Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs.
Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs.
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来自小鼠ESC和患者特异性囊性纤维化IPSC的多态肺和气道祖细胞产生。
DOI：
10.1016/j.stem.2012.01.018
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发表时间：
2012-04-06
期刊：
影响因子：
23.9
通讯作者：
Rajagopal, Jayaraj
中科院分区：
文献类型：
--
作者：
Mou, Hongmei;Zhao, Rui;Sherwood, Richard;Ahfeldt, Tim;Lapey, Allen;Wain, John;Sicilian, Leonard;Izvolsky, Konstantin;Musunuru, Kiran;Cowan, Chad;Rajagopal, Jayaraj
从患者特异性多能细胞衍生肺祖细胞是产生用于疾病建模和移植的分化的肺上皮的关键步骤。通过模拟小鼠肺发育过程中发生的信号传导事件，我们在一系列离散步骤中产生了小鼠肺祖细胞。将来自小鼠胚胎干细胞（ESC）的复制性内胚层转化为前肠内胚层，然后转化为复制性Nkx2.1+肺内胚层，最后转化为多能胚胎肺祖细胞和气道祖细胞。我们证明了精确定时的BMP、FGF和WNT信号传导是NKX2.1诱导所必需的。当皮下移植到小鼠中时，小鼠ESC衍生的Nkx2.1+祖细胞形成呼吸上皮（气管球）。然后，我们调整了这一策略，从人类囊性纤维化诱导的多能干细胞（iPSC）中产生疾病特异性肺祖细胞，为解剖人类肺部疾病创造了平台。这些疾病特异性人肺祖细胞在皮下移植到免疫缺陷小鼠时形成呼吸上皮。
Deriving lung progenitors from patient-specific pluripotent cells is a key step in producing differentiated lung epithelium for disease modeling and transplantation. By mimicking the signaling events that occur during mouse lung development, we generated murine lung progenitors in a series of discrete steps. Definitive endoderm derived from mouse embryonic stem cells (ESCs) was converted into foregut endoderm, then into replicating Nkx2.1+ lung endoderm, and finally into multipotent embryonic lung progenitor and airway progenitor cells. We demonstrated that precisely-timed BMP, FGF, and WNT signaling are required for NKX2.1 induction. Mouse ESC-derived Nkx2.1+ progenitor cells formed respiratory epithelium (tracheospheres) when transplanted subcutaneously into mice. We then adapted this strategy to produce disease-specific lung progenitor cells from human Cystic Fibrosis induced pluripotent stem cells (iPSCs), creating a platform for dissecting human lung disease. These disease-specific human lung progenitors formed respiratory epithelium when subcutaneously engrafted into immunodeficient mice.
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