Adult-like cardiac tissue. Credit: NIH.
Although most victims survive the 735,000 heart attacks that occur annually in the U.S., their heart tissue is often irreparably damaged – unlike many other cells in the body, once injured, heart cells cannot regenerate. According to a new UC San Francisco study, the issue may date back to our earliest mammalian ancestors, which may have lost the ability to regenerate heart tissue in exchange for endothermy – or as it’s known colloquially, “warm-bloodedness” – a Faustian evolutionary bargain that ushered in the age of mammals but left modern humans vulnerable to irreparable tissue damage after heart attack.
“Many of the lower vertebrates can regenerate body parts and organs, including the heart, but most mammals cannot. This feature was lost somewhere in the ectotherm-to-endotherm transition,” said Guo Huang, PhD, investigator at UCSF’s Cardiovascular Research Institute, assistant professor of physiology and senior author of the new study, published March 7 in the journal Science.
At first glance, there’s no obvious connection between a mammal’s ability to regulate its body temperature and its inability to repair heart damage. But the new study reveals that these seemingly disparate biological traits are inextricably linked – by thyroid hormones.
But Huang’s study revealed that these hormones are also responsible for shutting off cardiac cell division, thus preventing heart tissue from repairing itself after an injury. This discovery represents the first demonstrated connection between thyroid hormones, cardiac development and repair, and the evolution of endothermy.
“Before our study, scientists knew that thyroid hormones were important for controlling heart rate and heart contractility. But the link with heart regenerative potential had never been shown before,” Huang said.
Huang’s team took a multi-species approach, comparing heart cell “ploidy” – the number of copies of each chromosome pair in a cell – across 41 different vertebrate species. Ploidy is closely linked to a cell’s ability to divide and replicate. Virtually all actively dividing animal cells are diploid, containing only one pair of each chromosome, a copy inherited from mothers and another from fathers. By contrast, polyploid cells contain multiple copies of each pair and generally can’t divide.
This comparative approach revealed a clear connection between ploidy and body temperature. Cold-blooded animals – fish, amphibians and reptiles – had heart cells that were largely diploid and responded to cardiac injury by ramping up cell division. Warm-blooded mammals had heart cells that were overwhelmingly polyploid, and lab experiments confirmed that these cells rarely divide in response to cardiac damage.
“This led us to hypothesize that the same thyroid hormones responsible for regulating body temperature might also be responsible for the diploid-to-polyploid transition and the arrest of cardiac cell division,” Huang said.
The researchers confirmed their hunch in a series of lab experiments involving mice, a warm-blooded mammal in which heart cells normally cannot regenerate, and zebrafish, a cold-blooded animal noted for its ability to completely repair its heart, even if large chunks — up to 20 percent — are surgically amputated.
In the womb, mice have diploid heart cells that regularly replicate to produce new cardiac tissue. But the heart cells of newborn mice undergo rapid polyploidization and lose the ability to divide – events that coincide with a more than 50-fold increase in circulating thyroid hormones.
The researchers also produced genetically engineered mice whose heart cells lacked a functional receptor for thyroid hormone, which allowed their hearts to develop free from the influence of thyroid hormones. Unlike normal mice, these mutant mice were found to have significant numbers of actively dividing, diploid heart cells. Furthermore, when the scientists restricted blood flow to the heart – a condition that usually causes permanent damage to cardiac tissue – they observed a 10-fold increase in the number of dividing heart cells and 62 percent less scar tissue when compared with normal mice. Meanwhile, echocardiograms revealed an 11 percent improvement in heart function over normal mice after injury.
Just like in humans, thyroid hormones led to impaired cardiac regeneration in fish.
Authors: Additional authors on the paper are Kentaro Hirose, Alexander Y. Payumo, Stephen Cutie, Alison Hoang, Hao Zhang, Dominic Lunn, Rachel B. Bigley, Emily Wilson and Jeffrey E. Olgin of UCSF; Romain Guyot and Frederic Flamant of the University of Lyon; Hongyao Yu, Jiajia Wang and Guang Hu of the National Institute of Environmental Health Sciences; Megan Smith and Rochelle Buffenstein of Calico Life Sciences; Ellen Gillett and Frank Grützner of the University of Adelaide; Sandra E. Muroy, Tobias Schmid and Michael M. Yartsev of UC Berkeley; Kenneth A. Field and DeeAnn M. Reeder of Bucknell University; Malcom Maden of the University of Florida; Michael J. Wolfgang of the Johns Hopkins University School of Medicine; Thomas S. Scanlan of the Oregon Health & Science University; and Luke I. Szweda of the University of Texas Southwestern Medical Center.