Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice
Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice
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DOI：
10.1172/jci57673
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发表时间：
2011-07-01
影响因子：
15.9
通讯作者：
Vu, Thiennu H.
中科院分区：
文献类型：
--
作者：
Chapman, Harold A.;Li, Xiaopeng;Vu, Thiennu H.
层粘连蛋白及其整合素受体参与上皮细胞的分化和祖细胞的维持。我们在此报告了一个以前未被识别的表达层粘连蛋白受体α 6 β 4的小鼠肺泡上皮细胞（AECs）亚群，但很少或没有前表面活性剂C (pro-SPC)，被赋予了再生潜力。在体外，这个亚群作为祖细胞克隆扩增，但也向成熟细胞类型分化。整合素- 4本身并不是AEC增殖或分化所必需的。我们认为这是一种新颖的体内胚胎肺类器官实验，该实验表明纯化的β 4（+）成人AECs与E14.5肺单细胞悬液混合并植入肾胶囊下，在6天内自组织成独特的Clara细胞10-kDa分泌蛋白（CC10(+)）气道样结构和SPC（+）囊状结构。使用博来霉素肺损伤模型和SPC驱动的诱导cre来绘制AECs命运图，我们发现纤维化区域的大多数II型AECs不是来自先前存在的II型AECs，这表明SPC（-）祖细胞在修复过程中补充了II型AECs。我们的研究结果支持了成人肺中存在稳定的AEC祖细胞群的观点，提供了实质损伤后AEC祖细胞分化的体内证据，并确定了在肺修复过程中维持II型AEC的强大候选祖细胞。
Laminins and their integrin receptors are implicated in epithelial cell differentiation and progenitor cell maintenance. We report here that a previously unrecognized subpopulation of mouse alveolar epithelial cells (AECs) expressing the laminin receptor alpha 6 beta 4, but little or no pro-surfactant C (pro-SPC), is endowed with regenerative potential. Ex vivo, this subpopulation expanded clonally as progenitors but also differentiated toward mature cell types. Integrin beta 4 itself was not required for AEC proliferation or differentiation. An in vivo embryonic lung organoid assay, which we believe to be novel, was used to show that purified beta 4(+) adult AECs admixed with E14.5 lung single-cell suspensions and implanted under kidney capsules self-organized into distinct Clara cell 10-kDa secretory protein (CC10(+)) airway-like and SPC(+) saccular structures within 6 days. Using a bleomycin model of lung injury and an SPC-driven inducible cre to fate-map AECs, we found the majority of type II AECs in fibrotic areas were not derived from preexisting type II AECs, demonstrating that SPC(-) progenitor cells replenished type II AECs during repair. Our findings support the idea that there is a stable AEC progenitor population in the adult lung, provide in vivo evidence of AEC progenitor cell differentiation after parenchymal injury, and identify a strong candidate progenitor cell for maintenance of type II AECs during lung repair.