Obesity accelerates hair thinning by stem cell-centric converging mechanisms.
Obesity accelerates hair thinning by stem cell-centric converging mechanisms.
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DOI：
10.1038/s41586-021-03624-x
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发表时间：
2021-07
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
肥胖是一种世界性的流行病，易患许多与衰老相关的疾病，但其对器官功能障碍的确切影响在很大程度上是未知的。毛囊是生长头发的微型上皮器官，随着年龄的增长，毛囊干细胞（HFSC）的耗竭导致脱发。在这里，我们报告说，肥胖引起的压力，如高脂饮食（HFD）喂养主要针对HFSC，以加速头发稀疏。时序基因表达分析显示，连续四天的HFD喂养通过产生过量的活性氧而将活化的HFSC导向表皮角化，但在年轻小鼠中保留HFSC池。干细胞命运追踪、表观遗传学分析和反向遗传学的综合分析显示，进一步饲喂HFD随后通过自分泌/旁分泌IL-1 R信号转导诱导HFSC内的脂滴和NF-κB活化。这些整合的因素集中在HFSC中的Sonic hedgehog（Shh）信号转导的深刻抑制上，从而通过其异常分化进一步耗尽载脂HFSC并诱导毛囊小型化和最终脱发。相反，通过转基因或化合物的Shh激活挽救了HFD诱导的脱发。这些数据共同表明，肥胖诱导的干细胞炎症强烈抑制器官再生信号，加速微型器官的小型化，并表明日常预防器官功能障碍的重要性。
Obesity, a worldwide epidemic, predisposes to many ageing-associated diseases, yet its exact impact on organ dysfunction is largely unknown. Hair follicles, mini-epithelial organs that grow hair, miniaturize by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs). Here, we report that obesity-induced stress such as by high-fat diet (HFD) feeding primarily targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days directs activated HFSCs toward epidermal keratinization by generating excessive reactive oxygen species yet retains HFSC pools in young mice. Integrative analysis with stem cell fate tracing, epigenetic analysis and reverse genetics revealed that further feeding of HFD subsequently induces lipid droplets and NF-κB activation within HFSCs via autocrine/paracrine IL-1R signaling. Those integrated factors converge on the profound inhibition of Sonic hedgehog (Shh) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, Shh activation by transgenes or compounds rescues HFD-induced hair loss. These data collectively demonstrate that stem cell inflammageing induced by obesity robustly represses organ regeneration signals to accelerate the mini-organ miniaturization, and suggests the importance of daily prevention of organ dysfunction.
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影响因子：
64.5
作者：
Fujiwara H;Ferreira M;Donati G;Marciano DK;Linton JM;Sato Y;Hartner A;Sekiguchi K;Reichardt LF;Watt FM
通讯作者：
Watt FM
影响因子：
64.5
作者：
Ouspenskaia T;Matos I;Mertz AF;Fiore VF;Fuchs E
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10.5
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Novak JSS;Baksh SC;Fuchs E
通讯作者：
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64.5
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Claudia Salzer, Marion;Lafzi, Atefeh;Aznar Benitah, Salvador
通讯作者：
Aznar Benitah, Salvador
影响因子：
64.5
作者：
Hsu YC;Li L;Fuchs E
通讯作者：
Fuchs E