Two distinct signaling pathways in hair cycle induction: Stat3-dependent and -independent pathways

Abstract

The hair follicle is an epidermal derivative that undergoes cycles of growth, involution, and rest. The hair cycle has well-orchestrated kinetics regulated by interactions between mesenchymal and epithelial cells, although the intracellular signals remain unclear. We previously established keratinocyte-specific Stat3-disrupted mice, by which we demonstrated that signal transducer and activator of transcription 3 (Stat3) is required for wound healing and anagen progression in the hair cycle. Growth factor-dependent migration of Stat3-disrupted keratinocytes was severely impaired, suggesting that not only wound healing but also telogen-to-anagen progression required organized keratinocyte migration in response to mesenchymal stimuli. In the present study, to examine whether Stat3 activation in keratinocytes is a prerequisite for hair cycle progression, we applied methods for experimental anagen induction to Stat3-disrupted mice. It was demonstrated that anagen was successfully induced in Stat3-disrupted as well as wild-type mice by chemical or mechanical stimulation, i.e., by topical application of phorbol 12-myristate 13-acetate (PMA) or by hair plucking, respectively. This result indicated that anagen in these methods occurred in the absence of Stat3. Furthermore, PMA stimulated the migration of Stat3-disrupted keratinocytes in vitro , supporting a hypothesis that the protein kinase C (PKC) and Stat3 pathways occur independently in the postnatal anagen induction. Both Stat3-dependent and -independent migration of keratinocytes was inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin. Therefore, we infer that entry into anagen is mediated by at least two distinct signaling pathways: Stat3-dependent pathway for spontaneous hair cycling and Stat3-independent (probably PKC-dependent) pathway for exogenously induced hair cycling, whereas both pathways require PI3K activation.

PDGF isoforms induce and maintain anagen phase of murine hair follicles

“…Previous experimental data suggest that HF transition from telogen to anagen is associated with the activation of the Shh [11], Wnt [12]/ 15 beta-catenin [13]/ Lef-1 [13] and STAT3 [14] signaling pathways. Thus, we studied the expression of Shh, Wnt5a, Lef-1 and Stat3 in the anagen PDGF induced skin samples using immunohistochemical staining and real time-reverse transcriptase-(RT)-PCR.…”

“…In the present study, we have clearly demonstrated the effects of induction of anagen phase and maintenance of murine HFs by PDGF-AA and PDGF-BB. 14 Local injection of hepatocyte growth factor was reported to result in a delayed transition from anagen to telogen but only weak anagen induction activity [8]. Subcutaneous application of slow release gelatin hydrogel beads containing basic fibroblast growth factor or hepatocyte growth factor, and collagen hydrogel containing vascular endothelial growth factor led to the appearance of dark areas on the reverse (dermal) subcutaneous side of skin tissue and increased hair shaft elongation in mice [9].…”

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

“…The Stat3 pathway has been shown essential for DMBA/TPA-induced tumorigenesis (33). The putative link of Runx1 and Stat3 in skin tumorigenesis is perhaps not surprising, given that the Runx1 mutant phenotype is strikingly similar to that shown by Stat3 knockout mice (49,50). The relationship of these two transcription factors in skin tumorigenesis and HF regulation is intriguing and requires further exploration.…”

Interferon α/β Promotes Cell Survival by Activating Nuclear Factor κB through Phosphatidylinositol 3-Kinase and Akt

“…How STAT3 and PI-3K/Akt specifically relate to one another is not yet known. Recent findings indicate that IFN activates PI-3K through STAT3-independent pathways (49) and that PI-3K is required for STAT3-dependent and STAT3-independent signaling (50,51). Thus, STAT3 and PI-3K are complexly related in IFN signal transduction.…”