Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto 606-8507, Japan.
Stem Cell Reports. 2014 Sep 9;3(3):394-403. doi: 10.1016/j.stemcr.2014.07.005. Epub 2014 Aug 21.
No methods for isolating induced alveolar epithelial progenitor cells (AEPCs) from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been reported. Based on a study of the stepwise induction of alveolar epithelial cells (AECs), we identified carboxypeptidase M (CPM) as a surface marker of NKX2-1(+) "ventralized" anterior foregut endoderm cells (VAFECs) in vitro and in fetal human and murine lungs. Using SFTPC-GFP reporter hPSCs and a 3D coculture system with fetal human lung fibroblasts, we showed that CPM(+) cells isolated from VAFECs differentiate into AECs, demonstrating that CPM is a marker of AEPCs. Moreover, 3D coculture differentiation of CPM(+) cells formed spheroids with lamellar-body-like structures and an increased expression of surfactant proteins compared with 2D differentiation. Methods to induce and isolate AEPCs using CPM and consequently generate alveolar epithelial spheroids would aid human pulmonary disease modeling and regenerative medicine.
尚未有方法能从人胚胎干细胞（hESCs）和诱导多能干细胞（hiPSCs）中分离出诱导性肺泡上皮祖细胞（AEPCs）。基于对肺泡上皮细胞（AECs）逐步诱导的研究，我们鉴定出羧肽酶 M（CPM）是体外和胎肺人源及鼠源 NKX2-1(+)“腹侧化”前肠内胚层细胞（VAFECs）的表面标志物。我们利用 SFTPC-GFP 报告 hPSCs 及与胎肺成纤维细胞的 3D 共培养系统，发现从 VAFECs 中分离的 CPM(+)细胞能分化为 AECs，表明 CPM 是 AEPCs 的标志物。此外，CPM(+)细胞的 3D 共培养分化形成了具有板层小体样结构的球体，与 2D 分化相比，表面活性蛋白的表达增加。利用 CPM 诱导和分离 AEPCs 并生成肺泡上皮球体的方法将有助于人类肺部疾病建模和再生医学。
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