Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate

Abstract

BackgroundEpithelial-mesenchymal cross talk is centerpiece in the development of many branched organs, including the lungs. The embryonic lung mesoderm provides instructional information not only for lung architectural development, but also for patterning, commitment and differentiation of its many highly specialized cell types. The mesoderm also serves as a reservoir of progenitors for generation of differentiated mesenchymal cell types that include αSMA-expressing fibroblasts, lipofibroblasts, endothelial cells and others. Transforming Growth Factor β (TGFβ) is a key signaling pathway in epithelial-mesenchymal cross talk. Using a cre-loxP approach we have elucidated the role of the TGFβ type I receptor tyrosine kinase, ALK5, in epithelial-mesenchymal cross talk during lung morphogenesis.ResultsTargeted early inactivation of Alk5 in mesodermal progenitors caused abnormal development and maturation of the lung that included reduced physical size of the sub-mesothelial mesoderm, an established source of specific mesodermal progenitors. Abrogation of mesodermal ALK5-mediated signaling also inhibited differentiation of cell populations in the epithelial and endothelial lineages. Importantly, Alk5 mutant lungs contained a reduced number of αSMApos cells and correspondingly increased lipofibroblasts. Elucidation of the underlying mechanisms revealed that through direct and indirect modulation of target signaling pathways and transcription factors, including PDGFRα, PPARγ, PRRX1, and ZFP423, ALK5-mediated TGFβ controls a process that regulates the commitment and differentiation of αSMApos versus lipofibroblast cell populations during lung development.ConclusionALK5-mediated TGFβ signaling controls an early pathway that regulates the commitment and differentiation of αSMApos versus LIF cell lineages during lung development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0242-9) contains supplementary material, which is available to authorized users.

Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease

“…However, none of the fibroblast subpopulations we observed were consistent with previously described lipofibroblasts, characterised by the lipid-droplet trafficking protein perilipin 2 (also known as ADRP, or adipose differentiation-related protein), as this was similarly expressed in all human fibroblasts 8 36. Other proposed lipofibroblast markers including LIPA , LPL and FABP5 also did not differentiate any specific fibroblast population, suggesting the lipofibroblast designation is not as phenotypically relevant in human lung, or possibly that these cells were lost during scRNA-seq processing 37 38. Recent studies have reported varying results as to whether lipid-droplet-containing cells are present in the human lung 8 39.…”

Single-Cell Deconvolution of Fibroblast Heterogeneity in Mouse Pulmonary Fibrosis

“…Lipofibroblasts are lipid-containing interstitial fibroblasts ( McGowan and Torday, 1997 ; Torday and Rehan, 2016 ). The previously suggested markers for lipofibroblasts include Adrp ( El Agha et al, 2017 ; Schultz et al, 2002 ), Pparg ( Varisco et al, 2012 ), Fabp1 , Fabp 4 , Fabp5 ( Chen et al, 1998 , 2012 ; Li et al, 2016 ), and Lpl ( Imamura et al, 2002 ). We found that these Adrp and Pparg highly expressing MCs were clustered together to form a distinct subpopulation, and at the same time, this cluster also expresses considerable levels of Fabp1,4,5 , Lpl , and Lipa .…”

Caffeine administration modulates TGF-β signaling but does not attenuate blunted alveolarization in a hyperoxia-based mouse model of bronchopulmonary dysplasia

“…We examined the impact of caffeine on TGF-β signaling in the lung, since TGF-β signaling is critical for lung alveolarization (26)(27)(28), and deregulated TGF-β signaling is associated with alveolar simplification in mice in response to both hypoxia (29) and hyperoxia (16,30,31), in experimental models of BPD. Furthermore, caffeine impacts TGF-β signaling in lung-derived cell-lines (13).…”