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Addressing the interrelation between immunosenescence and post-myocardial infarction healing processes

Subject Area Cardiology, Angiology
Immunology
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 411619907
 
Final Report Year 2022

Final Report Abstract

Aging entails profound immunological transformations that can negatively impact myocardial homeostasis and predispose to myocardial diseases such as heart failure. However, preclinical research in the immune-cardiology field is mostly conducted in young healthy animals, which potentially weakens its translational relevance. In the present project, we have sought to mechanistically dissect how the aging T-cell compartment impacts myocardial homeostasis in aged mice, and to characterize how this altered cardio-immune crosstalk impacts the myocardial healing process after myocardial infarction (MI). More specifically, we have aimed at: a) dissecting how the aging T-cell compartment impacts myocardial cell biology in aged mice [working package (WP) 1]; b) characterizing the post-myocardial healing process in young versus aged mice (WP2); c) assessing whether modulation of the T-cell compartment in aged mice could impact the myocardial repair process (WP3); and d) scrutinizing some of our main observations in peripheral blood samples obtained from myocardial infarction patients (WP4). Our main findings can be summarized as follows: After performing single-cell transcriptomics of dissociated cells isolated from the heart and the heart draining lymph nodes of mice aging 2-, 6-, 12- and 18-month-old, we provide novel evidence that, with aging, the T-cell compartment undergoes clonal expansion with a pro-inflammatory bias, exposing the myocardium to chronic IFN-g signaling, which can recapitulate some inflammatory and metabolic shifts typically seen in failing hearts. Though physiological aging is not a disease entity, the agerelated cardio-immune alterations described herein may help explain how advanced age poses an increased risk for the development of heart failure. Performed a comprehensive characterization of the post-myocardial infarction healing responses in young versus aged mice and found evidence for dysregulated T-cell responses in the healing heart of elderly animals. Generated different "heterochronic chimeric mice” (i.e., animals harboring the cardiovascular and immune system of "different ages”) and enrolled them into myocardial infarction studies. A detailed description of our achievements and main observations is detailed below. For instance, we transplanted neonatal thymic tissues under the kidney capsule of aged mice to rejuvenate their T-cell compartment and then subjected the animals to experimental myocardial infarction. Likewise, together with Bernhard Haubner (Innsbruck) we adoptively transferred adult T-cells into neonatal mice and assessed how this impacted their myocardial regenerative capacity. Building on the experimental observations in mouse models, we further assessed markers of T-cell senescence in a cohort of MI patients. Taken together, our findings reveal novel aspects of cardio-immune crosstalk in health and post-MI repair, picturing the T-cell-derived interferon-gamma (IFN-g) as a major player impacting myocardial susceptibility to disease, blunting neonatal cardiac regenerative potential, and promoting adverse cardiac remodeling in elderly.

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