Abstract 516: Homotypic Fusion Can Generate Bi- and Multi-nucleated Cardiomyocytes in the Postnatal Murine Heart

Multinucleation is an important and prominent phenotype of postnatal mammalian cardiomyocytes, and its occurrence in early life correlates with the loss of regenerative potential in mice. This phenomenon is believed to be the result of mitosis followed by cytokinesis failure, although direct proof of this mechanism has not been provided for every single adult cardiomyocyte. Moreover, many multi-nucleated cells in other organs are formed after homotypic cell fusion. Although heterotypic cell fusion between cardiomyocytes and circulating cells has been described as a rare event, it is not known whether homotypic myocyte fusion occurs and if it can lead to bi- and multi-nucleation. We developed a novel mouse model wherein multi-color fluorescent protein reporter expression occurs stochastically only in cardiomyocytes (Myh6-MerCreMer;Rosa26-Confetti). Using pulse-chase experiments during development and at birth, we show that a small fraction of cardiomyocytes fuses with other myocytes to generate binucleated and multinucleated cells; we calculate a fusion rate of at least 2%, although this reflects the lower limit of the phenomenon due to technical limitations of our model. We reveal that this process occurs in the first week of life and is stable at one month of age. Our findings suggest a revision of the dogma in postnatal cardiac development by providing another mechanism for multinucleation of cardiomyocytes. Future experiments will address whether fusion is a reversible process and whether fused myocytes can undergo abscission in response to physiological or pathological cues.