|Defining the “F” in fibroblast: a definitive ientification of mesenchymal populations in healhty and fibroic lungs
|S.C.Rowan, X. Liu, C. Liang, Y. Wang, P.W. Noble, D. Jiang,
|Cedars-Sinai Medical Center, LA, USA & University College Dublin, Ireland
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|Pulmonary mesenchymal cells are critical players in the pathogenesis of fibrotic lung diseases like Idiopathic Pulmonary Fibrosis. They are increasingly recognized as highly heterogeneous but a consensus on the subpopulations present in the lung, and discriminative for each subtype, remains elusive.
We completed scRNA-seq analysis, and re-analysis of publicly available datasets, of mesenchymal cells from the post-natal, adult and the aged fibrotic lungs of humans. We delineated the transcriptome of lipofibroblasts, myofibroblasts, pericytes, mesothelial cells, smooth muscle cells, and a novel population delineated by Ebf1 expression. Comparative analysis of murine and human lung mesenchymal cells revealed homologous subpopulations with conserved transcriptomic signatures.
We demonstrated that all mesenchymal sub-populations, not solely myofibroblasts, contributed to the expression of extracellular matrix genes in fibrosis. We did not observe evidence of transdifferentiation between fibroblast subtypes in fibrosis. Rather these data suggest that mesenchymal fate decision occur during embryonic development and the identified subtypes remain distinct into adulthood and in the aged healthy and fibrotic lung.
This analysis challenges long held beliefs on the contribution of fibroblast subtypes to fibrotic lung disease and provides a basis for definitive identification of the different mesenchymal populations in development, heath and disease.