Study Identifies Simpler Way To Move Cells Between Stem & Heart Cells

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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 process by which embryonic stem cells develop into heart cells is a complex process involving the precisely timed activation of several molecular pathways and at least 200 genes. Now, Salk Institute scientists have found a simpler way to go from stem cells to heart cells that involves turning off a single gene.
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In 2015, Jones' lab, which studies proteins that manage cell growth and development, discovered that two different cellular processes cooperate to enable embryonic stem cells (ESCs) to develop into specific cell types like pancreas, liver and heart. The team found that the Wnt pathway loads up the cellular machinery to begin copying and activating genes, and then the Activin pathway ramps up that activity many fold. Together, the two pathways (named for key proteins) direct stem cells to an intermediate stage from which they further progress into cells of specific organs. By exposing the cells to a signaling molecule at two different timepoints, 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.

Wanting to better understand this effect, in the current work Jones and first author Conchi Estarás set out to manipulate the YAP gene in various ways to see what would happen. They began by using 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.

"Instead of requiring two steps to achieve specialization, removing YAP cut it to just one step," says Estarás, who is a Salk research associate.
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Source Medical Express

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