Stripp lab research: Molecular Regulation of Bronchiolar Stem/Progenitor cells

Molecular Regulation of Bronchiolar Stem/Progenitor cells

Our finding that bronchiolar stem cells are maintained within defined microenviornments within airways raises important questions regarding mechanisms leading to their appearance during lung development and long-term maintenance in adulthood. The fact that bronchiolar stem cells reside within a defined niche suggests that “stemness” is not an intrinsic property of the stem cell, but that it is a property conferred by unique cell-cell or paracrine factors that are provided by the stem cell niche. Some of these factors and signaling pathways have been defined in other organ systems but relatively little is known about microenvironmental regulation of stem cell behavior in the lung. We have used conditional transgenic and knock-in alleles that exploit the Cre-LoxP system to investigate signaling pathways regulating the behavior of airway progenitor and stem cells in vivo. Using this approach we have shown that genetic potentiation of the Wnt/β-catenin pathway in the late embryonic period of lung development alters the differentiation of bronchiolar progenitor cells leading to expansion of cells with characteristics of bronchiolar stem cells. In this model bronchiolar stem cells extend beyond the normal microenvironmental boundary that is observed in wild type mice, suggesting that they have acquired independence of stem cell niche-derived signals for their long-term maintenance (See Reynolds et al., 2008 in references). Other signaling pathways being investigated using these approaches include TGFβ/BMP and hedgehog. However, we believe that factors regulating the behavior of facultative progenitor cells, the bronchiolar Clara cell, are equally important in understanding mechanisms of epithelial maintenance, remodeling and stem cell activation. Critical questions being addressed include analysis of Clara cell differentiation potential and how this impacts bronchiolar stem cell activation. Methods we are applying to address these questions include analysis of gene expression at the whole lung level and at the single cell level coupled with analysis of cell proliferation.

Molecular Regulation of Bronchiolar Stem/Progenitor cells

Our finding that bronchiolar stem cells are maintained within defined microenviornments within airways raises important questions regarding mechanisms leading to their appearance during lung development and long-term maintenance in adulthood. The fact that bronchiolar stem cells reside within a defined niche suggests that “stemness” is not an intrinsic property of the stem cell, but that it is a property conferred by unique cell-cell or paracrine factors that are provided by the stem cell niche. Some of these factors and signaling pathways have been defined in other organ systems but relatively little is known about microenvironmental regulation of stem cell behavior in the lung.

We have used conditional transgenic and knock-in alleles that exploit the Cre-LoxP system to investigate signaling pathways regulating the behavior of airway progenitor and stem cells in vivo. Using this approach we have shown that genetic potentiation of the Wnt/β-catenin pathway in the late embryonic period of lung development alters the differentiation of bronchiolar progenitor cells leading to expansion of cells with characteristics of bronchiolar stem cells. In this model bronchiolar stem cells extend beyond the normal microenvironmental boundary that is observed in wild type mice, suggesting that they have acquired independence of stem cell niche-derived signals for their long-term maintenance (See Reynolds et al., 2008 in references). Other signaling pathways being investigated using these approaches include TGFβ/BMP and hedgehog. However, we believe that factors regulating the behavior of facultative progenitor cells, the bronchiolar Clara cell, are equally important in understanding mechanisms of epithelial maintenance, remodeling and stem cell activation. Critical questions being addressed include analysis of Clara cell differentiation potential and how this impacts bronchiolar stem cell activation. Methods we are applying to address these questions include analysis of gene expression at the whole lung level and at the single cell level coupled with analysis of cell proliferation.