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Mechanisms that regulate regional epithelial cell diversity and pathologic remodeling in airways are poorly understood. We hypothesized that regional differences in cell composition and injury‐related tissue remodeling result from the type and composition of local progenitors. We used surface markers and the spatial expression pattern of an  SFTPC ‐GFP transgene to subset epithelial progenitors by airway region. Green fluorescent protein (GFP) expression ranged from undetectable to high in a proximal‐to‐distal gradient. GFP hi  cells were subdivided by CD24 staining into alveolar (CD24 neg ) and conducting airway (CD24 low ) populations. This allowed for the segregation of three types of progenitors displaying distinct clonal behavior in vitro. GFP neg  and GFP low  progenitors both yielded lumen containing colonies but displayed transcriptomes reflective of pseudostratified and distal conducting airways, respectively. CD24 low GFP hi  progenitors were present in an overlapping distribution with GFP low  progenitors in distal airways, yet expressed lower levels of Sox2 and expanded in culture to yield undifferentiated self‐renewing progeny. Colony‐forming ability was reduced for each progenitor cell type after in vivo bleomycin exposure, but only CD24 low GFP hi  progenitors showed robust expansion during tissue remodeling. These data reveal intrinsic differences in the properties of regional progenitors and suggest that their unique responses to tissue damage drive local tissue remodeling. S tem  C ells  2012;30:1948–1960

Airway Epithelial Progenitors Are Region Specific and Show Differential Responses to Bleomycin‐Induced Lung Injury