Paradigms that define lung epithelial progenitor cell fate in development and regeneration

Abstract

Purpose of review: Throughout the lifespan, lung injury impedes the primary critical function essential for life-respiration. To repair quickly and efficiently is critical and is orchestrated by a diverse repertoire of progenitor cells and their niche. This review incorporates knowledge gained from early studies in lung epithelial morphogenesis and cell fate and explores its relevance to more recent findings of lung progenitor and stem cells in development and regeneration.

Recent findings: Cell fate in the lung is organized into an early specification phase and progressive differentiation phase in lung development. The advent of single cell analysis combined with lineage analysis and projections is uncovering new functional cell types in the lung providing a topographical atlas for progenitor cell lineage commitment during development, homeostasis, and regeneration.

Summary: Lineage commitment of lung progenitor cells is spatiotemporally regulated during development. Single cell sequencing technologies have significantly advanced our understanding of the similarities and differences between developmental and regenerative cell fate trajectories. Subsequent unraveling of the molecular mechanisms underlying these cell fate decisions will be essential to manipulating progenitor cells for regeneration.

Keywords: Lung development; cell fate; differentiation; lung regeneration; progenitor cells.

Figure 1:. Epithelial progenitor specification and differentiation during lung development.

(A) Lung identity is established at E9.0 with the induction of the transcription factor Nkx2.1 expression (yellow) by a combination of morphogens and transcription factors shown in the dark grey box (B) This is subsequently followed by the outpouching of the respiratory endoderm to form trachea and primary lung buds. The whole mount view of the lung is shown in the left while the morphology of a single branch is shown in the right side. The network of genes involved in maintaining Nkx2.1 expression (blue cells) is shown to the right. (C) By E12.5, the pseudoglandular stage involves the separation of the trachea (Tr) from the esophagus (Es). Whole mount view of the lung is on the left and the morphology of a single branch is on the right. During this stage, reciprocal mesodermal–endodermal interactions that govern the specification of Nkx2.1+ multipotent progenitor cells into a Sox2+ proximal (green cells) and Sox9+/Id2+ distal fate with concurrent alveolar cell fate specification programs (blue, red, orange cells) are shown in dark grey. (D) By the end of the pseudoglandular and into the canalicular stage, the majority of branching is complete. Whole mount view of the lung is on the left and the morphology of a single branch is on the right. The proximal Sox2+ progenitors begin to give rise differentiated cell lineages such as multiciliated and secretory cells (dark green cells). At the distal end, the specification of the Sox9+ cells to the alveolar fate is complete. The corresponding gene network involved in the specification is shown. (E) The proximal Sox2+ progenitors give rise to all proximal cell types: club cells, multi-ciliated cells, basal cells and neuroendocrine cells (green cells). The distal alveolar progenitors give rise to AT1s and AT2s (orange and red cells). The signaling networks that contribute to the differentiation of the progenitors are shown in the side.