To the Heart of the Issue

Cardiovascular disease is amongst the leading causes of death worldwide. And once damaged, the heart is unable to effectively heal itself.

When a fix, isn’t really a fix

Damage caused during a heart attack or long term disorders such as diabetes, blood pressure or heart disease, leads to the death of cardiac muscle tissue (cardiomyocytes).

In an attempt to repair itself, the heart creates fibrotic scar tissue. While scar tissue ensures the heart maintains structurally sound, unlike cardiomyocytes, these cells are stiff and cannot contract. Over time this causes complications in the organ, leading to heart failure.

Currently, the only true curative therapy for this problem is organ transplant. Transplant surgery carries some serious risks, and for some patients it isn’t a viable option. Long waiting lists and limited access to donor hearts means alternative treatments need to be sought out.

A promising alternative involving the generation of heart tissue from other cell types is currently being researched. This tissue can be derived from any type of cell, skin cells, bone marrow, stem cells etc.

This is being achieved through a process known as direct cardiac reprogramming.

Picture credit: Jordan Clarke

Programming is only for electronics right?

Direct cardiac reprogramming takes pharmacological agents, genes and other transcription factors and places them into a cell to encourage them to develop into cardiomyocytes. Seven years ago the first reprogramming of a cell into a cardiomyocyte occurred in mice using a three gene cocktail known as GMT, consisting of the genes: Gata4, Mef2c and Tbx5.

 

When NO way is the right way

In human cells, GMT based direct reprogramming is extremely inefficient, with as little as only 1% of cells actually being reprogrammed.

Recently my lab (Cardiac Regeneration Group from the O’Brien Institute, St Vincent’s Institute of Medical Research) has established the use of nitric oxide (NO) gas as a way of increasing the efficiency of direct cardiac reprogramming in fibroblasts (the scar tissue).

Nitric oxide (NO) was originally investigated as it is known to be vital in the development of the embryonic cardiovascular system. eNOS (endothelial nitric oxide synthase) is a naturally occurring enzyme in the human body. eNOS produces nitric oxide (NO). We have found that by injecting this enzyme into cells alongside the GMT cocktail, we are seeing a favourable increase in the number cells that are reprogramming into cardiomyocytes.

The investigation utilised cells obtained from human foetal foreskin, and we are now trying to optimise this process further by introducing the GMT plus eNOS cocktail into cardiac stem cells.

Cardiac stem cells have the ability to form all cell types that make the human heart. They already carry the intrinsic potential to become cardiomyocytes, but rarely ever do. The group hopes that introducing the nitric oxide plus GMT reprogramming cocktail to these cells will result in a highly efficient reprogramming process.

Cardiac Stem Cells founded by our lab Photo Credit: Zhang et al. (2016). Stem Cells. 2016:33:3100

If successful this could be a huge step forward in the search for an alternative treatment for heart failure. Not only could these tissues be used to improve the quality of life of patients, but they also have the capacity to save lives.

 

Useful Resources:

https://www.heartfoundation.org.au

http://www.closerlookatstemcells.org/stem-cells-and-medicine/heart-disease