Influences of blood flow on cardiomyocyte hypertrophy in the embryonic zebrafish heart.

摘要

Blood flow-associated mechanical forces have crucial influences on embryonic heart development. My thesis work focuses on understanding the cellular and molecular mechanisms underlying these influences. Using the zebrafish heart as a model, we have identified an important cardiomyocyte behavior that is under the regulation of blood flow. Cardiomyocyte hypertrophy is a complex cellular behavior involving coordination of cell size expansion and myofibril content increase. Our studies investigated the contribution of cardiomyocyte hypertrophy to cardiac chamber emergence, the process during which the primitive heart tube transforms into morphologically distinct chambers and increases its contractile strength. Focusing on the emergence of the zebrafish ventricle, we observed trends toward increased cell size and myofibril content. To examine the extent to which these trends reflect coordinated hypertrophy of individual cardiomyocytes, we developed a method for tracking cell size changes and myofibril dynamics in live embryos. Our data revealed a previously unappreciated heterogeneity of cardiomyocyte behavior during chamber emergence: although cardiomyocyte hypertrophy was prevalent, many cells did not increase their size or myofibril content during the observed timeframe. Despite the heterogeneity of cell behavior, we often found hypertrophic cells neighboring each other. Next, we examined the impact of blood flow on the regulation of cardiomyocyte behavior during this phase of development. When blood flow through the ventricle was reduced, cell size expansion and myofibril content increase were both dampened, and the behavior of neighboring cells did not seem to be coordinated. Together, our studies suggest a model in which blood flow has multiple influences on cardiac chamber emergence, promoting both cardiomyocyte enlargement and myofibril maturation, enhancing the extent of cardiomyocyte hypertrophy, and facilitating the coordination of neighboring cell behaviors. This detailed understanding of blood flow-induced cell behavior laid the foundation for exploration of the molecular mechanisms mediating the impact of mechanical forces in this context. Our initial work has suggested the involvement of actin remodeling in blood flowinduced cardiomyocyte hypertrophic growth. Further investigation in this direction may lead to the elucidation of a mechanosensation pathway in the developing heart, which could enlighten our understanding of certain congenital heart diseases.