Researchers at the University of Texas Southwestern Medical Center have found that newly born mice can regenerate damaged heart muscle, a process that requires extensive modification of certain subunits in the heart but results in full recovery and normal development of heart muscle.
In a paper published last month in Science, the group described their findings. They followed the development of the newborn mice after the excision of heart muscle, the limits of their regenerative ability and the cellular mechanisms involved.
Damage to heart muscle, resulting from events such as heart attacks, is irreparable not only in humans, but in many other mammals.
Simpler hearts found in cold-blooded organisms do have the ability to regenerate should they sustain damage, and this new study finds that this regenerative ability is also shared by the more complex hearts of mice, albeit only for a limited time.
Like many cells throughout an organism, cardiomyocytes, the cells that compose heart muscle, are in a state where they have effectively exited the normal cell cycle of growth and division.
While in this state of non-division, cardiomyocytes form smaller subunits called sarcomeres that are responsible for the contractions that generate the pumping action of the heart.
Damage to these cells produces a difficult situation, as regeneration is difficult once the heart has developed, especially for the more complex hearts of mammals.
Some cardiomyocytes are replaced throughout a mammal’s lifespan, although this replacement is not sufficient to deal with significant damage to heart muscle that arises from such events as a heart attack.
However, as the group notes in their paper, previous researcher have found that specific amphibians and fish have the ability to regenerate heart muscle, even through adulthood.
These organisms have a two-chamber heart and their cardiomyocytes have only one nucleus each; mammalian hearts have four chambers and their cardiomyocytes become binucleates, having two nuclei, shortly after birth. The reasons for this difference are not well understood.
“There are some unproven
hypotheses about the benefit of binucleation such as a more robust transcriptional machinery for cardiomyocytes, but it still does not address why myocytes stop dividing,” Hesham Sadek, associate professor at the University of Texas Southwestern Medical Center, wrote in an email to The News-Letter. “There are some reports that the mononucleated cardiomyocytes are responsible for the limited myocyte turnover that occurs in the adult heart.”
The neonatal (newly born) mice that Sadek and his colleagues used had small portions of their hearts surgically excised.
Tracking heart development in the mice as they grew, the group found that the mice were able to completely recover from the surgical resection and fully develop their hearts within one month.
This ability to recover from such significant damage is limited in mice to their first seven days of life after which point mice no longer were able to regenerate damaged cardiac muscle.
One notable change when the cardiac muscle attempts to recover in these mice is a reorganization of the sarcomeres throughout the heart and not just at the site of the damage. This phenomena still lacks a clear explanation.
“The disorganization/reorganization of cardiomyocyte sarcomeres has been known to occur for a while now. This is a fascinating phenomenon that obviously needs to be investigated extensively,” Sadek wrote.
It is still uncertain at this point from an evolutionary perspective as to why adult mammals lack this ability to regenerate cardiac muscle, yet the ability is present in the newly born.
“I am not sure why mammals would choose to switch off this regenerative capacity,” Sadek wrote. “Perhaps because cardiac injury in mammals (for example, that results from myocardial infarction) is a relatively new occurrence in mammalian history, as mammals died of infectious or traumatic etiologies before they developed aging related disease.”
Understanding the mechanism may present a new and exciting opportunity for medicine especially for regeneration of damaged tissue from such medical events as heart attacks.
“This is obviously a complex biological process where a number of different cell types have to proliferate, organize, communicate and start functioning normally,” Sadek wrote. “Perhaps if we can one day reawaken this regenerative mechanism in adult tissue (by manipulating a gene or a set of genes, for example), regeneration may actually be feasible.”
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