The same molecular pathway that is responsible for preventing adult heart cells from regenerating after being damaged - like after a heart attack - has been identified as involved in embryonic development of the mouse heart. Researchers from the Baylor College of Medicine anticipate learning more about this phenomenon could someday improve the treatment of heart disease.
In the new study, researchers focused on a population of cells called epicardial cells. They are a type of cardiac progenitor cells, which are virtually halfway between a stem cell and a differentiated cell. Epicardial cells support heart muscle cells, called cardiomyocytes, both during initial development and later during injury, like a heart attack. Researchers wanted to know how the Hippo pathway is involved in the differentiation of epicardial cells.
To find out, researchers created mice genetically altered to be deficient in key parts of the Hippo pathway. How do hearts of these mice develop differently from normal mice? Researchers also analyzed blood vessel structure and more than 18,000 cells isolated from heart tissue in the middle of development.
"This technology allowed us to determine the status of thousands of cells individually,” explained corresponding author Dr. James Martin. “For instance, we learned what genes were turned on and what molecules the cells were expressing. This high level of detail shed light into the cellular and molecular processes leading to an adult heart and how they are coordinated."
Researchers observed that the hearts of genetically Hippo-deficient were smaller than hearts from genetically normal mice. Additionally, blood vessels failed to develop correctly in the genetically altered mice.
They were also able to link specific genes and other molecular pathways surprisingly linked to the Hippo pathway during embryonic development of the mouse heart.
"We found cells suspended in intermediate states and producing factors important for regulating growth and proliferation of vascular endothelial cells," Martin explained. "That was all unexpected."
"We know that the Hippo pathway is involved in regeneration of the adult heart, but also controls the size of the developing heart," Martin concluded. "As the heart grows, more vascular cells need to move into the heart to provide blood vessels to sustain its growth and later support the function of the adult heart. We think that the Hippo pathway can sense the size of the growing heart and, by regulating a number of secreted factors, determine how many cardiac fibroblasts and endothelial cells develop in the heart.”
In the future, Martin and his team will investigate how they can improve blood vessels’ ability to regenerate in the adult heart to improve the treatment of heart disease.
The present study was published in the journal Developmental Cell.