NFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche.
NFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche.
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DOI：
10.1038/nature11847
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发表时间：
2013-03-07
期刊：
影响因子：
64.8
通讯作者：
Fuchs, Elaine
中科院分区：
文献类型：
--
作者：
Chang, Chiung-Ying;Pasolli, H. Amalia;Giannopoulou, Eugenia G.;Guasch, Geraldine;Gronostajski, Richard M.;Elemento, Olivier;Fuchs, Elaine
成体干细胞存在于特定的微环境中，在那里它们接收环境信号以维持组织内稳态。在哺乳动物中，毛囊内的干细胞微环境是上皮毛囊干细胞和黑素细胞干细胞的栖息地，它们维持着毛发再生和色素沉着的周期性循环。为了生成有色素的毛发，要实现同步，以便在新的毛发周期开始时，每种类型的干细胞激活谱系定型。剖析调控这种复杂协调的干细胞间相互作用一直很困难，因为影响一个谱系的突变常常会影响另一个谱系。在此我们确定转录因子NFIB是一种意想不到的干细胞行为协调因子。在小鼠中对Nfib进行毛囊干细胞特异性条件性靶向，使干细胞同步性解偶联。值得注意的是，这并非通过扰乱毛发周期和毛囊结构，而是通过促进黑素细胞干细胞的增殖和分化来实现的。黑色素的早期产生局限于微环境底部的黑素细胞干细胞。距离毛乳头较远的黑素细胞干细胞未受损伤，从而防止了黑素细胞干细胞分化突变体所特有的毛发变白现象。此外，我们确定KIT配体是一种促进黑素细胞干细胞分化的毛乳头信号。另外，通过染色质免疫沉淀结合高通量测序和转录谱分析，我们确定内皮素2（Edn2）是在NFIB缺陷型毛囊干细胞中异常激活的NFIB靶标。在野生型小鼠中异位诱导Edn2重现了NFIB缺陷型表型。相反，内皮素受体拮抗剂和/或KIT阻断抗体可防止NFIB缺陷型微环境中黑素细胞干细胞的过早分化。我们的研究结果揭示了黑素细胞和毛囊干细胞的行为如何依赖微环境内的协同因子，以及在损伤、应激和疾病状态下这种依赖如何被解偶联。
Adult stem cells reside in specialized niches where they receive environmental cues to maintain tissue homeostasis. In mammals, the stem cell niche within hair follicles is home to epithelial hair follicle stem cells and melanocyte stem cells, which sustain cyclical bouts of hair regeneration and pigmentation. To generate pigmented hairs, synchrony is achieved such that upon initiation of a new hair cycle, stem cells of each type activate lineage commitment. Dissecting the inter-stem-cell crosstalk governing this intricate coordination has been difficult, because mutations affecting one lineage often affect the other. Here we identify transcription factor NFIB as an unanticipated coordinator of stem cell behaviour. Hair follicle stem-cell-specific conditional targeting of Nfib in mice uncouples stem cell synchrony. Remarkably, this happens not by perturbing hair cycle and follicle architecture, but rather by promoting melanocyte stem cell proliferation and differentiation. The early production of melanin is restricted to melanocyte stem cells at the niche base. Melanocyte stem cells more distant from the dermal papilla are unscathed, thereby preventing hair greying typical of melanocyte stem cell differentiation mutants. Furthermore, we pinpoint KIT-ligand as a dermal papilla signal promoting melanocyte stem cell differentiation. Additionally, through chromatin-immunoprecipitation with high-throughput-sequencing and transcriptional profiling, we identify endothelin 2 (Edn2) as an NFIB target aberrantly activated in NFIB-deficient hair follicle stem cells. Ectopically induced Edn2 recapitulates NFIB-deficient phenotypes in wild-type mice. Conversely, endothelin receptor antagonists and/or KIT blocking antibodies prevent precocious melanocyte stem cell differentiation in the NFIB-deficient niche. Our findings reveal how melanocyte and hair follicle stem cell behaviours maintain reliance upon cooperative factors within the niche, and how this can be uncoupled in injury, stress and disease states.
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影响因子：
64.5
作者：
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Fuchs, Elaine