Lung Epithelial Progenitor Cells: Lessons from Development

Abstract

The current enthusiasm for stem cell research stems from the hope that damaged or diseased tissues may one day be repaired through the manipulation of endogenous or exogenous stem cells. The postnatal human respiratory system is highly accessible and provides unique opportunities for the application of such techniques. Several putative adult lung epithelial stem cells have been identified in the mouse model system. However, their in vivo capabilities to contribute to different lineages, and their control mechanisms, remain unclear. If stem cell-based therapies are to be successful in the lung, it is vitally important that we understand the normal behavior of adult lung stem cells, and how this is regulated. Lung embryonic progenitor cells are much better defined and characterized than their adult counterparts. Moreover, experiments on a variety of developing tissues are beginning to uncover general mechanisms by which embryonic progenitors influence final organ size and structure. This provides a framework for the study of lung embryonic progenitor cells, facilitating experimental design and interpretation. A similar approach to investigating adult lung stem cells could produce rapid advances in the field.

Surfactant Protein–C Chromatin-Bound Green Fluorescence Protein Reporter Mice Reveal Heterogeneity of Surfactant Protein C–Expressing Lung Cells

“…GFP was observed in CCSPpositive (SPC-negative) bronchiolar cells and AT1 cells. Further supporting this idea, our microarray analysis indicated that GFP 1 cells express genes known to be highly expressed in multipotent progenitor cells of the fetal lung distal tip cells that contribute to both bronchiolar and alveolar lineages during lung development (46). Chapman and colleagues showed that a subpopulation of alveolar epithelial cells expressing a6b4 serves as a multipotent progenitor, although in contrast to our results, the a6b4-positive alveolar epithelial progenitors did not express SPC (21).…”

“…Sixteen genes (29 probes) that were up-regulated in AT1 cells compared with AT2 cells were down-regulated in SPC-GFP 1 cells, compared with SPC-GFP 2 cells ( Figure 5D and Figure E5B). Functional annotation clustering in DAVID (the Database for Annotation, Visualization and Integrated Discovery; http://david.niaid.nih.gov) revealed a distinct gene expression signature in GFP 1 cells, including genes that are reported to be highly expressed in distal tip progenitor cells during branching morphogenesis (46), such as Etv5, Elf5, Spry2, Shh, Id2, Foxp1, and Foxp2 ( Figure 5E). In addition, 85 genes known to encode membrane-localized proteins were upregulated in GFP 1 cells compared with GFP 2 cells (Table E2), suggesting that at least some of these membrane-localized proteins may serve as novel surface markers for detecting AT2 cells.…”

Lung cancer stem cells: tools and targets to fight lung cancer

“…Cellular turnover in the adult lung tissue is very slow when compared with the small intestine (Blenkinsopp, 1967;Barker et al, 2008;Rawlins, 2008), and only extreme conditions such as pollutant-or pathogen-induced injuries lead to a massive lung cell proliferation. During organ regeneration, lung cells which usually fulfil differentiated functions in the normal tissue actively start to proliferate and act as progenitor cells that can give rise to several cell types (Stripp and Reynolds, 2008).…”

The building blocks of mammalian lung development

“…The work of many laboratories has suggested that these cells are a multipotent epithelial progenitor population (reviewed in Cardoso and Lu, 2006). Compared with the epithelial stalk cells, the distal tip cells have a unique pattern of gene expression including high levels of Bmp4, Shh, Nmyc, Sox9, Id2, and Etv4/5 (reviewed in Rawlins, 2008), faster cell cycle kinetics (Okubo et al, 2005), and a subtly different morphology (Liu et al, 2004). Moreover, lung epithelial-specific deletion, or overexpression, of Nmyc results in phenotypes consistent with a premature loss, or overproliferation, of epithelial progenitor cells (Okubo et al, 2005).…”