Myocardial Infarction, Precision-Engineered T Regulatory Cells to the Rescue

Despite decades of extensive basic and clinical studies, myocardial infarction (MI) still remains as one of the leading causes of mortality and morbidity worldwide, due to the complex underlying pathologies with intertwined inflammatory and fibrotic processes that persist beyond the initial onset of heart attack 1 .Since cardiac fibrosis is one of the most important factors underlying the progression of cardiac disease and heart failure by depositing excessive extracellular matrix, increasing myocardial stiffness and impairing diastolic filling, translational studies for developing experimental therapeutics have extensively focused on approaches for controlling fibrosis.In a landmark Nature study published in 2019, Epstein and colleagues established a proof of concept for repurposing chimeric antigen receptor (CAR) T cell therapy to treat cardiac fibrosis 2 .The study identified fibroblast activation protein (FAP) as a highly enriched surface antigen on activated myofibroblasts (cells that are responsible for driving maladaptive extracellular matrix deposition and fibrosis), while exhibiting minimal expression in quiescent fibroblasts or healthy tissues.CAR-CD8 killer T cells engineered to target FAP were shown to selectively ablate these pathogenic myofibroblasts in a murine model of heart failure, resulting in a substantial reduction in fibrotic burden and concomitant improvement of heart function 2 .In a follow-up Science report, the Epstein group later refined the strategy by using mRNA-loaded lipid nanoparticles to generate transient CAR-T cells in vivo, potentially mitigating safety concerns associated with permanent T-cell modification 3 .In addition to fibrosis, low-grade inflammation sustained by persistent activation of innate and adaptive immune cells promotes continued cytokine release, fibroblast activation, and extracellular matrix turnover, exacerbating fibrotic signaling and impairing tissue homeostasis.Recent advances suggest that immune cell-based therapies that can collectively control excessive inflammation, enable effective repair, and prevent maladaptive fibrosis may be more effective as compared to approaches solely targeting the fibrosis aspect of heart failure.Indeed, existing literatures support the notion that increasing T-regulatory cells (Treg) can promote inflammation resolution and improve cardiac repair 4 .Tregs play a critical immunomodulatory role in cardiovascular disease by restraining pathogenic leukocytes including inflammatory macrophages and effector T cells that collectively drive inflammation, tissue injury, and adverse cardiac remodeling 5,6 .In the injured heart,