(WHS-K2.05) "Elucidating the Role of sFRP2 in Modulating Organ Fibrosis"
Thursday, May 16, 2024
9:15 AM – 10:15 AM East Coast USA Time
Background Fibrosis is the typical response to injury, which leads to distorted architecture, pathologic signaling and ultimately organ dysfunction. In cardiac tissue specifically, a fibrotic response to injury can lead to a decrease in the heart’s ability to function, which plays a significant role in the pathogenesis of most heart diseases. Secreted frizzled-related protein (sFRP2) has been identified as a mesenchyme derived factor that augments post-myocardial infarction repair, in part by down-regulating fibrosis. Yet, the molecular mechanism that regulates sFRP2’s effect on fibroblasts in modulating tissue fibrosis is incompletely understood. Methods We have generated a transgenic mouse model in which we can temporally and spatially regulate the expression of sFRP2 in injury-induced activated FSP1+ fibroblasts. These transgenic mice received bone marrow transplantation (BMT) from C57Bl/6 mice to ensure specificity of sFRP2 protein in fibroblasts, since FSP1 is also expressed in hematopoietic cells. sFRP2 expression was induced post-infarct following tamoxifen treatment in mice expressing sFRP2 under FSP1 promoter. These mice were assessed in vivo and in vitro for injury-induced fibrotic responses in two distinct models, heart and skin. Results Post-injury induction of sFRP2 exerted an anti-fibrotic effect in comparison to control Cre mice in heart as well as skin. sFRP2 overexpression in heart following myocardial infarction resulted in reduced scar size, improved function, and reduced adverse cardiac remodeling. In addition, assessment of the collagen content following excisional wound (skin injury) demonstrated significant reduction in dermal collagen deposition in sFRP2 overexpressing transgenic mice. Significant reduction in Wnt signaling, TGF beta signaling and collagen production was identified in mice overexpressing sFRP2. Conclusion Post-injury sFRP2 over-expression in mouse FSP1-fibroblasts resulted in reduction in fibrosis in two different organ injury models. Elucidating the mechanism that modulate sFRP2’s antifibrotic role will provide valuable insights on how this protein targets fibrosis and promotes regenerative repair. Identification of sFRP2’s role will also provide a potential use for such regulators as a way to target specific post-injury fibrotic processes such as Wnt and TGF beta signaling and inhibit pathological fibrosis without interfering with normal wound healing.