.

Skin Wound Repair Is Not Altered in the Absence of Endogenous AnxA1 or AnxA5, but Pharmacological Concentrations of AnxA4 and AnxA5 Inhibit Wound Hemostasis

“…This finding was surprising considering the fact that AnxA5 promotes membrane repair in cultured perivascular cells after laser-induced injury. Alternatively, these cells may not represent the main source of mesenchymal cells during skin repair [Etich et al, 2013]. Moreover, massive tissue destruction in full-thickness wounds stimulates the substantial influx of perivascular cells from the surrounding intact skin, which could compensate for the lack of repair in the damaged cells within the wound.…”

“…at a final concentration of 1 μ M or 2 μg/g body weight of wild-type mice. Full-thickness wounds of 6-mm diameter were inflicted on the backs of wild-type and mutant mice, and 200 μl of 0.9% NaCl was injected subcutaneously to prevent dehydration [Etich et al, 2013]. Bleeding was monitored and the total volume of blood loss from cranial wounds was determined.…”

“…Morphometric parameters were determined using ImageJ software. For flow cytometry analysis, cells were isolated from wounds as previously described [Etich et al, 2013]. Briefly, wounds were incubated with 0.2% (w/v) collagenase type 1 (Worthington) in DMEM-F12 and 10% FCS for 1.5 h at 37 ° C. Cells were washed, passed through a 40-μm strainer (BD) and stained for 15 min on ice in 5% FCS/PBS with primary conjugated monoclonal antibodies specific for CD45, Ly6G, F4/80, CD11c, CD3, CD31 and Sca1 (BD).…”

Scar‐free cutaneous wound healing in the leopard gecko, Eublepharis macularius

“…; Etich et al. ; Kramann et al. ), and are rapidly recruited to the wound bed following the initial phase of inflammation (Duffield et al.…”

“…The current findings are consistent with previous observations that scar-free wound healing is characterised by delayed onset of collagen deposition and limited to nonexistent participation by myofibroblasts. By contrast, myofibroblasts are key participants in fibrosis (Darby et al 1990;Epstein et al 1999;Etich et al 2013;Kramann et al 2013), and are rapidly recruited to the wound bed following the initial phase of inflammation (Duffield et al 2013). In addition to contraction of the defect, myofibroblasts also secrete abundant ECM, particularly parallel bundles of type I collagen (Duffield et al 2013), as early as 3-4 DPW in scar-forming mammals (Levenson et al 1965;Greaves et al 2013).…”