Abstract
Fibrosis accompanying wound healing can drive the failure of many different organs. Activated fibroblasts are the principal determinants of post-injury pathological fibrosis along with physiological repair, making them a difficult therapeutic target. Although activated fibroblasts are phenotypically heterogeneous, they are not recognized as distinct functional entities. Using mice that express GFP under the FSP1 or αSMA promoter, we characterized two non-overlapping fibroblast subtypes from mouse hearts after myocardial infarction. Here, we report the identification of FSP1-GFP+ cells as a non-pericyte, non-hematopoietic fibroblast subpopulation with a predominant pro-angiogenic role, characterized by in vitro phenotypic/cellular/ultrastructural studies and in vivo granulation tissue formation assays combined with transcriptomics and proteomics. This work identifies a fibroblast subtype that is functionally distinct from the pro-fibrotic αSMA-expressing myofibroblast subtype. Our study has the potential to shift our focus towards viewing fibroblasts as molecularly and functionally heterogeneous and provides a paradigm to approach treatment for organ fibrosis.
Highlights
Fibrosis accompanying wound healing can drive the failure of many different organs
Two markers expressed in the post-injury fibroblasts are fibroblast specific protein 1 (FSP1; S100A4) and α smooth muscle actin; neither marker is exclusively specific to fibroblasts[10,11,12,13]
FSP1 and α smooth muscle actin (αSMA) are present in distinct cells post injury
Summary
Fibrosis accompanying wound healing can drive the failure of many different organs. Activated fibroblasts are the principal determinants of post-injury pathological fibrosis along with physiological repair, making them a difficult therapeutic target. Two markers expressed in the post-injury (activated) fibroblasts are fibroblast specific protein 1 (FSP1; S100A4) and α smooth muscle actin (αSMA); neither marker is exclusively specific to fibroblasts[10,11,12,13] These markers are absent in the quiescent fibroblasts of heart, kidney, and lung. FSP1+ and αSMA+ fibroblasts have been reported to be non-overlapping fibroblast populations in the injured heart, skin, liver, and kidney[5,6,11,12,13,16], but their population dynamics as well as their functional and molecular differences in the context of tissue repair are lacking. We used transgenic mice in which FSP1 and αSMA-expressing cell populations were genetically tagged with GFP We isolated these fibroblast subpopulations from the injured murine heart, taking specific care to exclude non-fibroblast populations, which are known to express the FSP1 protein. Around 15% of the GFP+/FSP1+ cell population did not stain with CD45 or CD31 as identified through flow cytometry analysis and confocal microscopy, indicating the presence of a non-hematopoietic and non-endothelial FSP1-expressing cell subset (Supplementary Fig. 1, A, B)
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