Cell Cycle Activation Increases Cardiomyocyte Replication to Repair Heart Damage
Mammalian heart tissue is not very regenerative in the normal course of events. The cells are slow to divide and make up their numbers, even in response to damage, whether that caused by a heart attack or other structural failure in aging tissues, or the more minor wear and tear of everyday life. Given this, one of the present themes in regenerative research is to find ways to spur greater rates of cell division in heart tissue, a compensatory strategy, but possibly beneficial enough to be worth trying. Approaches such as blocking the Hippo pathway, or delivering microRNAs that influence some of the same machinery look promising in animal studies. Here, researchers outline another approach to trigger the cell cycle and thus increase the pace at which heart cells divide, but with a focus on achieving this goal in transplanted cells rather than native cells.
Biomedical engineers report a significant advance in efforts to repair a damaged heart after a heart attack, using grafted heart-muscle cells to create a repair patch. The key was overexpressing a gene that activates the cell-cycle of the grafted muscle cells, so they grow and divide more than control grafted cells. Up to now, an extremely low amount of engraftment of cardiomyocytes has been a stumbling block in hopes to use grafted cells to repair hearts after a heart attack. Without the successful repair that a graft could potentially offer, the damaged heart is prone to later heart failure and patient death.
In experiments in a mouse model, researchers showed that gene overexpression of the cell-cycle activator CCND2 increased the proliferation of grafted cardiomyocytes. This led to increased remuscularization of the heart at the dead-tissue site of the heart attack, a larger graft size, improved cardiac function and decreased size of the dead tissue, or infarct. Besides regenerating muscle, the grafted cells also increased new blood vessel formation at the border zone of the infarct, apparently through increased activation of the paracrine mechanism. The team used cardiomyocytes that were derived from human induced pluripotent stem cells, as they work toward a goal of eventual clinical treatment for human heart attack patients.
Researchers first showed that overexpression of CCND2 in the human induced pluripotent stem cells-derived cardiomyocytes, or hiPSC-CMs, increased the proportion of cells that exhibited markers for the S and M phases of the cell-cycle, and for cytokinesis, as measured in cell culture. When they injected overexpressing hiPSC-CMs into the infarct region and the border of the infarct in the mouse model, the left ventricle ejection fraction was significantly greater at week four and the infarct size was significantly smaller, as compared with mice receiving normal hiPSC-CMs that did not overexpress CCND2. Both treatments were improvements as compared with untreated mice. Overexpression also led to an increased number of engrafted hiPSC-CMs, as measured by bioluminescence and human cell markers.