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Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction Through Cytokinesis of Adult Cardiomyocytes

Cyclin A2 mediates cardiac regeneration of infarcted porcine hearts. A Change of Heart After Myocardial Infarction When blood flow is blocked off to the heart, the heart suffers permanent damage in part because cardiomyocytes are terminally differentiated and cannot proliferate. But what if these cells could be stimulated to divide? Some animals—like newts—have the ability to regenerate body parts when they are injured. Others—like zebrafish—can even regenerate heart tissue. Now, Shapiro et al. report that gene therapy can elicit a regenerative response in pig hearts. Cyclin A2 (Ccna2) has been shown to induce cardiac repair in small-animal models after myocardial infarction (MI). The authors have extended these studies by looking in the more translationally relevant pig model of MI. They found that Ccna2 delivered by an adenovirus improved heart function when compared with an adenoviral control. Cardiomyocytes in the pigs showed evidence of increased proliferation. If these data hold true in human studies, patients with MI can take heart. Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2 gene to infarcted porcine hearts invokes a regenerative response. We used a catheter-based approach to occlude the left anterior descending artery in swine, which resulted in substantial myocardial infarction. A week later, we performed left lateral thoracotomy and injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into peri-infarct myocardium. Six weeks after treatment, we assessed cardiac contractile function using multimodality imaging including magnetic resonance imaging, which demonstrated ~18% increase in ejection fraction of Ccna2-treated pigs and ~4% decrease in control pigs. Histologic studies demonstrate in vivo evidence of increased cardiomyocyte mitoses, increased cardiomyocyte number, and decreased fibrosis in the experimental pigs. Using time-lapse microscopic imaging of cultured adult porcine cardiomyocytes, we also show that Ccna2 elicits cytokinesis of adult porcine cardiomyocytes with preservation of sarcomeric structure. These data provide a compelling framework for the design and development of cardiac regenerative therapies based on cardiomyocyte cell cycle regulation.