Injury activated alveolar progenitors (IAAPs): the underdog of lung repair

Abstract

Alveolar epithelial type II cells (AT2s) together with AT1s constitute the epithelial lining of lung alveoli. In contrast to the large flat AT1s, AT2s are cuboidal and smaller. In addition to surfactant production, AT2s also serve as prime alveolar progenitors in homeostasis and play an important role during regeneration/repair. Based on different lineage tracing strategies in mice and single-cell transcriptomic analysis, recent reports highlight the heterogeneous nature of AT2s. These studies present compelling evidence for the presence of stable or transitory AT2 subpopulations with distinct marker expression, signaling pathway activation and functional properties. Despite demonstrated progenitor potentials of AT2s in maintaining homeostasis, through self-renewal and differentiation to AT1s, the exact identity, full progenitor potential and regulation of these progenitor cells, especially in the context of human diseases remain unclear. We recently identified a novel subset of AT2 progenitors named "Injury-Activated Alveolar Progenitors" (IAAPs), which express low levels of Sftpc, Sftpb, Sftpa1, Fgfr2b and Etv5, but are highly enriched for the expression of the surface receptor programmed cell death-ligand 1 (Pd-l1). IAAPs are quiescent during lung homeostasis but activated upon injury with the potential to proliferate and differentiate into AT2s. Significantly, a similar population of PD-L1 positive cells expressing intermediate levels of SFTPC are found to be expanded in human IPF lungs. We summarize here the current understanding of this newly discovered AT2 progenitor subpopulation and also try to reconcile the relationship between different AT2 stem cell subpopulations regarding their progenitor potential, regulation, and relevance to disease pathogenesis and therapeutic interventions.

Keywords: Alveolar type 2; Fgfr2b; Injury-activated alveolar progenitor; Lung injury repair; Pd-l1.

Fig. 1

Continuum of AT1 and AT2 formation from lung ontogeny to homeostasis. During early lung development (E12.5), AT1 and AT2 progenitors and bipotent progenitors (BPs) form from distal lung progenitor cells (Id2⁺Sox9⁺). From E13.5 to E17.5, Hopx⁺ AT1 progenitors differentiate into mature AT1 cells. Mature AT1 cells can be classified through the expression of insulin-like growth factor binding protein 2 (Igfbp2). Igfbp2⁺AT1 cells are terminally differentiated cells while Igfbp2⁻AT1s are progenitors for mature AT1s. AT1 progenitors at E14.5 onwards can also contribute to the AT2 lineage. Sftpc⁺ AT2 progenitors differentiate into mature AT2 cells. scRNAseq data indicate that mature AT2 cells can be subdivided into 2 groups (called cluster A and B). Cluster A is Sftpc^Low, Fgfr2b^Low and Hopx^High and could represent the progenitors for the IAAPs which express Pd-l1. It remains unclear if cluster A can contribute to the Hopx⁺Igfbp2⁻ AT1 progenitor cells. Cluster B is Sftpc^High Fgfr2b^High and represents mature AT2s. In this group, AEPs, Il-1r⁺ AT2s and Sca1⁺ AT2s stem cells are present. AT2 progenitors also contribute to the AT1 lineage from E14.5 onwards. The contribution of BPs to the AT1 and AT2 lineage during development is still unclear

Fig. 2

Possible function of Pd-l1 in IAAPs. In homeostasis, IAAPs are quiescent and do not significantly interact with the resident mesenchymal niche for mature AT2s. Around 50% of the IAAPs express Pd-l1. The function of Pd-l1⁻ IAAPs is still unclear. We propose that Pd-l1/Pd-1 signaling inhibits T cell activation, thereby keeping the inflammatory signals low. Mature AT2s interact with the resident mesenchymal niche which is essential for their survival. After injury, mature AT2s cells are dying and release damage activated molecular patterns (DAMPs) such as Il-1 which act on the macrophages for their recruitment and activation and on IAAPs for their proliferation. Inflammatory signals from the macrophages such as Il-1 and Tnfa also contribute to the proliferation of the IAAPs. IAAPs are also interact with the mesenchymal niche to receive survival/proliferative signals such as Fgfs. Activated/proliferative IAAPs progressively differentiate into Pd-l1⁻ mature AT2s to replenish the impaired mature AT2 pool. These Pd-l1⁻ AT2s also re-enforce the inflammatory niche. During resolution, activated Pd-l1^Low IAAPs give rise to Pd-l1^High quiescent IAAPs which mitigate inflammation through Pd-l1/Pd-1 signaling in macrophages