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Heart disease is the number one killer in the world, claiming the lives of over 7.4 million people in 2012. A new development has been made in the quest to heal a broken heart, and no, it was not a combination of dark chocolate and Adele. Juan Carlos Izpisua Belmonte of the Salk Institute has been working for over a decade to identify the molecular mechanism necessary to regenerate injured cardiac cells, and his lab has shown that it can be accomplished in live mice. This proof of principle demonstration could eventually lead to new treatments for cardiac patients. Izpisua Belmonte was senior author of the paper, which was published in Cell Stem Cell.
Many animals are quite adept at healing themselves, replacing limbs and organs as needed. While humans have homologs of many of the genes used to make these repairs like other animals, most of ours begin to slow down and turn off after birth, when all of our body parts are done forming. Upon reaching adulthood, humans just aren’t great at repairing injured tissues because the genes that know how to rebuild them aren’t being expressed the way they used to.
“Organ regeneration is a fascinating phenomenon that seemingly recapitulates the processes observed during development. However, despite our current understanding of how embryogenesis and development proceeds, the mechanisms preventing regeneration in adult mammals have remained elusive,” Izpisua Belmonte said in a press release.
Izpisua Belmonte’s lab discovered in 2003 that a certain signaling pathway preceded cardiac tissue regeneration. The process was fully explained in a paper published in 2010. His team discovered that injured heart cells weren’t healed through stem cells, but by cardiac cells that were actually dedifferentiated. They were more like precursor cells. The next logical question became if this could be achieved in mammals, but Izpisua Belmonte states he had to tread carefully.
“When you speak about these things, the first thing that comes to peoples’ minds is that you’re crazy,” he explained. “It’s a strange sounding idea, since we associate regeneration with salamanders and fish, but not mammals.”
While there are many scientists exploring tissue regeneration in a variety of ways, Izpisua Belmonte’s lab explored microRNAs—molecules that assist in post-transcriptional gene regulation. They ultimately identified four molecules that were highly suppressed during the regeneration of cardiac cells in zebrafish, but are also found in rodents and humans. Testing with live mice and cultured human heart tissue revealed that mammals do not shut off those miRNAs following cardiac injury like zebrafish do.
However, when those miRNAs were artificially repressed in the mouse model following a heart attack, the cardiac cells reverted back to a dedifferentiated state, like the zebrafish. The mice were able to repair the damage with less scarring and better blood flow than controls. Up to six months after the treatment, the differences between the two groups were still obvious. As the average life expectancy of a lab mouse is about 2 years, this was an incredible long-term result. Going forward, Izpisua Belmonte hopes to replicate these results in larger hearts for even longer periods of time.
