Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme

Andrea B. Alber, Hector A. Marquez, Liang Ma, George Kwong, Bibek R. Thapa, Carlos Villacorta-Martin, Jonathan Lindstrom-Vautrin, Pushpinder Bawa, Feiya Wang, Yongfeng Luo, Laertis Ikonomou, Wei Shi and Darrell N. Kotton ()
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Andrea B. Alber: Center for Regenerative Medicine of Boston University and Boston Medical Center
Hector A. Marquez: Center for Regenerative Medicine of Boston University and Boston Medical Center
Liang Ma: Center for Regenerative Medicine of Boston University and Boston Medical Center
George Kwong: Center for Regenerative Medicine of Boston University and Boston Medical Center
Bibek R. Thapa: Center for Regenerative Medicine of Boston University and Boston Medical Center
Carlos Villacorta-Martin: Center for Regenerative Medicine of Boston University and Boston Medical Center
Jonathan Lindstrom-Vautrin: Center for Regenerative Medicine of Boston University and Boston Medical Center
Pushpinder Bawa: Center for Regenerative Medicine of Boston University and Boston Medical Center
Feiya Wang: Center for Regenerative Medicine of Boston University and Boston Medical Center
Yongfeng Luo: Keck School of Medicine, University of Southern California
Laertis Ikonomou: University at Buffalo
Wei Shi: University of Cincinnati College of Medicine
Darrell N. Kotton: Center for Regenerative Medicine of Boston University and Boston Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39099-9

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