Derivation of lung epithelia from iPS cells for advanced disease modeling

Boston University Medical Campus, Boston MA

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Abstract

Project Summary/Abstract Diseases affecting the lung parenchyma or alveoli cause significant morbidity and mortality in the US today. Treatments for these diseases are often ineffective and the development of novel therapeutics is hampered by an incomplete understanding of disease pathogenesis due in part to an inability to access living alveolar cells from patients. The derivation of an inexhaustible supply of patient-specific alveolar epithelial and mesenchymal cells would allow studies of disease pathogenesis in primary-like cells carrying each patient’s entire genetic background, and consequently the development of new therapeutics. This application proposes to renew a long-standing project focused on the in vitro derivation of lung lineages from patient-specific induced pluripotent stem cells (iPSCs) for disease modeling. In this renewal we apply our diverse biobank of interstitial lung disease (ILD) patient-specific iPSCs that carry mutations impacting alveolar type 2 cell (AT2) function. We proposed to differentiate these cells and their gene-edited progeny into iPSC-derived AT2 cells (iAT2s) to test the hypothesis that a variety of distinct upstream mechanistic drivers of AT2 dysfunction, including some that are epithelial-intrinsic and others that rely on extrinsic paracrine epithelial-mesenchymal cross talk, converge in AT2 responses that are shared and stereotypic, such as: a) canonical NFkB activation, b) dampened alveolar progenitor cell function, and c) emergence of alveolar-basal intermediate (ABI) cell states; we hypothesize that these convergent AT2 responses result in mesenchymal fibrogenic activation driven by targetable ligand- receptor pairs. We test this hypothesis through 3 specific aims designed to: 1) identify aberrant iAT2 programs that are “epithelial-intrinsic”; 2) test the hypothesis that human dysfunctional iAT2s (regardless of upstream driver) upregulate ABI cell states not from epithelial-autonomous mechanisms but rather in response to multicellular “cross-talk” with other lineages, such as mesenchymal cells; and 3) define non- intrinsic aberrant epithelial and mesenchymal programs that are initiated by AT2 dysfunction but rely on epithelial-mesenchymal “cross-talk”.