A Maverick Review of Common Stem/Progenitor Markers in Lung Development

Several attempts have been made to reconstruct the whole lung using pluripotent stem cells (PSCs) to treat terminal stage diseases, such as chronic obstructive pulmonary disease [COPD] and idiopathic pulmonary fibrosis [IPF], for which whole-organ transplantation is currently the only treatment option. The development of induced differentiation technologies has made it possible to regenerate lungs from the 'bottom-up' via stepwise protocols. Nonetheless, the earliest lung multipotent progenitors, namely lung primordial stem cells, have not been identified to date. Considering the intricate crosstalk network that regulates lung development, stepwise protocols to differentiate PSCs into lung progenitors have raised some key questions: (1) the heterogeneity of these induced progenitors, and (2) obtaining a high-purity population. One important strategy to overcome these hurdles is to identify relevant markers or factors that regulate the complex network in lung morphogenesis according to those erected in vivo and ex vivo experiments. For screening lung primordial stem cells, several markers are 'on the shelf', and this review explores the most common or substantiated candidates. We artificially divided these markers into positive selecting and negative limiting proximal or distal markers as well as early progenitor markers that can be used to identify lung primordial stem cell, which represents the earliest progenitor during lung morphogenesis.