Neuro-adipose regulated spatial activation of macrophages in cardiac repair

• Applicant: Dr. Suphansa Sawamiphak
• Subject Area: Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548239319

Myocardial infarction (MI) is a leading cause of morbidity and mortality globally. Current therapeutic strategies primarily focus on mitigating left ventricular pathological remodelling post-injury or modulating cardiovascular risk factors do not meet the clinical need. Alternative strategies attempted to replace lost cardiomyocytes through stem cell-, biomaterial-, or pharmacology-based interventions show limited efficacy. Unlike adult human hearts with negligible regenerative potential that repair myocardial damage by forming permanent non-contractile fibrotic scar, zebrafish hearts can fully regenerate. It has become clear from studies elucidating intrinsic mechanism of scarless repair of the teleost heart that an effective therapeutic strategy must promote myocardial self-renewal and simultaneously regulate fibrotic response to enable timely scar regression to relieve stiffening strain on the contractile tissue. Importantly, these events orchestrating regenerative repair of the heart are achievable through intricate interactions among the nervous, immune, and cardiovascular system. Our recent findings revealed that transient fibrotic response critical for scar resolution and myocardial regrowth requires neural signalling of macrophage activation. A key question arising from this newly recognized neuroimmune crosstalk, namely why does this mechanism fail to promote regenerative repair in the human heart? Here, we aim to tackle the influence of obesity, the most prevalent risk factor of human MI, on the neural regulation of immune response to cardiac injury. By modelling acute MI in the presence of obesity zebrafish, we will address causal relationship between the metabolic stress condition and regenerative potential. Furthermore, we aim to unravel the role of obesity-driven remodeling of cardiac tissue microenvironment in local neural output and response of resident macrophages to the signalling cue. Results from the study proposed here are anticipated to improve our understanding in the nervous-immune orchestration of scarless repair of the heart, with direct translational implications to timely control fibrotic response and harness the pro-regenerative potential of immune cells in clinical setting when MI is commonly present with metabolic syndrome.

• DFG Programme: Research Grants