Role of Fibroblast Growth Factor 10 in Mesenchymal Cell Differentiation During Lung Development and Disease

Abstract

During organogenesis and pathogenesis, fibroblast growth factor 10 (Fgf10) regulates mesenchymal cell differentiation in the lung. Different cell types reside in the developing lung mesenchyme. Lineage tracing in vivo was used to characterize these cells during development and disease. Fgf10-positive cells in the early lung mesenchyme differentiate into multiple lineages including smooth muscle cells (SMCs), lipofibroblasts (LIFs) as well as other cells, which still remain to be characterized. Fgf10 signaling has been reported to act both in an autocrine and paracrine fashion. Autocrine Fgf10 signaling is important for the differentiation of LIF progenitors. Interestingly, autocrine Fgf10 signaling also controls the differentiation of pre-adipocytes into mature adipocytes. As the mechanism of action of Fgf10 on adipocyte differentiation via the activation of peroxisome proliferator-activated receptor gamma (Pparγ) signaling is quite well established, this knowledge could be instrumental for identifying drugs capable of sustaining LIF differentiation in the context of lung injury. We propose that enhanced LIF differentiation could be associated with improved repair. On the other hand, paracrine signaling is considered to be critical for the differentiation of alveolar epithelial progenitors during development as well as for the maintenance of the alveolar type 2 (AT2) stem cells during homeostasis. Alveolar myofibroblasts (MYFs), which are another type of mesenchymal cells critical for the process of alveologenesis (the last phase of lung development) express high levels of Fgf10 and are also dependent for their formation on Fgf signaling. The characterization of the progenitors of alveolar MYFs as well the mechanisms involved in their differentiation is paramount as these cells are considered to be critical for lung regeneration. Finally, lineage tracing in the context of lung fibrosis demonstrated a reversible differentiation from LIF to "activated" MYF during fibrosis formation and resolution. FGF10 expression in the lungs of idiopathic pulmonary fibrosis (IPF) vs. donors as well as progressive vs. stable IPF patients supports our conclusion that FGF10 deficiency could be causative for IPF progression. The therapeutic application of recombinant human FGF10 is therefore very promising.

Keywords: Fgf10; alveolar myofibroblasts; fibrosis; lipofibroblasts; lung.

FIGURE 1

(A) Schematic of the cells in the distal part of the lung at E13.5 showing the different lung domains including the mesothelium (meso), the submesothelial mesenchyme (SMM), the subepithelial mesenchyme (SEM), the epithelium (epi) and the position of the different mesenchymal cell progenitors located at this stage. (B) Interaction between AT2 and LIF. LIF produce leptin and triglycerides that are essential for surfactant production. The Pthrp/ Pparγ axis is critical for LIF formation and maintenance. (C) Fgf10-positive cells lineage-traced at E11.5 and analyzed at E18.5. (D) Fgf10 acts directly on the mesenchyme to induce the differentiation of LIF progenitors. Tgfβ1 antagonizes this differentiation (adapted from El Agha et al., 2014; Al Alam et al., 2015; Chao et al., 2015). (E) Table summarizing the cell types expressing Fgf10 in the lung during development and disease. IPF, Idiopathic pulmonary fibrosis; PH, pulmonary hypertension.

FIGURE 2

Schematic representation of alveologenesis and cell types involved. (A) During the saccular stage (stage preceding the beginning of alveologenesis), the lung exhibits primitive alveoli (called saccules), which are surrounded by blood vessels, collagen fibers and nerves. (B) The alveolar saccule in the saccular stage is characterized by the presence of AT1/2, coating the walls of the saccule, surfactant production, production of collagen and elastin by fibroblasts as well as expansion of the capillary tree. (C) During the alveolar stage, the lung undergoes a subdivision of the saccules by a process called “secondary septation” that will give rise to mature alveoli. (D) Secondary septa start to appear at the place of elastin deposition, which is produced by alveolar MYF. The septa elongate toward the alveolar sac airspace. A double layer of capillaries become thinner giving rise to a one-layer network for more efficient gas exchange. (E) The origin and fate of “activated” MYFs was investigated using lineage-tracing approaches. LIFs are progenitors for “activated” MYFs in lung fibrosis. Some of the labeled “activated” MYFs dedifferentiate to LIF during fibrosis resolution. Pparγ activation blocks LIF-to-MYF transdifferentiation induced by Tgfβ1 and enhances “activated” MYF-to-LIF transdifferentiation. (adapted from Chao et al., 2016; El Agha et al., 2017).