Epithelial-to-Mesenchymal Stem Cell Transition in a Human Organ: Lessons from Lichen Planopilaris
Epithelial-to-Mesenchymal Stem Cell Transition in a Human Organ: Lessons from Lichen Planopilaris
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DOI：
10.1016/j.jid.2017.09.047
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发表时间：
2018-03-01
影响因子：
6.5
通讯作者：
Paus, Ralf
中科院分区：
文献类型：
--
作者：
Imanishi, Hisayoshi;Ansell, David M.;Paus, Ralf
上皮向间充质转化（EMT）对胚胎发育和伤口愈合至关重要，并发生在纤维化疾病和癌症中。在这里，我们发现EMT也发生在炎症性永久性脱发（planopilaris）期间，人类头皮毛囊的上皮干细胞（eSC）生态位内。我们表明，通过拮抗E-cadherin，结合转化生长因子- β 1、表皮生长因子和ifn - γ给药，可以在健康的人类eSCs中原位诱导分子EMT特征，据我们所知，这在以前没有报道过。此外，通过抑制转化生长因子- β信号通路，过氧化物酶体增殖物激活受体- γ激动剂可以在体外阻止甚至部分逆转原代人eSCs内EMT的诱导。此外，我们发现过氧化物酶体增殖物激活受体- γ激动剂也能减弱EMT信号，甚至在离体扁平苔藓毛囊中也是如此。我们介绍了扁平地衣作为成人eSCs病理EMT的模型疾病，报告了在健康人（迷你）器官中治疗性操纵eSC EMT的临床前试验，并表明过氧化物酶体增殖激活受体- γ激动剂是抑制和部分逆转人毛囊eSCs体外EMT的有希望的药物，包括扁平地衣。
Epithelial-to-mesenchymal transition (EMT) is critical for embryonic development and wound healing, and occurs in fibrotic disease and carcinoma. Here, we show that EMT also occurs within the bulge, the epithelial stem cell (eSC) niche of human scalp hair follicles, during the inflammatory permanent alopecia, lichen planopilaris. We show that a molecular EMT signature can be experimentally induced in healthy human eSCs in situ by antagonizing E-cadherin, combined with transforming growth factor-beta 1, epidermal growth factor, and IFN-gamma administration, which to our knowledge has not been reported previously. Moreover, induction of EMT within primary human eSCs can be prevented and even partially reversed ex vivo by peroxisome proliferator-activated receptor-gamma agonists, likely through suppression of the transforming growth factor-beta signaling pathway. Furthermore, we show that peroxisome proliferator-activated receptor-gamma agonists also attenuates the EMT signature even in lesional lichen planopilaris hair follicles ex vivo. We introduce lichen planopilaris as a model disease for pathological EMT in human adult eSCs, report a preclinical assay for therapeutically manipulating eSC EMT within a healthy human (mini-) organ, and show that peroxisome proliferator-activated receptor-gamma agonists are promising agents for suppressing and partially reversing EMT in human hair follicles eSCs ex vivo, including in lichen planopilaris.