Getting Straight to The Heart of The Matter in Stem Cells

Source: Salk Institute

Summary: The process of embryonic stem cells developing into heart cells is very complex and involves many different pathways. Now, researchers have found a simpler way to go from stem cells to heart cells that involves turning off a single gene.

Embryonic Stem Cells (ESCs) are stem cells derived from embryos that are able to grow or differentiate into all derivatives of the 3 primary germ layers – ectoderm, endoderm, and mesoderm which describes their pluripotent nature. Adult stem cells are multipotent and can generate only a limited number of cell types, whereas, ESCs can generate all cell types in the body. The process of ESCs developing into any other cell type particularly heart cells (cardiomyocytes) is a very complex process involving the precisely timed activation of several molecular pathways and at least 200 genes. Researchers from Salk Institute have found a simpler way to go from stem cells to heart cells that involves turning off a single gene. The research findings were published in the journal Genes & Development.

Stem cells to heart cells by turning off a single gene

This cartoon illustrates how the Yap protein (dog) inhibits the expression of the Wnt gene, preventing an intermediate complex (couple sitting on the balloon) from binding to DNA and signaling to various types of cellular machinery (diver, seated boy) to turn on the cardiomyocyte genes (swimmer in the ocean). Credit: Salk Institute

The research team discovered that 2 different cell processes work together to enable ESCs to differentiate into specific cell types like pancreas, liver and heart. The Wnt pathway loads up the cellular machinery to start copying and activating genes and the Activin pathway ramps up that activity many folds. Both the pathways, together direct stem cells to an intermediate stage from which they further progress into cells of specific organs. When the cells are exposed to a signaling molecule at 2 different time points, the team could trigger first Wnt, then Activin, and end up with specialized cells. In the process of their experimentation, the team also discovered a third pathway—governed by a protein called YAP—which seemed to put the brakes on the Activin pathway, thereby keeping stem cells from specializing.

To better understand this effect, in the current work, the research team set out to manipulate the YAP gene in various ways to see what would happen. They used the molecular scissors known as CRISPR-Cas9 to cut the gene out of ESCs’ DNA so they could no longer make the YAP protein. Then the duo exposed the cells to the signaling molecule to see what, if anything, happened. To their great surprise, the cells went from the stem cell stage directly to beating heart cells. The work offers scientists a streamlined method to arrive at functioning heart cells for both research and regenerative therapies.

Prof. Kathy Jones said, “This discovery is really exciting because it means we can potentially create a reliable protocol for taking normal cells and moving them very efficiently from stem cells to heart cells”, “Researchers and commercial companies want to easily generate cardiomyocytes to study their capacity for repair in heart attacks and disease—this brings us one step closer to being able to do that.”

More Information: Conchi Estarás et al. YAP repression of theWNT3gene controls hESC differentiation along the cardiac mesoderm lineage, Genes & Development (2017). DOI: 10.1101/gad.307512.117

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