Abstract
SUMMARY Basal cells (BCs) are the primary stem cell population of adult human airways and a key target for hPSC-based models of airway development, disease and regenerative medicine. Recent studies have revealed substantial regional differences between human proximal and distal airway cell types, including BCs. Here, we show that the NOGGIN-BMP signaling axis governs proximal-distal patterning of hPSC-derived lung progenitors leading to the generation of region-specific induced BCs (iBCs). Continuous BMP inhibition through NOGGIN, coupled with tapered WNT activation, generates proximal iBCs that molecularly and functionally resemble human proximal airway BCs and differentiate in vitro and in vivo into the full repertoire of specialized proximal airway cell types, including ionocytes and pulmonary neuroendocrine cells. In sharp contrast, BMP activation with tapered WNT generates distal airway-like cells and distal BCs with limited ionocyte differentiation potential. Progeny of proximal iBCs derived from G551D CFTR mutant hiPSCs also recapitulate a cystic fibrosis-associated ionocyte phenotype.
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SUMMARY
Recent studies have mapped substantial regional differences between human proximal and distal airway cell types, including basal cells (BCs) – the primary stem cell population in human adult airways. Regionally distinct airway basal stem cells derived from human induced pluripotent stem cells (hiPSCs) have broad applications in regenerative medicine and airway disease studies. Here, we report that the NOGGIN-BMP signaling axis is critical for proximal-distal regional patterning of hiPSC-derived lung progenitors. Continuous BMP inhibition (through NOGGIN) and tapering WNT activation efficiently generate BCs that resemble those in human proximal airways at both molecular and functional levels. These hiPSC-derived proximal basal cells (defined as proximal iBCs) are capable of self-renewal and competent differentiation, both in vitro and in vivo, into the full repertoire of specialized cell types found in normal human proximal airways, including ionocytes and pulmonary neuroendocrine cells. Conversely, BMP activation and tapering WNT generate airway and BCs resembling those in human distal airways, with limited ionocyte differentiation potential. The progeny of proximal iBCs derived from hiPSCs with G551D mutation in the CFTR gene recapitulate the ionocyte phenotype characteristic of cystic fibrosis.
Competing Interest Statement
The authors have declared no competing interest.
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