2 Chemicals Found To Boost Heart Reprogramming

Scientists discover a way to encourage the reprogramming of heart scar tissue into healthy muscle cells

Heart failure is so deadly in part because it frequently leaves a host of scar tissue in its wake. This inhibits correct and healthy heart function, further impairing cardiovascular function following the traumatic event. Previous research has revealed that this scar tissue can however be reprogrammed - meaning directly instructed to turn into another type of cell.

What is reprogramming?

A great deal of past media attention has been on stem cell work, but cellular reprogramming has gained more of the limelight in recent years due to new breakthroughs in understanding. All cells are under the control of various signals that keep them in line and dictate to them which cell type to become or remain. One way of making new cells is the use of stem cells, which are able to become lots of different cell types. Stem cells are inherently flexible, and with the right signals you can coax them into becoming a range of different cells. Reprogramming's goal is to skip the middleman (stem cells) and instruct adult cells to switch right into another type through a cocktail of different chemical signals. Find the right combination, and you end up with a bone cell, or a skin cell for example. There are advantages and disadvantages to each approach, but reprogramming is emerging as a faster and more efficient method in many cases. 

Creating new heart muscle cells

Prior research at the Gladstone Institutes has uncovered that the correct ratio and amount of 3 transcription factors, Gata4, Mef2c and Tbx5 (GMT), is able to induce formation of heart muscle cells (cardiomyocytes) from scar tissue. Unfortunately the success rate was only 10%, which was insufficient for clinical translation. In additional research building on these findings, a research team have now pinpointed 2 chemicals that provide a significant efficiency boost, after sifting through 5,500 chemicals. 

The newly discovered chemicals, transforming growth factor (TGF)-β inhibitor SB431542 and the WNT inhibitor XAV939, were able to speed up reprogramming eightfold, reduce the conversion time from 6-8 weeks to only 1 week, and led to over 8 times more reprogrammed cells. These 2 chemicals also required only expression of Tbx5 (GMT) (one of the original 3 transcription factors) to work. Through this combination of SB431542, XAV939 and GMT the scientists were able to effectively regenerate cardiac scar tissue in mice. 

"While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient. With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process. With our enhanced method of direct cardiac reprogramming, we hope to combine gene therapy with drugs to create better treatments for patients suffering from this devastating disease"

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