Endogenous fibroblastic progenitor cells in the adult mouse lung are highly enriched in the Sca-1 positive cell fraction

Originally identified as a marker specifying murine hematopoietic stem cells, the Sca-1 antigen has since been shown to be differentially expressed by candidate stem cells in tissues including vascular endothelium, skeletal muscle, mammary gland, and prostate of adult mice. In the adult murine lung, Sca-1 has previously been identified as a selectable marker for the isolation of candidate non-hematopoietic (CD45(neg)), non-endothelial (CD31(neg)) bronchioalveolar stem cells (BASC) located at the bronchioalveolar duct junction which co-express Surfactant Protein C (SP-C) and the Clara Cell Specific Protein (CCSP). Our systematic analysis of CD45(neg)CD31(neg)Sca-1(pos) cells in fetal, neonatal, and adult lung shows that very few of these cells are detectable prior to birth but expand exponentially postnatally coinciding with the transition from the saccular to the alveolar stage of lung development. Unlike candidate BASC, the CD45(neg)CD31(neg)Sca-1(pos)CD34(pos) cell fraction we describe co-expresses immunophenotypic markers (Thy-1 and PDGFRalpha) which define lung fibroblastic rather than epithelial cells. The mesenchymal signature of the CD45(neg)CD31(neg)Sca-1(pos)CD34(pos) cell fraction is further confirmed by transcriptional profiling; by cell culture studies demonstrating enrichment for clonogenic lipofibroblastic and non-lipofibroblastic progenitors; and by immunohistochemical localization of Sca-1 in perivascular cells of the lung parenchyma. Although the CD45(neg)CD31(neg)Sca-1(pos)CD34(pos) cell phenotype does define endogenous clonogenic progenitor cells in the adult murine lung, our data indicates that these progenitors are predominantly representative of mesenchymal cell lineages and highlights the pressing need for the identification of alternative markers and robust functional assays for the resolution of epithelial and fibroblastic stem and progenitor cell populations in the adult lung......