Investigating the Molecular Triggers for Heart Regeneration Following Injury

Zebrafish are a highly regenerative species, capable of completely regrowing lost heart tissue. This is not the case in mammals, where the heart regenerates very poorly, with injury leading to scar tissue and loss of function. Thus researchers are exploring the mechanisms of regeneration in zebrafish and other highly regenerative species, such as salamanders, in search of important differences that might become the basis for regenerative therapies. The research here is an example of this sort of work. In any case where trigger mechanisms for regeneration are better mapped, there is the possibility that regeneration might be enhanced via intervention at one of the triggers.

Heart muscle cells called cardiomyocytes hold on to the capacity to reprogram themselves and alter their fate in response to heart damage. Although several signalling cues are known to be involved in this regeneration activity, it is not well understood how heart injury switches on these pathways to initiate heart cell reprogramming. "Recent studies suggest that biomechanical forces generated by blood flow can contribute to heart development through modulating cell signalling. We wanted to explore this further by seeing whether mechanical forces caused by altered blood flow during heart injury also activate these signalling pathways to control heart cell reprogramming and regeneration."

The team first looked at how heart injury affects signalling of an important heart development molecule called Notch in zebrafish. They found that injury-induced Notch activity peaks at 24 hours after injury but diminishes as the heart regenerates, so that by 96 hours it has returned to normal. If Notch is blocked, however, this prevents heart cell growth and stops heart precursor cells from reprogramming and maturing into cells that can replace the damaged cells.

They next explored whether heart injury could alter blood flow forces and, in turn, control injury-induced Notch signaling. Klf2a is a molecule that responds to changes in blood flow and switches on certain genes in response. In regions of the injured heart where blood flow was most disrupted, they found that levels of Klf2a were increased. In addition, they found that levels of Klf2a overlapped with the levels of Notch.

Further experiments revealed that, when mutated, Trpv4 - a molecule that is known to 'sense' changes in blood flow and can switch on the gene for Klf2a - led to a reduced amount of genes that drive heart cell growth and fewer cells maturing to replace the damaged tissue. Additionally, the team found that changes in blood flow controls heart cell reprogramming and growth via another two molecules, BMP and Erbb2. As these molecules are important for heart regeneration in mammals, the changes observed in the zebrafish may also hold true for other organisms, including humans.



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