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NFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche

机译:NFIB是共享小生境中上皮-黑素细胞干细胞行为的调控者

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摘要

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 pigmentation1"4. To generate pigmented hairs, synchrony is achieved such that upon initiation of a new hair cycle, stem cells of each type activate lineage commitment2'5. Dissecting the inter-stem-cefl 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 N6b 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-immunoprecipi-tation with high-throughput-sequencing and transcriptional profiling, we identify endotheh'n 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.
机译:成体干细胞位于专门的壁ches中,在那里它们受到环境提示以维持组织稳态。在哺乳动物中,毛囊内的干细胞生态位是上皮毛囊干细胞和黑素细胞干细胞的所在地,它们维持毛发再生和色素沉着的周期性发作。1“ 4。毛发周期,每种类型的干细胞都激活谱系承诺2'5。剖析支配这种复杂协调的干-cef1串扰是困难的,因为影响一个谱系的突变通常会影响另一个谱系。小鼠毛囊干细胞特定条件下对N6b的条件靶向使干细胞同步性脱钩,值得注意的是,这不是通过扰动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。黑色素的作用仅限于在利基位的黑色素细胞干细胞。毫发无损地保护了来自真皮乳头的t,从而防止了黑素细胞干细胞分化突变体典型的头发变白。此外,我们将KIT配体定位为促进黑色素细胞干细胞分化的真皮乳头信号。此外,通过具有高通量测序和转录谱的染色质免疫沉淀技术,我们鉴定了内皮素2(Edn2)作为在NFIB缺陷型毛囊干细胞中异常激活的NFIB目标。异位诱导的Edn2在野生型小鼠中概括了NFIB缺陷型。相反,内皮素受体拮抗剂和/或KIT阻断抗体可防止NFIB缺陷位的早熟黑素细胞干细胞分化。我们的发现揭示了黑素细胞和毛囊干细胞的行为如何保持对利基环境中合作因子的依赖,以及在伤害,压力和疾病状态下如何将其解耦。

著录项

  • 来源
    《Nature》 |2013年第7439期|98-102|共5页
  • 作者单位

    Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA;

    Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA;

    HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA;

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical School, Cincinnati, Ohio 45229, USA;

    Department of Biochemistry, Developmental Genomics Group, NYS Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, New York 14203, USA;

    HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA;

    Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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