Epigenetic switches that turn stem cells into blood vessels. Researchers claim to have identified two enzymes involved in altering expression of certain genes that are required for differentiation of embryonic stem cells into endothelial cells.

Researchers at the University of Illinois, Chicago have uncovered a molecular mechanism that guides embryonic stem cells into becoming mature endothelial cells (cells that specialize into blood vessels).

Understanding the underlying processes of this mechanism could allow scientists to develop highly efficient techniques of converting stem cells into endothelial cells – tissue repair and regenerating blood vessels in the heart to bypass blockages could become more competent. The study was published in the journal Stem Cell Reports.

Fresh Discovery

Researchers claim to have identified two enzymes involved in altering the expression of certain genes that are required for the differentiation of embryonic stem cells into endothelial cells.

The enzymes function via ‘epigenetic modification’. In this mechanism, DNA or some of the proteins (histones) that interact with it undergo a chemical change. This change alters the activity of certain genes without altering the DNA itself. More precisely, modifications in the histones can cause an up-regulation in the expression of certain genes, by exposing them to the cellular machinery involved in DNA translation.

“Epigenetic modifications to histones can trigger the activation of a large number of genes simultaneously, instead of regulating one gene at a time,” says Jalees Rehman, Associate Professor of Medicine and Pharmacology at UIC, and co-author of the study. “We wanted to see if we could identify epigenetic regulators of stem cell differentiation – a highly complex process, involving the transition of a cell that can form any type of tissue early on in development, into one that is locked in to producing only one cell type.”

Study

One way in which histones are modified is by the addition or deletion of chemical tags – methyl groups –by specific enzymes known as histone demethylases.

The research team, headed by Asrar Malik, Professor and Head of Pharmacology at the UIC College of Medicine, investigated this process in mice. They studied how numerous of these enzymes altered gene expression in the embryonic stem cells that were maturing into endothelial cells. Two of these enzymes, namely KDM4A and KDM4C, were seen to be produced in large quantities during the process of stem cell transformation. These enzymes were seen to regulate genes that were promoters – genes responsible for switching on other genes specific to endothelial cell formation.

Turning To Zebrafish

To study the effects of depleting the above-mentioned enzymes in embryos, researchers turned to zebra fish. Without the two enzymes, the fish embryos were not capable of forming blood vessels. Furthermore, it was seen that depleting KDM4A had a more pronounced effect than depleting KDM4C, indicating that KDM4A has a more significant and early role in the development of blood vessels.

Future Prospects

According to Rehman, the team has only looked into some of the genes activated by the epigenetic switches. A more comprehensive understanding of the pathways of blood-vessel development requires identifying various other genes that are activated by these switches as well.

Apart from activation, gene pathways that are switched off during the process of transformation must also be investigated to fully understand how stem cells vigilantly organize an array of molecular signals and determine their ultimate fate.