Activin Controls Skin Morphogenesis and Wound Repair Predominantly via Stromal Cells and in a Concentration-Dependent Manner via Keratinocytes

Abstract

The transforming growth factor-beta family member activin is a potent regulator of skin morphogenesis and repair. Transgenic mice overexpressing activin in keratinocytes display epidermal hyper-thickening and dermal fibrosis in normal skin and enhanced granulation tissue formation after wounding. Mice overexpressing the secreted activin antagonist follistatin, however, have the opposite wound-healing phenotype. To determine whether activin affects skin morphogenesis and repair via activation of keratinocytes and/or stromal cells, we generated transgenic mice expressing a dominant-negative activin receptor IB mutant (dnActRIB) in keratinocytes. The architecture of adult skin was unaltered in these mice, but delays were observed in postnatal pelage hair follicle morphogenesis and in the first catagen-telogen transformation of hair follicles. Although dnActRIB-transgenic mice showed slightly delayed wound re-epithelialization after skin injury, the strong inhibition of granulation tissue formation seen in follistatin-transgenic mice was not observed. Therefore, although endogenous activin appeared to affect skin morphogenesis and repair predominantly via stromal cells, overexpressed activin strongly affected the epidermis. The epidermal phenotype of activin-overexpressing mice was partially rescued by breeding these animals with dnActRIB-transgenic mice. These results demonstrate that activin affects both stromal cells and keratinocytes in normal and wounded skin and that the effect on keratinocytes is dose-dependent in vivo.

Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

“…These findings demonstrate that aberrant expression and activity of activin are associated with abnormal skin development and impaired wound healing and suggest that activin regulates migration, proliferation, and differentiation of many cell types in the skin, including keratinocytes. This was confirmed by our recent results, which demonstrated that activin receptor signaling in keratinocytes is important for hair follicle morphogenesis and wound re-epithelialization (Bamberger et al, 2005). In addition, a role of activin in the regulation of keratinocyte proliferation and differentiation was found in in vitro studies with keratinocyte monocultures, where a weak inhibitory effect of activin on keratinocyte proliferation and induction of keratinocyte differentiation by this factor was demonstrated (Shimizu et al, 1998;Seishima et al, 1999).…”

Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris

“…Its soluble protein product follistatin binds and neutralizes members of the TGFb superfamily 15 , including activin, which is involved in scar formation in skin. Accordingly, mice overexpressing follistatin display reduced wound healing 18 , whereas overexpression of activin results in epidermal thickening and dermal fibrosis in normal skin and enhanced granulation tissue formation after wounding 32 . Our study in European subjects did not detect associations at either of the two previously described acne risk loci 6 .…”

Mast Cells Are Dispensable for Normal and Activin-Promoted Wound Healing and Skin Carcinogenesis

“…In previous studies, we demonstrated that activin promotes wound healing and chemically induced skin carcinogenesis, in particular by activating various types of stromal cells (10,12,13,29). Furthermore, other laboratories demonstrated that activin affects different types of immune cells in vitro and in vivo [reviewed by (29,30)].…”

“…Thus, we previously showed that transgenic mice overexpressing activin A in keratinocytes under control of the keratin 14 promoter (Act mice) are characterized by enhanced granulation tissue formation and accelerated reepithelialization after wounding, and also by enhanced skin carcinogenesis and malignant progression (10,12). Interestingly, acceleration of wound repair by activin is at least in part mediated via stromal cells (13). The role of the stroma in the protumorigenic effect of activin was even more remarkable, because inhibition of activin signaling in keratinocytes did not reduce tumorigenesis.…”