Elucidating fibroblast heterogeneity as a pathway to target organ fibrosis

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 DESCRIPTION (provided by applicant): Following surgical or traumatic injury, organs and tissues can heal by regeneration but more often than not, the repair process is complicated by fibrosis, resulting in reduced function and eventually organ failure. Activated fibroblasts (FBs) are the central mediators of both repair and fibrosis making it difficult to target fibrosis withou affecting repair. It is now well accepted that FBs represent a heterogeneous population of cells, yet we have a poor understanding of the molecular, cellular and functional basis of this heterogeneity. Our preliminary data have identified two major and distinct activated FB populations in mouse heart, skin and kidney following injury: Fibroblast specific protein 1 (FSP1)-expressing FBs and α-smooth muscle actin (αSMA)-expressing FBs, which appear at different time points after injury and remained as discrete populations during the healing process. Using mice which express GFP under FSP1 or α-SMA promoters we isolated these activated FB populations post cardiac injury and compared the gene expression profile of each population to those of FBs isolated from the uninjured heart. RNA sequencing indicated distinct molecular signatures. Particularly, pro-fibrotic genes such as type I collagen (Col I) and TGFβ signaling were significantly upregulated in αSMA-FBs, whereas genes involved in cellular homeostasis, tissue remodeling and cell-cell communication were upregulated in FSP1-FBs. Several studies, including from our group, have suggested that Secreted Frizzled-related protein 2 (sFRP2), a putative wnt pathway inhibitor, mediates wound repair by inhibiting fibrosis. We developed a novel mouse model in which we can induce expression of sFRP2 in activated FBs following injury. We found that early post-injury sFRP2 activation resulted in reduced fibrosis after myocardial, kidney and skin injuries without inhibiting tissue repair. Interestingly, our preliminary data showed that sFRP2 inhibited Col I synthesis and TGFβ signaling (but not Wnt signaling) only in αSMA-FBs but not in FSP-1 FBs in vitro. As such, sFRP2 represents an anti-fibrotic paracrine factor which may reduce tissue fibrosis by exerting distinct molecular effects on the post-injury (i.e. activated) FB subtypes. At the conclusion of this research application we will have characterized the cellular and functional heterogeneity of the major injury-activated FB populations and also have elucidated the mechanistic basis of the pro-reparative, antifibrotic effects of sFRP2 via its targeted and distinct effects on α-SMA-expressing FBs.