Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.
Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.
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谱系阴性祖细胞大受伤后动员肺上皮。
DOI：
10.1038/nature14112
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发表时间：
2015-01-29
期刊：
影响因子：
64.8
通讯作者：
Chapman, Harold A.
中科院分区：
文献类型：
--
作者：
Vaughan, Andrew E.;Brumwell, Alexis N.;Xi, Ying;Gotts, Jeffrey E.;Brownfield, Doug G.;Treutlein, Barbara;Tan, Kevin;Tan, Victor;Liu, Feng Chun;Looney, Mark R.;Matthay, Michael A.;Rock, Jason R.;Chapman, Harold A.
广泛地说，组织再生以两种方式实现：通过共同分化细胞的增殖和/或通过特化干细胞/祖细胞的部署。这些途径中的哪一个适用于器官和损伤特异性。目前肺的范例表明，上皮修复可归因于表达成熟谱系标志物的细胞。与此相反，我们在这里定义的再生作用，以前的特点，罕见的谱系阴性上皮干/祖细胞（LNEPs）细胞存在于正常远端肺。流感或博来霉素损伤后，静止的LNEP激活Δ Np 63/细胞角蛋白5（Krt 5+）重塑程序。活化的细胞增殖并广泛迁移以占据成熟谱系耗尽的严重损伤区域，于是它们向成熟上皮分化。谱系追踪显示，预先存在的成熟上皮细胞在这种修复中的贡献很少，而通过单细胞测序确定的确定性表面轮廓分离的LNEPs的原位移植直接证明了该群体的增殖能力和多能性。LNEP需要Notch信号传导来激活Δ Np 63/Krt 5+程序，而随后的Notch阻断促进肺泡细胞命运。损伤后持续的Notch信号传导导致实质微蜂窝，指示再生失败。来自纤维化患者的肺显示类似的蜂窝状囊肿，具有过度活跃的Notch信号传导的证据。我们的研究结果表明，不同的干细胞/祖细胞库根据损伤程度重新填充损伤组织，再生或纤维化的结果可能部分取决于LNEP Notch信号传导的动力学。
Broadly, tissue regeneration is achieved in two ways: by proliferation of common differentiated cells and/or by deployment of specialized stem/progenitor cells. Which of these pathways applies is both organ and injury-specific. Current paradigms in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers. In contrast we here define the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEPs) cells present within normal distal lung. Quiescent LNEPs activate a ΔNp63/cytokeratin 5 (Krt5+) remodeling program after influenza or bleomycin injury. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, whereupon they differentiate toward mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch signaling to activate the ΔNp63/Krt5+ program whereas subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signaling post-injury led to parenchymal micro-honeycombing, indicative of failed regeneration. Lungs from fibrosis patients show analogous honeycomb cysts with evidence of hyperactive Notch signaling. Our findings indicate distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of injury, and the outcomes of regeneration or fibrosis may ride in part on the dynamics of LNEP Notch signaling.
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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
DOI：
10.1152/ajplung.90209.2008
发表时间：
2008-07-01
影响因子：
4.9
作者：
Rawlins, Emma L.;Hogan, Brigid L. M.
通讯作者：
Hogan, Brigid L. M.
影响因子：
14.8
作者：
Krupnick, Alexander S.;Lin, Xue;Li, Wenjun;Okazaki, Mikio;Lai, Jiaming;Sugimoto, Seiichiro;Richardson, Steven B.;Kornfeld, Christopher G.;Garbow, Joel R.;Patterson, G. Alexander;Gelman, Andrew E.;Kreisel, Daniel
通讯作者：
Kreisel, Daniel
影响因子：
3.7
作者：
Seibold MA;Smith RW;Urbanek C;Groshong SD;Cosgrove GP;Brown KK;Schwarz MI;Schwartz DA;Reynolds SD
通讯作者：
Reynolds SD
DOI：
10.1165/rcmb.2006-0410oc
发表时间：
2007-06-01
影响因子：
6.4
作者：
Wang, Jieru;Edeen, Karen;Mason, Robert J.
通讯作者：
Mason, Robert J.