Abstract
Introduction: Mammal cardiomyocytes (CMs) lose their proliferative capacity early after birth and switch to an adult phenotype, characterized by organized sarcomeres. The mechanisms that control this switch remain largely elusive. Among the changes experienced by the heart at birth is a sudden increase in mechanical load. Hypothesis: This study tests the hypothesis that variations in mechanical loading may regulate both the proliferation and the maturation of cardiomyocytes. Methods: Engineered heart tissues (EHTs) were generated using neonatal rat heart cells, with a modified protocol allowing to alter mechanical load. Unloading is obtained by reducing the distance between the silicon posts that anchor the extremities of the EHT, while overloading is induced by changing Young’s module of posts using metal braces. Adult heart unloading in vivo was achieved by heterotopically transplanting a mouse heart into the neck of syngeneic recipient mice, which were injected with EdU twice per week. Both hearts, native and transplanted, were harvested at day 30. Results: In line with our hypothesis, mechanical unloading of developed EHTs significantly increased the percentage of EdU-, Ki67- and pH3-positive CMs at 72 hours. In contrast, increasing afterload induced CM maturation, characterized by increased cross-sectional area and force of contraction, associated with reduced proliferation. Consistently, heterotopically transplanted hearts showed a significant increase in the the number of proliferating CMs in both ventricles, which were almost absent in native hearts. Conclusions: Our data indicate that mechanical unloading induce CM proliferation in both rat EHTs and an in vivo in a mouse model of heterotopic heart transplantation. These results support our initial hypothesis and indicate that mechanical loading is a master regulator of cardiomyocytes proliferation and maturation. Ongoing experiments aim at identifying the molecular mechanisms that regulate this process.
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