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New Biologic to Treat Heart Failure Modulates Immune and Stromal Networks for Endogenous Repair

ABSTRACT: Chronic heart failure remains a global epidemic without a cure. We report a first-in-class biologic that induces myocardial repair through multiple coordinated pathways including immune cell activation, anti-inflammation, and stromal cell recruitment to promote extracellular matrix (ECM) remodeling. Proteomics reveals a signature enriched in ECM reorganization and immune-modulatory pathways. The biologic acts in a site-specific, biphasic repair program: (1) an initial immune activation phase and (2) resolution characterized by the emergence of TREM2+ reparative macrophages and recruitment of stromal cells. These processes re-establish a regenerative milieu reminiscent of the neonatal heart. By integrating immune, stromal, and cardiomyocyte crosstalk, the biologic establishes a durable pro-reparative microenvironment that restores myocardial structure and function. This immune-guided strategy is a new paradigm for treating chronic ischemic heart failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE318772 | GEO | 2026/04/01

REPOSITORIES: GEO

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Project description:<p>Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition in the myocardium, is a critical target for heart disease treatments. Pw1 (paternally expressed gene 3) is an imprinted gene expressed from the paternally allele, and de novo purine biosynthesis (DNPB) is a crucial pathway for nucleotide synthesis. However, the roles of PW1 and DNPB in ECM production by cardiac fibroblasts during myocardial ischemia are not yet understood. To induce myocardial damage, we performed left anterior descending coronary artery ligation. We generated Pw1CreER-2A-eGFP and Pw12A-CreER knock-in mouse lines to evaluate the expression of the two Pw1 alleles in normal and injured hearts. Bisulfite sequencing was employed to analyze the DNA methylation of the Pw1 imprinting control region. We identified the phosphoribosylformylglycinamidine synthase (Pfas) gene, encoding the DNPB enzyme PFAS, as a direct target of PW1 using chromatin immunoprecipitation sequencing and real-time quantitative polymerase chain reaction. The role of DNPB in ECM production and cardiac fibrosis post-injury was examined in vitro using cultured cardiac fibroblasts and in vivo with Pfas-deficient mice. Our study demonstrates that myocardial infarction reduces DNA methylation at the imprinting control region of the maternally imprinted gene Pw1, triggering a switch from monoallelic imprinting to biallelic expression of Pw1 in cardiac fibroblasts. In activated cardiac fibroblasts, increased Pw1 expression promotes purine biosynthesis and induces ECM production by transcriptionally activating the DNPB factor Pfas. Notably, we identified that DNPB is essential for ECM production in activated fibroblasts and that loss of Pfas in fibroblasts limits cardiac fibrosis and improves heart function after heart injury. This study reveals that post-injury, the imprinting of Pw1 is disrupted, highlighting a novel role for the downstream DNPB pathway in cardiac fibrogenesis. Targeting DNPB presents a promising therapeutic strategy for improving cardiac repair following injury.</p>

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New Biologic to Treat Heart Failure Modulates Immune and Stromal Networks for Endogenous Repair

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