Hair follicle specific ACVR1/ALK2 critically affects skin morphogenesis and attenuates wound healing

Abstract

The bone morphogenic protein signaling (BMP) is intricately involved in the quiescence and regulation of stem cells through activation of BMP receptors. Hair follicle stem cells play a critical role in cutaneous homeostasis and regeneration. Here, we utilize a novel mouse model with targeted overexpression of the BMP receptor ALK2/ACVR1 in hair follicle stem cells, to characterize its role in skin development and postnatal wound healing. Initial histologic evaluation demonstrated significant dysregulation in hair follicle morphogenesis in mutant mice. These demonstrated increased numbers of individual hair follicles with altered morphology and localization. Mutant follicles were found to exhibit elevated proliferative activity as well as increased prevalence of CD34 and ITGA6 positive follicle stem cells. Interestingly, constitutive overexpression of ALK2 resulted in attenuation of cutaneous wound healing. These findings demonstrate that hair follicle specific ALK2 is intricately involved in maintenance of the stem cell niche and wound healing.

Figure 1

NFATc1 regulated caALK2 overexpression results in aberrant hair morphology. (A) Photographs of NFATc1/caALK2 mutant mice and litter mate controls after depilation. (B) HE staining of adult skin with quantification of (C) hair follicle number and (D) hair follicle size. (E) Immunofluorescence of skin and hair follicle in double transgenic reporter mouse NFATc1-Cre/ROSA26mTmG. Values are expressed as mean ± SEM. * p < 0.05.

Figure 2

Hair follicle ALK2 critically regulates cell proliferation, stem cell maintanence and wound healing. (A) Immunofluorescence for pSmad 1/5/8 in adult mutant and wild-type skin. (B) Immunofluorescence for proliferation marker Ki67. (C) Flow cytometry quantification of cells expressing CD34 and Itga6. (D) Wound healing curve and corresponding representative photographs demonstrate attenuated wound closure in mutant mice (n=8). Values are expressed as mean ± SEM. * p < 0.05.