Investigating cardiac repair in a new adult mammalian model for regeneration, the spiny mouse, Acomys cahirinus

Nearly 800,000 Americans have a heart attack each year which results in the death of many cells and the production of scar tissue in the surviving ventricular tissue. The contractile force of the heart is never recovered and typically declines to a point where survival is threatened. The reason for this is because there is no regenerative or repair capacity in the adult mammalian heart.

However, we have discovered an adult mammal, the spiny mouse of the genus Acomys, that does not respond to organ damage in the typical mammalian fashion by scarring, but instead can completely regenerate tissues such as the skin, skeletal muscle and the ear. In the heart we have shown that the contractile force of the spiny mouse heart shows a remarkable recovery over a 4-week period following an induced heart attack and that there is very little fibrotic tissue laid down.

In this project we will investigate whether the cells of the spiny mouse heart can proliferate after a heart attack, which tissues of the heart respond to damage and what gene pathways are induced to stimulate this recovery. Discovering the mechanisms of how the adult spiny mouse recovers from a heart attack and translating this to humans will have a dramatic effect on the health of our society.

This project includes new undergraduate courses that will engage students in meaningful research activities.

Several tissues of the adult spiny mouse, Acomys, can completely regenerate after wounding including skin, muscle and the ear in contrast to the lab mouse which responds by fibrosis and scarring. We have shown that after a myocardial infarction the ventricle tissue of the spiny mouse heart shows very little fibrosis and can recover its contractile force over a 4-week period whereas the lab mouse does not and the ventricle shows widespread damage and a spreading of fibrosis throughout the tissue.

This project is intended to, firstly, answer the question of whether this is true cardiac regeneration by cardiomyocyte proliferation in histological studies using fibrosis markers, proliferation markers and cell death markers in comparison to the response of the lab mouse. We will be particularly concerned with whether Acomys forms a scar which then resolves or never forms a scar at all which we will further explore using a cryoinjury model.

Secondly, we will perform RNA-seq to look at the global gene expression profile of the damaged Acomys heart compared to Mus with a focus on known epicardial and cardiomyocyte signaling pathways and perform functional tests of these pathways using pharmacological inhibition. We will also identify the miRNA profiles which are present in the damaged Acomys heart and begin a functional analysis of selected candidates.

Thirdly, we will perform a single cell RNA-seq analysis of the damaged hearts to identify potentially new cellular gene networks which may be responsible for the improved response in Acomys.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.