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How To Generate Cardiac Cells From Stem Cells.

LA JOLLA, Calif., December 22, 2017 -- Coaxing 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.

The work could provide scientists a streamlined method to arrive at functioning heart cells (cardiomyocytes) for both research and regenerative therapies.

The technology would help researchers and commercial companies easily generate cardiomyocytes to study their capacity for repair in heart attacks and disease.

In 2015, the Katherine A. Jones lab 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.

They also discovered a third pathway, governed by a protein called YAP, that seemed to put the brakes on the Activin pathway, thereby keeping stem cells from specializing.

The researchers 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, a huge savings for industry in terms of reagent materials and expense.

Further analysis revealed that the same genes were being turned on as would be activated via the normal Wnt-Activin stem-cell specialization process.

This revealed a hidden, specific cellular lineage directly to beating cardiomyocytes.

"It's both fascinating and medically and commercially useful to find genes that are differently regulated still lead to the same result," Jones said.

Because removing a gene entirely can have unintended effects, the team next wants to test whether they can turn off the YAP gene using small commercially available inhibitor molecules, and still derive functioning cardiac cells from stem cells.

Citation: Conchi Estaras et al, "YAP repression of theWNT3gene controls hESC differentiation along the cardiac mesoderm lineage," Genes & Development, 2017; DOI: 10.1101/gad.307512.117


Contact: Katherine A. Jones,

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Title Annotation:Advanced Stem Cell Technology
Publication:Stem Cell Business News
Date:Jan 22, 2018
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