Presenting Author: Olesya Plazyo
, Research Investigator at Univ. of Michigan Med. Sch.
Abstract:
Scleroderma (SSc), a female-biased autoimmune disease that causes inflammation and fibrosis in skin and internal organs, lacks effective treatment options. Our previous work, including single-cell RNA sequencing (scRNA-Seq) of skin from a large cohort of SSc patients, suggested that Hippo pathway regulates a female-specific immune gene network and drives myofibroblast differentiation in SSc skin. Our objective herein was to assess if inhibiting Hippo pathway pharmacologically can suppress disease signaling in SSc. We targeted distinct steps of Hippo pathway using 3 inhibitors (TRULI, Verteporfin, and MGM-CP1) that were applied to SSc skin biopsies ex vivo, followed by in-depth scRNA-Seq analyses to characterize molecular changes in affected cell populations. We found that Verteporfin, which prevents interaction of TEADs with YAP and VGLL3, selectively depleted myofibroblasts and endothelial-mesenchymal transition cells – the stromal cells pathologically activated in SSc. It also reduced expression of inflammatory, pro-fibrotic, and endothelial activation markers. Moreover, cell-cell interactions that sustain disease signaling were markedly hindered by Verteporfin. We saw a striking overlap between the genes downregulated by Verteporfin and those upregulated in SSc vs healthy patients. Thus, targeting Hippo pathway by Verteporfin effectively reverses molecular hallmarks of SSc. Our data further showcase the utility of this novel approach for modeling drug targeting ex vivo.
Targeting Hippo pathway diminishes disease signaling in scleroderma skin.
Category
Poster and Podium (Block Symposium)
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Date: May 4 Presentation Time: 03:15 PM to 04:30 PM Room: Exhibit Hall F1