PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

Luis R. Rodriguez; Soon Yew Tang; Willy Roque Barboza; Aditi Murthy; Yaniv Tomer; Tian-Quan Cai; Swati Iyer; Katrina Chavez; Ujjalkumar Subhash Das; Soumita Ghosh; Charlotte Cooper; Thalia T. Dimopoulos; Apoorva Babu; Caitlin F. Connelly; Garret A. FitzGerald; Michael F. Beers

doi:10.1172/jci.insight.172977

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

Luis R. Rodriguez,¹ Soon Yew Tang,² Willy Roque Barboza,¹ Aditi Murthy,¹ Yaniv Tomer,¹ Tian-Quan Cai,³ Swati Iyer,¹ Katrina Chavez,¹ Ujjalkumar Subhash Das,² Soumita Ghosh,² Charlotte Cooper,¹ Thalia T. Dimopoulos,¹ Apoorva Babu,⁴ Caitlin F. Connelly,³ Garret A. FitzGerald,² and Michael F. Beers¹

Published November 7, 2023 - More info

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Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F_2a, and its cognate receptor FPr (Ptfgr) are implicated as a TGFβ1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (I^ER-Sftpc^I73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated I^ER-Sftpc^I73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. I^ER-Sftpc^I73T mice crossed to a Ptgfr null (FPr^-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr^+/+ cohorts. I^ER-Sftpc^I73T/FPr^-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an “inflammatory/transitional” cell state in a PGF_2a/ FPr dependent manner. Collectively, the findings provide evidence for a role for PGF_2a signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

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PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice

Luis R. Rodriguez,1 Soon Yew Tang,2 Willy Roque Barboza,1 Aditi Murthy,1 Yaniv Tomer,1 Tian-Quan Cai,3 Swati Iyer,1 Katrina Chavez,1 Ujjalkumar Subhash Das,2 Soumita Ghosh,2 Charlotte Cooper,1 Thalia T. Dimopoulos,1 Apoorva Babu,4 Caitlin F. Connelly,3 Garret A. FitzGerald,2 and Michael F. Beers1

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