11 May Endogenous lung stem cells and contribution to disease | COPD Stem cell therapy
Maintenance of the airway epithelium through the action of multiple interdependent regenerative zones suggests that a more thorough understanding of progenitor cell types and their behaviour in normal and diseased states may yield important insights into disease pathophysiology. Examples of basic biological questions that have potential to shed light on mechanisms of normal maintenance, repair and aberrant tissue remodelling include:
Basic studies to define the behaviour of airway progenitor cells in normal and diseased states. Epithelial maintenance is dependent upon a balance between turnover and renewal. If the rate of epithelial turnover is held constant, maintenance is purely a function of progenitor cell self-renewal versus differentiation. There is currently no information in the existing literature that describes the probability with which different progenitor cell types are maintained through self-renewal, or whether this property is impacted by divergence from the steady state, such as might be the case with acute or chronic lung disease. The existence of multiple progenitor cell types that can be hierarchically organized, such as those of the bronchiolar epithelium, increase the complexity of this question. It is possible, for example, that bronchiolar stem cells are maintained through a highly regulated process involving extrinsic signals from the stem cell niche to ensure long-term maintenance of a stem cell pool of a defined size. The likelihood that stem cells are activated to participate in epithelial maintenance would inevitably be related to longevity of the transit-amplifying progenitor cell pool. For example, if TA cell maintenance occurs through a stochastic mechanism, as proposed by Jones and co-workers 32, 33, the probability of which is influenced by extrinsic factors such as injury and/or inflammation, the contribution of stem cells towards epithelial maintenance will be strongly influenced by disease. Understanding the basic behaviour of progenitor cells and how this is impacted by disease would provide novel insights into disease pathogenesis and reveal new therapeutic targets that may allow modification of disease outcome.
Improved molecular definition of progenitor cell types and their response to injury and repair. A key component of future studies will be to interrogate the molecular profile of stem cells. Previous studies have identified a broader repertoire of molecular markers for identification and analysis of bronchiolar progenitor cells 85. Furthermore, bronchioalveolar stem cells (BASCs) were recently isolated and sorted, based upon their Sca-1+CD45−CD31−CD34+ immunophenotype 60. However, recent cytometric analysis in combination with mouse models suggests these markers do not distinguish putative stem cells from the abundant pool of Clara cells (Teisanu et al, submitted). Previous attempts to isolate airway epithelial stem cells also included enrichment based upon the ability to efflux the DNA dye Hoechst 33 342 dye 86, but recent data indicate that this does not result in significant enrichment 87. Collectively, these data demonstrate that the use of stem cell properties from other tissues to fractionate airway epithelial stem cells is not a valid approach. Rather, new markers, preferably those that identify a novel cell surface phenotype, will need to be identified, using a combination of techniques including cellular fractionation and microarray analysis.
Development of in vitro culture models to investigate the behaviour and regulation of stem cells. A common functional assessment of stem cell character is determination of self-renewal and differentiation capacity in vitro. Isolated BASCs have been cultured and shown to demonstrate both of these qualities in vitro60. However, caveats associated with this assay result preclude appropriate assessment of stem cell behaviour. A more appropriate endpoint would be the coupling of in vitro methods for propagation of progenitor cell types with development of transplantation assays, analogous to those used for functional testing of cells of the haematopoietic lineage to assess the behaviour of these cells in vivo88, 89.
Comparative stem/progenitor cell biology between mammalian species. A major shortfall of current studies is the lack of correlative human data. In order to develop successful cell and molecular therapeutics that translates into the clinic, stem cells in human airway epithelium need to be identified. Comparative studies aimed at revealing similarities and differences in epithelial maintenance between species will provide valuable information relating to the predictive ability of animal models of human disease.
The existence of endogenous lung epithelial stem cells remains a controversial issue. To facilitate a more thorough understanding of progenitor cell behaviour and the putative stem cell hierarchy will require development of novel endpoints to answer the fundamental questions outlined above. These studies will bring the scientific community one step closer to the development of cellular and molecular strategies for the therapeutic treatment of lung disease.