Heart failure is one of the main health problems worldwide, and the urgent medical needs relating to it have positioned cardiovascular research as one of the most actively evolving fields in regenerative medicine. Heart failure usually results from a deficiency of specialized cardiac muscle cells known as cardiomyocytes, being well documented in amphibia and fish and in developing mammals. After birth, however, human heart regeneration becomes limited to very slow cardiomyocyte replacement.
Although advances are contributing to the development of more efficient therapies, successful and efficient heart repair strategies are still lacking. Now, a study from researchers at the Spanish National Center for Cardiovascular Research shows that the ends of heart muscle cell chromosomes rapidly erode after birth, limiting the cells’ ability to proliferate and replace damaged heart tissue. The team state that their findings suggest potential new interventions to boost the heart’s capacity to repair itself after a heart attack. The study is published in The Journal of Cell Biology.
Previous studies show that newborn babies can repair injured myocardium, but, in adults, heart attacks cause permanent damage, often leading to heart failure and death. Newborn mice can also regenerate damaged heart tissue. Their heart muscle cells, or cardiomyocytes, can proliferate and repair the heart in the first week after birth, with this regenerative capacity lost as the mice grow older and the majority of their cardiomyocytes withdrawing from the cell cycle. Based on this, the lab wondered whether the cause of this cell cycle arrest might involve telomeres, repetitive DNA sequences that protect the ends of chromosomes. They hypothesized that if telomeres grow too short, cells can mistake chromosome ends for segments of damaged DNA, leading to the activation of a checkpoint that arrests the cell cycle. The current study investigates the length of telomeres in newborn mouse cardiomyocytes to show that the telomeres rapidly eroded in the first week after birth.
The current study shows that erosion of telomeres in newborn mice coincides with a decrease in telomerase expression and is accompanied by the activation of the DNA damage response and a cell cycle inhibitor called p21. Results show that telomerase-deficient mice have shorter telomeres than wild-type animals and their cardiomyocytes already begin to stop proliferating one day after birth.
Data findings show that when the hearts of one-day-old mice are injured, telomerase-deficient cardiomyocytes failed to proliferate or regenerate the injured myocardium. In contrast, results show that wild-type cardiomyocytes were able to proliferate and replace the damaged tissue. It was also observed that knocking out the cell cycle inhibitor p21 extended the regenerative capacity of cardiomyocytes, allowing one-week-old p21-deficient mice to repair damaged cardiac tissue much more effectively than week-old wild-type animals.
The team surmise that their findings show telomere dysfunction as a crucial signal for cardiomyocyte cell-cycle arrest after birth and suggest interventions to augment the regeneration capacity of mammalian hearts. They go on to add that maintaining the length of cardiomyocyte telomeres might boost the regenerative capacity of adult cells, improving the recovery of cardiac tissue following a heart attack. For the future, the researchers state that they are now developing telomerase overexpression mouse models to see if we can extend the regenerative window.
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