Blood Flow Changes Signal Heart Cells to Regenerate

Altered blood flow resulting from heart injury switches on a communication cascade that reprograms heart cells and leads to heart regeneration in zebrafish, according to a study published today in eLife. These signaling pathways are also present in mammals, so the results could help scientists find ways to repair heart tissue after a heart attack.

Heart muscle cells retain the capacity to reprogram themselves in response to heart damage. Although several signaling cues are known to be involved in this regeneration activity, how heart injury switches on these pathways has not been well understood.

“Recent studies suggest that biomechanical forces generated by blood flow can contribute to heart development through modulating cell signaling,” explains first author Manuel Gálvez-Santisteban of the University of California, San Diego. “We wanted to explore this further by seeing whether mechanical forces caused by altered blood flow during heart injury also activate these signaling pathways to control heart cell reprogramming and regeneration.”

The team first looked at how heart injury affects signaling of an important 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, heart cell growth and reprogramming stops.

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. They also found that levels of Klf2a and Notch overlapped.

Trpv4 is a molecule that is known to sense changes in blood flow that can switch on the gene for Klf2a. When mutated, heart cell growth and maturation was impaired. Additionally, the team found that changes in blood flow controls heart cell reprogramming and growth via another two molecules, BMP and Erbb2.

“Our findings show how the heart senses and adaptively responds to environmental changes caused by injury and provide insight into how flow-mediated mechanisms may regulate heart cell reprogramming and heart regeneration,” concludes senior author Neil Chi, also of UC San Diego.