Signalling pathways in cardiac regeneration

Regeneration is a homeostatic mechanism evolved to maintain or restore the original architecture of a damaged tissue by recapitulating part of its original embryonic development. Our focus has been to intervene in signalling mechanisms at work in the regeneration process to increase the efficiency of mammalian tissue repair. In response to traumatic injury, both skeletal and cardiac muscle activate signalling cascades involved in inflammation, cell death and fibrosis, often at the expense of cell survival and regeneration. In contrast, mice expressing a local isoform of insulin-like growth factor 1 (mIGF1) as a muscle-specific transgene maintain skeletal muscle integrity and ageing, counter muscle decline in degenerative muscle disease, and show enhanced stem cell homing to damaged muscle. Under the control of a cardiac-specific promoter, the mIGF1 transgene directs efficient repair of infarcted heart tissue without scar formation. In both models, novel signalling pathways are employed, suggesting specific mechanisms through which mIGF1 improves regeneration and providing potential targets for clinical intervention.