Competitive balance of intrabulge BMP/Wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation

Abstract

Hair follicles facilitate the study of stem cell behavior because stem cells in progressive activation stages, ordered within the follicle architecture, are capable of cyclic regeneration. To study the gene network governing the homeostasis of hair bulge stem cells, we developed a Keratin 15-driven genetic model to directly perturb molecular signaling in the stem cells. We visualize the behavior of these modified stem cells, evaluating their hair-regenerating ability and profile their molecular expression. Bone morphogenetic protein (BMP)-inactivated stem cells exhibit molecular profiles resembling those of hair germs, yet still possess multipotentiality in vivo. These cells also exhibit up-regulation of Wnt7a, Wnt7b, and Wnt16 ligands and Frizzled (Fzd) 10 receptor. We demonstrate direct transcriptional modulation of the Wnt7a promoter. These results highlight a previously unknown intra-stem cell antagonistic competition, between BMP and Wnt signaling, to balance stem cell activity. Reduced BMP signaling and increased Wnt signaling tilts each stem cell toward a hair germ fate and, vice versa, based on a continuous scale dependent on the ratio of BMP/Wnt activity. This work reveals one more hierarchical layer regulating stem cell homeostasis beneath the stem cell-dermal papilla-based epithelial-mesenchymal interaction layer and the hair follicle-intradermal adipocyte-based tissue interaction layer. Although hierarchical layers are all based on BMP/Wnt signaling, the multilayered control ensures that all information is taken into consideration and allows hair stem cells to sum up the total activators/inhibitors involved in making the decision of activation.hair follicle stem cells | β-catenin | BMPR1A

Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration

“…Previously described K5TetOff/TreH2BGFP animals were fed 1 mg/g Dox food for 4 wk starting at 3-4 wk of age (P21-P28) (9,10). For Nail LRCs lineage tracing, K15CrePR/Rosa26LacZ mouse (12) were topically treated with 5 mg of RU [(wt/vol) in 100% ethanol] daily for 16 d from P43 to P59 as reported (18).…”

“…Transcriptionally, we observed a downregulation of two BMP signaling inhibitors, Bambi and Decorin. In hair follicles, BMP signaling is critical for maintaining quiescent SC homeostasis and regulating proper hair differentiation (16)(17)(18)(19)(20)(21) and, more recently, we have demonstrated the requirement for BMP signaling in sweat gland development in vivo (2). Msx2 and Foxn1, both downstream targets of BMP signaling, regulate normal nail differentiation (22) and compound mutations of Msx2 and Foxn1 result in severe nail abnormalities.…”

Cessation of Epithelial Bmp Signaling Switches the Differentiation of Crown Epithelia to the Root Lineage in a β-Catenin-Dependent Manner

“…Wnt/␤-catenin signaling is essential for the EMT by upregulating pro-EMT transcription factors such as Snai1 and Twist (37). Bmp/Smad4 signaling negatively regulates Wnt/␤-catenin signaling in lung epithelial cells by inducing the Wnt inhibitor Wif1 (38), in hair bulge epithelial stem cells by inhibiting the expression of Wnt7a and Wnt7b (39), in intestinal epithelial cells by directly inhibiting transcription of the ␤-catenin gene (40), or in nasopharyngeal carcinoma cells by inducing miR-200a to suppress ␤-catenin translation (41). Western blotting and qRT-PCR assay indicated that the level of nuclear ␤-catenin protein and mRNA (Ctnnb1) in AKO dental epithelia was significantly upregulated (Fig.…”

FOXN1 Transcription Factor in Epithelial Growth and Wound Healing

“…Nevertheless, it was shown that there is competition between BMP and Wnt signaling within the bulge stem cells, affecting the balance of stem cell activity. Inhibited BMP and raised Wnt signaling (observed also in the skin of nude mice) favors the activation of quiescent SCs, indicating that BMP acts as a switch for activation/ inactivation of the bulge stem cell niche (46). Thus, the downregulation or loss of Foxn1 could contribute to SC activation and the creation of a proregenerative environment in nude mice.…”