Strong Induction of Activin Expression after Injury Suggests an Important Role of Activin in Wound Repair

Abstract

Activins are members of the transforming growth factor beta (TGF beta) superfamily, which comprises a growing group of dimeric proteins. TGF beta and several other members of this superfamily are known to play an important role in wound healing. However, expression of activin during wound healing has not been demonstrated so far. In this study we have analyzed the expression pattern of activin and activin receptors in normal and wounded skin. We found a large induction of activin A and a minor induction of activin B mRNA expression 1 day after skin injury and high expression levels of activin A and B were found within the first 7 days after wounding. At 13 days after injury, expression of activin A mRNA had returned to the basal level, whereas high levels of activin B persisted. In situ hybridization studies revealed expression of activin A in the granulation tissue below the wound and activin B in the hyperproliferative epithelium at the wound edge and in the migrating epithelial tongue. All known types of activin receptors as well as the activin binding protein follistatin were expressed in normal and wounded skin. However, no significant induction of receptor gene expression was seen during the repair process. The distribution of activins and activin receptors in the wound suggests multiple autocrine and paracrine activities of the ligands during wound healing. Our data provide evidence for a novel function of activin and indicate that--besides TGF beta s themselves--other members of this superfamily might also play an important role in tissue repair.

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

“…D Rotzer et al the hyperproliferative wound epidermis (Hu¨bner et al, 1996, and this study), and indicates that endogenous activin also regulates the levels of Id proteins. Thus, in addition to TGF-b (Ling et al, 2002;Kretschmer et al, 2003;Siegel et al, 2003;Kowanetz et al, 2004), activin was identified as a novel regulator of Id gene expression.…”

“…For this purpose, we analysed the expression of these transcriptional regulators during the healing process of full-thickness excisional mouse wounds (Figures 2 and 3), since activin is highly expressed between day 1 and day 7 of wound repair (Hu¨bner et al, 1996). The time points that we chose for the expression analysis are characteristic for the three different phases of repair.…”

“…Expression was strongest in basal and lower suprabasal cells. Interestingly, the Id expression pattern showed an inverse relationship to the one of activin that is predominantly found in the upper, more differentiated cells of the wound epidermis (Hu¨bner et al, 1996;Wankell et al, 2001b; SW, unpublished data). …”

“…In addition, high levels of Id proteins in the hyperproliferative wound epidermis may enhance proliferation and prevent premature onset of early differentiation of wound keratinocytes, thereby contributing to wound reepithelialization. In suprabasal cells of the wound epidermis, high levels of activin and/or TGF-b (Frank et al, 1996;Hu¨bner et al, 1996) are likely to suppress Id expression, resulting in growth inhibition and induction of differentiation of these cells.…”

“…Thus, transgenic mice overexpressing the activin b A chain in the epidermis were characterized by dermal fibrosis and by a hyperthickened epidermis (Munz et al, 1999). After skin injury, activin b A and b B mRNAs and activin A protein levels increase significantly (Hu¨bner et al, 1996;Cruise et al, 2004), suggesting an important role of activin in wound repair. Indeed, transgenic mice overexpressing the activin antagonist follistatin in the epidermis are characterized by strongly delayed wound healing (Wankell et al, 2001a).…”