It is widely accepted that heart muscle cells in mammals stop replicating shortly after birth, limiting the ability of the heart to repair itself after injury. A study published by Cell Press in the journal Cell now shows that heart muscle cells in mice undergo a brief proliferative burst prior to adolescence, increasing in number by about 40% to allow the heart to meet the increased circulatory needs of the body during a period of rapid growth. The findings suggest that thyroid hormone therapy could stimulate this process and enhance the heart's ability to regenerate in patients with heart disease.
"We not only challenge 120-year-old dogma by showing that cardiac muscle cells are capable of extensive replication well into early preadolescence, but we also identify endocrine and local growth factors that could facilitate this process," says senior study author Ahsan Husain of the Emory University School of Medicine. "In the future, regenerative heart therapies in children may be possible by directly activating replication of cardiac muscle cells, without having to administer stem cells to the heart."
Past research has suggested that heart muscle cells stop dividing by the time mice are about one week old. But the heart grows substantially in mammals between birth and adolescence to accommodate an increase in the growing body's need for oxygenated, nutrient-rich blood. Heart muscle cells grow in size during preadolescence, but only to a limited degree, so the cellular processes accounting for the heart's rapid growth during this period have been unclear.
This shows an immunohistochemical identification of mitotic nuclei (red staining, aurora B+ nuclei) in a transverse cut left ventricle tissue section. DAPI was used to identify nuclei (blue) and alpha-sarcomeric actin was used to identify cardiomyocytes (green). Note widespread mitoses in left ventricular cardiomyocytes.
Credit: Cell, Naqvi et al.
Shedding light on this mystery, a research team led by Husain, Nawazish Naqvi of the Emory University School of Medicine, and Robert Graham of the Victor Chang Cardiac Research Institute found that preexisting heart muscle cells retain their ability to replicate until well after birth. These cells undergo an intense 24-hour spurt of cell division in preadolescent 15-day-old mice, increasing in number by about half a million or 40%. This process was initiated by a surge in blood levels of thyroid hormone, which activated a signaling pathway known to trigger cell proliferation. Moreover, the ability of the heart to recover after injury was enhanced in the period before adolescence, corresponding to approximately 8 to 10 years of age in humans, compared with later in development.
"The brevity of this proliferative burst could explain why it has previously gone undetected," Graham says. "We may be able to take advantage of this window of opportunity, for example, by giving thyroid hormone to improve repair of the heart in babies born with heart defects, or to reactivate heart muscle cells in adults who experience a heart attack later in life."