Identification of mesenchymal cell populations during neonatal lung development and their regulation by Fgf18

ABSTRACT: Alveologenesis is the final stage of lung development in which the internal surface area of the lung is increased to facilitate efficient gas exchange in the mature organism. The first phase of alveologenesis involves the formation of septal ridges (secondary septae) which are covered by alveolar type 1 (AT1) and alveolar type 2 (AT2) cells and contain mesenchymal cells, capillaries, and an elastin rich extracellular matrix (ECM). The second phase involves thinning of the alveolar septa. Mesenchymal cells include a transient population of alveolar myofibroblasts (MyoFB) and a stable but poorly described population of lipid rich cells that have been referred to as lipofibroblasts or matrix fibroblasts (MatFB). Using a unique Fgf18CreER lineage trace mouse line, cell sorting, single cell RNA sequencing, and primary cell culture, we have identified multiple subtypes of mesenchymal cells in the neonatal lung, including an immature progenitor cell that gives rise to mature MyoFB. We also show that the endogenous and targeted ROSA26 locus serves as a sensitive reporter for MyoFB maturation. We identify FGF18 as a key paracrine signal that coordinates MyoFB and MatFB function through distinct FGF signaling pathways. Conditional deletion of FGF18 disrupts septal ridge formation, alters MAPK and AKT signaling dynamics, and remodels communication between MyoFB and MatFB populations. Mechanistically, loss of FGF18 accelerates MyoFB maturation, reduces mesenchymal proliferation, and expands a MatFB-associated double-positive cell (DPC) state that co-expresses MyoFB and MatFB gene programs.

ORGANISM(S): Mus musculus

PROVIDER: GSE261508 | GEO | 2024/04/17

REPOSITORIES: GEO