Suppressing MEOX1 helped reprogram scar-forming cells in a mouse model of heart attack
Suppressing MEOX1 helped reprogram scar-forming cells in a mouse model of heart attack
In a paper in Circulation published on September 8, the authors described an experiment in mice after a heart attack. They combined factors that activate the heart muscle program in cells with a short RNA that suppressed MEOX1, a protein that regulates the scarring program. After six weeks, mice in this group had more cells with heart muscle characteristics, smaller scars, and better heart pumping function.
After a heart attack, connective tissue cells called fibroblasts become myofibroblasts and form a scar. These cells are abundant in the injured heart. However, when reprogramming factors were delivered in the same way, they converted into cardiomyocytes, the contracting cells of heart muscle, less readily than fibroblasts from healthy hearts. The authors compared the two cell types to identify the reason for this difference.
A comparison of gene activity in individual cells and tests of ten regulatory proteins pointed to MEOX1. A short RNA that reduced its production increased the number of cells containing proteins characteristic of heart muscle by roughly fourfold. The number of spontaneously contracting cells also increased by roughly fourfold. Additional MEOX1 reduced reprogramming efficiency, and a modified version of the protein resistant to this RNA reversed the improvement.
MEOX1 binds to DNA and regulates the activity of other genes. TGF-β1, a signaling protein involved in scar formation, increased MEOX1 levels. MEOX1 in turn sustained the activity of a group of genes associated with scarring. A MEOX1 variant with impaired DNA binding lost its inhibitory effect.
In the mouse experiment, both groups received reprogramming factors, and one group also received MEOX1 suppression. Genetic labels allowed the researchers to distinguish the original myofibroblasts from pre-existing cardiomyocytes. The MEOX1 suppression group had more cells carrying both the original myofibroblast label and proteins characteristic of cardiomyocytes. After six weeks, the ejection fraction, the proportion of blood expelled by the left ventricle with each contraction, was 38,1% versus 28,85% in the control group, and the scar was smaller.
The same combination increased the number of cells with heart muscle characteristics in human fibroblasts grown in the laboratory. The result linked two tasks: activating the heart muscle program in scar-forming cells and weakening the scarring program maintained by MEOX1.