Abstract

There are 23 million heart failure patients worldwide, which has an enormous socio-economic impact. The only effective treatment for end-stage heart failure is heart transplantation, and regeneration of the heart is one of the best potential alternative treatments. Using a switchable mouse model of Myc and Cyclin T1 overexpression, we have demonstrated that increased levels of Cyclin T1 is sufficient to enable Myc driven transcription in adult hearts. Once transiently activated, Myc transcription leads to extensive cell-cycle entry through to cell division and a large increase in cardiomyocyte number in vivo. Our data indicate that Cyclin T1 is the critically rate-limiting factor for Myc in adult mouse heart and their co-expression can switch heart into a regenerative state. These results represent a significant milestone in the regenerative field and could be exploited therapeutically in the treatment of heart disease. As a first step towards translation, we have developed a modified synthetic mRNA that expresses Myc and Cyclin T1 mRNA as a prototypical therapeutic agent. These results represent a major step towards the development of a regenerative therapeutics based on stimulating cardiomyocyte proliferation in adults.