Generation of Region-specific Airway Basal Stem Cells from Human Pluripotent Stem Cells via Regulation of BMP-NOGGIN Axis

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.