Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Stem Cells. 2012 Aug;30(8):1781-5. doi: 10.1002/stem.1153.
Hair follicles (HFs) are equipped with stem cell niches that allow regeneration. Tumor necrosis factor-α converting enzyme (TACE), also known as A disintegrin and metalloproteinase 17, is a proteolytic enzyme that regulates a variety of cell surface molecules including TNF-α, via ectodomain shedding. We found TACE expression on mouse HFs and conditionally depleted it in cells that expressed sex-determining region Y-related high-mobility-group box 9 (SOX9) transcription factor, an HF stem cell transcription factor (Tace(flox/flox) -Sox9-Cre, hereafter, "Tace/Sox9"). Tace/Sox9 mice were born with brittle hair with prolonged anagen phase. They underwent diffuse, progressive, and ultimately whole-body hair loss by 20 weeks old. Tace/Sox9 HFs lacked CD34(+) bulge cells as demonstrated via immunofluorescence microscopy and flow cytometry. Real-time PCR revealed downregulation of transcription factors Sox9, Lhx2, and Gata3 and upregulation of Lef1. In vitro colony-forming capacity was abolished in Tace/Sox9 keratinocytes, and HFs exhibited increased proliferation in situ, collectively demonstrating that Tace/Sox9 mice failed to establish the bulge niche and to maintain "stemness" of HF stem cells. Epidermal growth factor receptor (EGFR) signaling was impaired in Tace/Sox9 keratinocytes, and mice depleted of Egfr in SOX9-expressing tissues exhibited hair phenotype nearly identical to Tace/Sox9 mice, demonstrating EGFR signaling as a pathway downstream of TACE in HF homeostasis. This study provides mechanistic implication for human TACE-deficiency and for hair abnormality caused by EGFR inhibitors.
毛囊（HFs）配备了干细胞龛，允许再生。肿瘤坏死因子-α转化酶（TACE），也称为 A 型分解素和金属蛋白酶 17，是一种蛋白水解酶，通过细胞外结构域脱落调节包括 TNF-α 在内的多种细胞表面分子。我们发现 TACE 在小鼠 HFs 上的表达，并在表达性别决定区 Y 相关高迁移率族盒 9（SOX9）转录因子的细胞中条件性耗尽它，这是一种 HF 干细胞转录因子（Tace(flox/flox)-Sox9-Cre，以下简称“Tace/Sox9”）。Tace/Sox9 小鼠出生时头发脆弱，生长期延长。它们在 20 周龄时经历弥漫性、进行性、最终全身脱发。通过免疫荧光显微镜和流式细胞术证实，Tace/Sox9 HFs 缺乏 CD34(+)隆起细胞。实时 PCR 显示转录因子 Sox9、Lhx2 和 Gata3 下调和 Lef1 上调。Tace/Sox9 角质形成细胞的体外集落形成能力被废除，并且 HFs 原位显示出增殖增加，这共同表明 Tace/Sox9 小鼠未能建立隆起龛并且维持 HF 干细胞的“干性”。Tace/Sox9 角质形成细胞中的表皮生长因子受体（EGFR）信号受损，并且在 SOX9 表达组织中耗尽 Egfr 的小鼠表现出与 Tace/Sox9 小鼠几乎相同的毛发表型，表明 EGFR 信号作为 HF 稳态中 TACE 的下游途径。这项研究为人类 TACE 缺乏症和 EGFR 抑制剂引起的毛发异常提供了机制意义。
