Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme
Andrea B. Alber, Héctor Márquez, Liang Ma, George Kwong, Bibek R. Thapa, Carlos Villacorta-Martín, Jonathan Lindstrom-Vautrin, Pushpinder Bawa, Feiya Wang, Yongfeng Luo, Laertis Ikonomou, Wei Shi, Darrell N. Kotton
Abstract
While the generation of many lineages from pluripotent stem cells has resulted in basic discoveries and clinical trials, the derivation of tissue-specific mesenchyme via directed differentiation has markedly lagged. The derivation of lung-specific mesenchyme is particularly important since this tissue plays crucial roles in lung development and disease. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer. We identify the pathways (RA and Shh) necessary to specify lung mesenchyme and find that mouse iPSC-derived lung mesenchyme (iLM) expresses key molecular and functional features of primary developing lung mesenchyme. iLM recombined with engineered lung epithelial progenitors self-organizes into 3D organoids with juxtaposed layers of epithelium and mesenchyme. Co-culture increases yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional crosstalk. Our iPSC-derived population thus provides an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics.