MASTERMIND

This project focuses on regulators of the mechanical stretch-sensing machinery in the human hearts. We aim to better define their contribution to the resistance of human cardiac myocytes to diastolic stretch. The mechanical response to stretch of the myocardium is a critical determinant of cardiac performance in healthy and pathological hearts and impaired left ventricular relaxation with elevated filling pressures is observed in the vast majority of patients with heart failure (HF). However, the techniques and methods to characterize myocardial stretch-response have only recently emerged and the field is largely understudied, notably in human HF. This project is based on a recent discovery by the coordinator’s team related to a novel human & primate-specific microRNA that targets the mechanical stretch-sensing system and provides a favorable viscoelastic environment for relaxation and force generation of human cardiomyocytes. Transcriptomics experiments revealed targets that are associated with the cytoskeleton, the myofibril organization and the mechanosensing machinery of cardiomyocytes. The experimental program is developed on innovative human cell- & tissue- based models combined with specific stretching techniques. A multi-step program will combine several complementary approaches in order to measure changes in the mechanical and electro-mechanical responses to the candidate microRNA in normal and diseased human iPSC-derived cardiomyocytes. A unique and ultra-sensitive system has been developed by the coordinator’s team to allow the recording of forces generated by hiPSC-cardiomyocytes in response to progressive mechanical strains. High-performance computing imaging analysis will be used to characterize cytoskeletal remodeling and electro-mechanical coupling at the cell level. These approaches will be complemented with analyses on human hearts samples.