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Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury | |
2015 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
卷号 | 517期号:7536页码:621-5 |
发表状态 | 已发表 |
DOI | 10.1038/nature14112 |
摘要 | 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(1-4). Current models in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers(5-8). By contrast, here we define the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells present within normal distal lung. Quiescent LNEPs activate a Delta Np63 (a p63 splice variant) and cytokeratin 5 remodelling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards 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 signalling to activate the DNp63 and cytokeratin 5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signalling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signalling. Our findings indicate that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signalling. |
URL | 查看原文 |
收录类别 | SCI |
WOS研究方向 | Science & Technology - Other Topics |
WOS类目 | Multidisciplinary Sciences |
WOS记录号 | WOS:000348775000045 |
WOS关键词 | STEM-CELLS ; IN-VITRO ; ALVEOLAR ; MAINTENANCE ; REPAIR ; AIRWAY ; MOUSE ; NOTCH ; TRANSPLANTATION ; BIOLOGY |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/119976 |
专题 | 个人在本单位外知识产出 |
通讯作者 | Vaughan, Andrew E.; Chapman, Harold A. |
作者单位 | 1.Univ Calif San Francisco, Dept Med, Cardiovasc Res Inst, San Francisco, CA 94143 USA 2.Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA 3.Howard Hughes Med Inst, Stanford, CA 94305 USA 4.Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany 5.Univ Calif San Francisco, Sch Med, Dept Anat, San Francisco, CA 94143 USA |
推荐引用方式 GB/T 7714 | Vaughan, Andrew E.,Brumwell, Alexis N.,Xi, Ying,et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury[J]. NATURE,2015,517(7536):621-5. |
APA | Vaughan, Andrew E..,Brumwell, Alexis N..,Xi, Ying.,Gotts, Jeffrey E..,Brownfield, Doug G..,...&Chapman, Harold A..(2015).Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.NATURE,517(7536),621-5. |
MLA | Vaughan, Andrew E.,et al."Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury".NATURE 517.7536(2015):621-5. |
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