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Scientists Transform Beating Heart Stem Cells Into Brain Cells

Jeff Saucerman, PhD, is part of UVA’s Department of Biomedical Engineering, a joint program of the School of Medicine and the School of Engineering.

By turning off a single gene, University of Virginia researchers and their collaborators caused stem cells already becoming heart cells to change course and become future brain cells. And that could help scientists understand how specific genes affect the development of your body and the role they play in developmental diseases, potentially leading to new therapies.

“Previously, it’s been thought that the paths that cells take towards becoming a heart cell or a nerve cell are very rigid,” said researcher Jeff Saucerman, PhD, of UVA’s Department of Biomedical Engineering. “This study is showing that this process is actually much more fluid.”

JUMPING TO A NEW FATE

Stem cells are kind of a blank slate. They’re “pluripotent,” meaning that they can transform into any type of cell in the body. There are a series of steps involved in this transformation process, called canalization. Until now, it was thought that once stem cells start undergoing canalization, they can’t change course to become other, different cell types.

But Saucerman’s collaborators at the Gladstone Institutes in San Francisco, led by Benoit G. Bruneau, PhD, used CRISPR genome-editing approaches to turn off the Brm gene in mouse stem cells undergoing canalization into heart cells. This resulted in the mouse cells lacking a protein called Brahma. 

Turning off Brm prevented stem cells from becoming beating heart cells. Additionally, they had switched from being heart precursors to becoming precursors for brain cells. 

COLLABORATION YIELDS GROUNDBREAKING DATA

“This study was the first to explore the effect of Brahma on cardiac differentiation,” said Ali Khalilimeybodi, PhD, a researcher on Saucerman’s team who developed the computer model used to guide the research. “And by using the computational models, we get a deeper understanding of the mechanism that Brahma can coerce changes in the cell fate, or differentiation, process.”

Saucerman emphasized the somewhat unconventional approach of supporting real world experimentation with computer model data. “In this case, they had already done a lot of experiments. We went back and forth a lot, including more and more of the data.” This process helped refine the model for better predictions and guidance. “The model really highlights this irreversible biochemical switch. If you disrupt this switch, a stem cell takes a detour down the brain route. The modeling provides a mathematical explanation for this developmental process,” Saucerman noted.

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