MRC-BHF Cardiovascular Stem Cell Research Strategic Development Grant

Heart muscle does not grow back following a heart attack. For this reason, a stem cell approach to regenerate the heart is attractive. We focus on using embryonic stem cells (primitive cells with the ability to become every cell type desired) or a rare and unexpected stem cell we discovered, which exists in heart muscle itself. These experiments are aimed at solving several fascinating and important problems. Where do these cardiac stem cells come from during life, and what do they become in healthy and diseased hearts? Can we improve their number or function to enhance the repair and regeneration of the heart? What specific genes and connections of genes control cardiac muscle creation? Using advanced robotic methods that test hundreds or thousands of conditions, and advanced genetic methods that measure every gene in the cells, we will study which genes are active in heart-forming cells and which are important for the cells function.

In humans and other mammals, the inability of adult myocardium to overcome cell death with equivalent muscle cell creation makes heart muscle cell number unusually well-posed as a therapeutic target. Notwithstanding a few exemplars, the clinical aspirations arising from this biological limit have led to a plethora of largely repetitive empirical trials with weak outcomes overall, little proven impact on myocyte formation and, typically, weak scientific underpinnings. The need is unequivocal for better, deeper, more systematic knowledge?including genomic, post-genomic and functional characterization of relevant cardiopoietic cells, if a step change is ever to occur in progress towards cardiac regeneration as a workable clinical goal. Inherently, the problem requires a team-based or consortium approach, as is sought by the present MRC-BHF call. This Cardiovascular Stem Cell Research Strategic Development Grant at Imperial College London is a coordinated effort of the National Heart and Lung Institute (NHLI) headed by Professor Michael Schneider FMedSci, an innovative pioneer in cardiovascular stem cell biology, and the MRC Clinical Sciences Centre (CSC) headed by Professor Amanda Fisher FMedSci, a distinguished authority on stem cell epigenetics. Members of the proposed Cardiovascular Stem Cell Research Strategic Development Grant include key experts in mouse genetics, genomics and epigenetics, focused collectively on a series of essential fundamental problems: (1) fate-mapping to define the embryological origin of cardiac progenitor cells and their subsequent contribution to the heart in health and disease; (2) sirtuins and insulin-like growth factor-1 as epigenetic modulators of cardiac repair; (3) chromatin profiling and epigenetic reprogramming of cardiac progenitor cells; (4) high-throughput high-content analyses of cardiac progenitor cell differentiation and function; and (5) next-generation genomics for gene, pathway and chromatin studies in cardiac progenitor cells. A 6,0000 m2 Cardiovascular Research Centre is under construction at Imperial?s Hammersmith campus, adjacent to expanded MRC facilities, and a highly robust recruitment drive is already underway. Apart from the specific questions to be addressed, the overriding goal of this proposal is alignment, integration and capacity-building, establishing an internationally competitive cardiovascular stem cell community that would help lead UK science in this realm and warrant a full-scale Centre in three years? time.