p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration.
p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration.
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p63（+）KRT5（+）远端气道干细胞对于肺部再生至关重要。
DOI：
10.1038/nature13903
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发表时间：
2015-01-29
期刊：
影响因子：
64.8
通讯作者：
McKeon F
中科院分区：
文献类型：
--
作者：
Zuo W;Zhang T;Wu DZ;Guan SP;Liew AA;Yamamoto Y;Wang X;Lim SJ;Vincent M;Lessard M;Crum CP;Xian W;McKeon F
许多突然失去肺组织的患者以某种方式完全恢复;在这里，这种恢复可以追溯到肺干细胞的离散群体，这些干细胞不仅对肺再生至关重要，而且可以克隆，然后移植到其他小鼠身上以贡献新的肺组织。本文的在线版本（doi：10.1038/nature13903）包含补充材料，可供授权用户使用。患者在肺组织大量丢失后能恢复到什么程度还不清楚。然而，临床经验表明，大规模的肺再生可以发生在儿童和成人灾难性肺损伤后，以前在小鼠中的研究已经将来自远端气道的细胞亚群与H1N1流感病毒介导的损伤后观察到的再生过程联系起来。本期发表的两篇论文表明，当肺内部的上皮细胞受损时，一种罕见的干细胞群被诱导增殖并迁移到受损部位，在那里它们分化成几种细胞类型。Frank McKeon及其同事描述了一种罕见的小鼠远端气道细胞亚群，它们在暴露于流感后增殖。这些细胞可以促进移植后的肺再生，并在细胞培养中保持其内在的谱系承诺，这表明这些细胞亚群可能在基于干细胞的治疗中具有潜力。Harold Chapman和同事使用谱系追踪来识别小鼠远端肺中在博来霉素或流感介导的损伤后被激活的静止细胞群。这些细胞表达细胞角蛋白5，并通过Notch信号通路修复上皮，尽管在这种情况下持续的Notch信号通路会导致囊肿的形成。来自患有肺纤维化的患者的数据也显示存在过度活跃的Notch和类似的囊肿。本文的在线版本（doi：10.1038/nature13903）包含补充材料，可供授权用户使用。诸如慢性阻塞性肺病和肺纤维化的肺部疾病涉及氧气交换表面和气道的进行性和不可阻挡的破坏，并且已经成为全球死亡的主要原因。除了不切实际的器官移植外，缓解治疗仍然有限，再生医学的可能性缺乏经验支持。然而，临床上已知的是，从坏死性肺炎或急性呼吸窘迫综合征中突然大量丧失肺组织的患者通常在六个月内恢复完全的肺功能。相应地，我们最近证明了H1N1流感病毒感染后小鼠的肺再生，并将表达Trp63（p63）和角蛋白5的远端气道干细胞（称为DASCp63/Krt5）与这一过程联系起来。在这里，我们表明，预先存在的，本质上致力于DASCp63/Krt5进行增殖性扩张，以应对流感引起的肺损伤，并组装成新生的肺泡间质性肺炎的网站。我们还表明，在体内选择性消融DASCp63/Krt5阻止了这种再生，导致纤维化前病变和氧交换不足。最后，我们证明了单个DASCp63/Krt5衍生的谱系分化为I型和II型肺细胞以及移植到感染的肺后的细支气管分泌细胞，并且还最小化了内源性干细胞损失对该过程的结构后果。这些细胞在培养中繁殖的能力，同时保持其内在的谱系承诺，表明它们在急性和慢性肺部疾病的干细胞治疗中的潜力。本文的在线版本（doi：10.1038/nature13903）包含补充材料，可供授权用户使用。
Many patients experiencing sudden loss of lung tissue somehow undergo full recovery; here this recovery is traced to a discrete population of lung stem cells that are not only essential for lung regeneration but can be cloned and then transplanted to other mice to contribute new lung tissue. The online version of this article (doi:10.1038/nature13903) contains supplementary material, which is available to authorized users. The extent to which patients can recover after massive loss of lung tissue has been unclear. However, clinical experience has shown that large-scale lung regeneration can occur in children and adults following catastrophic lung damage, and previous studies in mice have linked a subset of cells from distal airway to a regeneration process observed after H1N1 influenza virus mediated injury. Two papers published in this issue show that when the epithelial cells lining the interior of the lung are damaged, a rare stem cell population is induced to proliferate and migrate to the damaged site where they differentiate into several cell types. Frank McKeon and colleagues describe a rare subset of mouse distal airway cells that proliferate after exposure to influenza. These cells can contribute to lung regeneration after transplantation and maintain their intrinsic lineage commitment in cell culture, suggesting that such cell subsets may have potential in stem-cell-based therapies. Harold Chapman and colleagues used lineage tracing to identify a population of quiescent cells in the mouse distal lung that are activated after bleomycin or influenza-mediated injury. These cells express cytokeratin 5 and repair the epithelium through a Notch signalling pathway, although persistent Notch signalling in this context then leads to the formation of cysts. Data from patients suffering from lung fibrosis also show the presence of hyperactive Notch and similar cysts. The online version of this article (doi:10.1038/nature13903) contains supplementary material, which is available to authorized users. Lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia or acute respiratory distress syndrome often recover full pulmonary function within six months. Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5, called DASCp63/Krt5, to this process. Here we show that pre-existing, intrinsically committed DASCp63/Krt5 undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. We also show that the selective ablation of DASCp63/Krt5 in vivo prevents this regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that single DASCp63/Krt5-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. The ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases. The online version of this article (doi:10.1038/nature13903) contains supplementary material, which is available to authorized users.
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影响因子：
64.5
作者：
Kumar PA;Hu Y;Yamamoto Y;Hoe NB;Wei TS;Mu D;Sun Y;Joo LS;Dagher R;Zielonka EM;Wang de Y;Lim B;Chow VT;Crum CP;Xian W;McKeon F
通讯作者：
McKeon F
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作者：
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作者：
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3.5
作者：
Schmidt, D;Hubsch, U;Aufderheide, M
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DOI：
10.1164/rccm.200311-1535oc
发表时间：
2005-04-15
影响因子：
24.7
作者：
Lawson, WE;Polosukhin, VV;Blackwell, TS
通讯作者：
Blackwell, TS