Generation of human alveolar epithelial type I cells from pluripotent stem cells

被引:19
作者
Burgess, Claire L. [1 ,2 ,3 ,4 ]
Huang, Jessie [1 ,2 ,3 ,4 ]
Bawa, Pushpinder S. [1 ,2 ]
Alysandratos, Konstantinos-Dionysios [1 ,2 ,3 ,4 ]
Minakin, Kasey [1 ,2 ,3 ,4 ]
Ayers, Lauren J. [1 ,2 ,3 ,4 ]
Morley, Michael P. [5 ]
Babu, Apoorva [5 ]
Villacorta-Martin, Carlos [1 ,2 ]
Yampolskaya, Maria [6 ]
Hinds, Anne [3 ,4 ]
Thapa, Bibek R. [1 ,2 ,3 ,4 ]
Wang, Feiya [1 ,2 ]
Matschulat, Adeline [3 ,4 ,7 ]
Mehta, Pankaj [6 ]
Morrisey, Edward E. [5 ]
Varelas, Xaralabos [1 ,2 ,3 ,4 ,7 ]
Kotton, Darrell N. [1 ,2 ,3 ,4 ]
机构
[1] Boston Univ, Ctr Regenerat Med, Boston, MA 02118 USA
[2] Boston Med Ctr, Boston, MA 02118 USA
[3] Boston Univ, Chobanian & Avedisian Sch Med, Pulm Ctr, Boston, MA 02118 USA
[4] Boston Univ, Chobanian & Avedisian Sch Med, Dept Med, Boston, MA 02118 USA
[5] Univ Penn, Perelman Sch Med, Penn CHOP Lung Biol Inst, Philadelphia, PA 19104 USA
[6] Boston Univ, Dept Phys, Boston, MA 02215 USA
[7] Boston Univ, Chobanian & Avedisian Sch Med, Dept Biochem & Cell Biol, Boston, MA 02118 USA
关键词
PULMONARY-FIBROSIS; LUNG DEVELOPMENT; IPS CELLS; DIFFERENTIATION; TRANSDIFFERENTIATION; EXPRESSION; EXPOSURE; REGENERATION; PROGENITOR; REGULATORS;
D O I
10.1016/j.stem.2024.03.017
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of the distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human in vitro AT1 model system via directed differentiation of induced pluripotent stem cells (iPSCs). We use primary adult AT1 global transcriptomes to suggest benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched in these cells. Next, we generate iPSC-derived alveolar epithelial type II cells (AT2s) and find that nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier producing characteristic extracellular matrix molecules and secreted ligands. Our results provide an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s.
引用
收藏
页码:657 / 675.e8
页数:28
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