Posted on Apr 09, 2021, 4 p.m.
Although humans show minimal regenerative capability, zebrafish can regenerate their hearts through a mechanism whereby heart muscle cells (cardiomyocytes) revert to a less mature state and then proliferate to replace the damaged tissue. Ogawa et al. show that Krüppel-like factor 1 (Klf1/Eklf), a transcription factor well known for its role in red blood cell development, is an essential factor for heart regeneration in zebrafish. Klf1 is specifically expressed in cardiomyocytes after injury, and its activation is sufficient to stimulate new cardiomyocyte production without injury. This potent effect is achieved through reprogramming of gene networks regulating cardiomyocyte differentiation and mitochondrial metabolism.
Researchers in Australia have identified a gene in zebrafish that can regenerate damaged heart muscles. The team, sharing its discovery in Science, believes this gene may be able to help humans repair their own cardiac muscles after a heart attack.
Kazu Kikuchi, MD, who lead the research at the Victor Chang Cardiac Research Institute (VCCRI) in Sydney, detailed why this could be such a crucial finding for the future of cardiac care.
“Our research has identified a secret switch that allows heart muscle cells to divide and multiply after the heart is injured. It kicks in when needed and turns off when the heart is fully healed,” he said in a prepared statement. “In humans where damaged and scarred heart muscle cannot replace itself, this could be a game-changer.”
Zebrafish share more than 70% of all human genes, Kikuchi added, and those similarities suggest that that “has the potential to save many, many lives and lead to new drug developments.”
Bob Graham, MD, head of the VCCRI’s molecular cardiology and biophysics division, elaborated on the potential of this discovery in the same statement.
“The team has been able to find this vitally important protein that swings into action after an event like a heart attack and supercharges the cells to heal damaged heart muscle,” he added. “It's an incredible discovery.”
The gene in question, the researchers noted, is not the same part of the body responsible for initial heart development. This fact alone, Graham explained, stands as a momentous takeaway from the team’s work.
“The gene may also act as a switch in human hearts. We are no whopping further research into its function may provide is with a clue to turn on regeneration in human hearts, to improve their ability to pump blood around the body.”
“This is clear evidence that the regeneration you get after a heart injury is not the same as what happens during the development of the heart but involves an entirely different pathway; an issue that has been debated for years,” he said.
Read the group’s full analysis here.
Cardiac regeneration requires dedifferentiation and proliferation of mature cardiomyocytes, but the mechanisms underlying this plasticity remain unclear. Here, we identify a potent cardiomyogenic role for Krüppel-like factor 1 (Klf1/Eklf), which is induced in adult zebrafish myocardium upon injury. Myocardial inhibition of Klf1 function does not affect heart development, but it severely impairs regeneration. Transient Klf1 activation is sufficient to expand mature myocardium in uninjured hearts. Klf1 directs epigenetic reprogramming of the cardiac transcription factor network, permitting coordinated cardiomyocyte dedifferentiation and proliferation. Myocardial expansion is supported by Klf1-induced rewiring of mitochondrial metabolism from oxidative respiration to anabolic pathways. Our findings establish Klf1 as a core transcriptional regulator of cardiomyocyte renewal in adult zebrafish hearts.
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