Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung.
Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung.
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先天性膈疝胎儿肺的体外模型中人类诱导多能干细胞衍生的肺类器官
DOI：
10.1002/sctm.20-0199
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发表时间：
2021-01
影响因子：
6
通讯作者：
Spence JR
中科院分区：
文献类型：
--
作者：
Kunisaki SM;Jiang G;Biancotti JC;Ho KKY;Dye BR;Liu AP;Spence JR
来自多能干细胞的三维肺类器官（LOs）有可能增强我们对疾病机制的理解，并为新生儿肺部疾病提供新的治疗方法。我们使用从Bochdalek先天性膈疝（一种与出生时胎儿肺压迫和肺发育不全相关的多基因疾病）的胎儿和婴儿中产生的无转基因人诱导多能干细胞建立了可重复的肺发育离体模型。CDH LOs的分子和细胞比较显示NKX2.1+祖细胞、II型肺泡上皮细胞和PDGFRα+肌成纤维细胞的生成受损。然后，我们通过体外压缩将这些LOs置于与疾病相关的机械线索下，观察到与肺祖细胞、肺泡上皮细胞和间充质成纤维细胞相关的基因发生了显著变化。总的来说，这些数据表明CDH肺发育不全的原发性细胞内在和继发性机械原因，并支持将这种基于干细胞的方法用于CDH疾病建模。我们利用从Bochdalek先天性膈疝（CDH）的胎儿和婴儿中提取的不含转基因的人诱导多能干细胞，建立了可重复的离体肺发育模型。CDH肺发育不全的原发性和继发性原因均已确定，机械压迫与肺类器官上皮和间充质基因调控的改变有关。
Three‐dimensional lung organoids (LOs) derived from pluripotent stem cells have the potential to enhance our understanding of disease mechanisms and to enable novel therapeutic approaches in neonates with pulmonary disorders. We established a reproducible ex vivo model of lung development using transgene‐free human induced pluripotent stem cells generated from fetuses and infants with Bochdalek congenital diaphragmatic hernia (CDH), a polygenic disorder associated with fetal lung compression and pulmonary hypoplasia at birth. Molecular and cellular comparisons of CDH LOs revealed impaired generation of NKX2.1+ progenitors, type II alveolar epithelial cells, and PDGFRα+ myofibroblasts. We then subjected these LOs to disease relevant mechanical cues through ex vivo compression and observed significant changes in genes associated with pulmonary progenitors, alveolar epithelial cells, and mesenchymal fibroblasts. Collectively, these data suggest both primary cell‐intrinsic and secondary mechanical causes of CDH lung hypoplasia and support the use of this stem cell‐based approach for disease modeling in CDH. We established a reproducible ex vivo model of lung development using transgene‐free human induced pluripotent stem cells generated from fetuses and infants with Bochdalek congenital diaphragmatic hernia (CDH). Both primary cell‐intrinsic and secondary causes of CDH lung hypoplasia were identified, and mechanical compression was associated with alterations in lung organoid epithelial and mesenchymal gene regulation.
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人类肺发育和疾病的三维模型来自多能干细胞。
影响因子：
21.3
作者：
Chen YW;Huang SX;de Carvalho ALRT;Ho SH;Islam MN;Volpi S;Notarangelo LD;Ciancanelli M;Casanova JL;Bhattacharya J;Liang AF;Palermo LM;Porotto M;Moscona A;Snoeck HW
通讯作者：
Snoeck HW
DOI：
10.1152/ajplung.00342.2004
发表时间：
2005-07-01
影响因子：
4.9
作者：
Chapin, CJ;Ertsey, R;Kitterman, JA
通讯作者：
Kitterman, JA
DOI：
10.1152/ajplung.2000.279.6.l1159
发表时间：
2000-12-01
影响因子：
4.9
作者：
Guilbert, TW;Gebb, SA;Shannon, JM
通讯作者：
Shannon, JM
DOI：
10.1152/ajplung.00221.2006
发表时间：
2007-03-01
影响因子：
4.9
作者：
Deimling, Julie;Thompson, Kate;Post, Martin
通讯作者：
Post, Martin
影响因子：
7.7
作者：
Dye BR;Hill DR;Ferguson MA;Tsai YH;Nagy MS;Dyal R;Wells JM;Mayhew CN;Nattiv R;Klein OD;White ES;Deutsch GH;Spence JR
通讯作者：
Spence JR