Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.

New collaborative research from the Mommersteeg Group and MRC WIMM researchers shows that a protein called Runx1 plays a significant role in the formation of the cardiac scar that forms after the heart is injured, a scar that is known to inhibit heart regeneration. In the zebrafish, a freshwater fish known to be able to fully regenerate its heart after damage, they show that the absence of Runx1 results in enhanced regeneration. This indicates a potential new therapeutic target for heart repair.

One of the major obstacles in heart regeneration is the formation of a fibrotic scar. This scar is thought to result from the deposition of collagen and fibrin by epicardial myofibroblasts after a heart attack. Preventing scarring therefore has significant therapeutic potential.

Runx1Paper20202.jpg

Associate Professor Mathilda Mommersteeg and her team, in collaboration with Jana Koth and Roger Patient from the MRC Weatherall Institute of Molecular Medicine (Radcliffe Department of Medicine), are investigating the role of transcription factor Runx1 during zebrafish heart regeneration.

Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell-types, during both development and adulthood. The Mommersteeg Group first identified Runx1 through their research into the role of a gene called lrrc10 in the Mexican cavefish, a fish that, like the zebrafish, demonstrates an ability to repair its heart after damage .

Following this initial identification, the team and their collaborators looked into the gene in more detail. Using fluorescent transgenic reporters and single-cell sequencing, they have shown that runx1 becomes widely expressed in the heart after injury, specifically in populations of endocardial cells and thrombocytes. These populations express genes associated with scarring such as fibrin and collagen and smooth muscle genes that suggest an identity similar to myofibroblasts; the cells implicated in directly forming the cardiac scar after injury.

In runx1 mutant zebrafish, however, these subsets of endocardial cells and thrombocytes are absent, and the wounds contain less collagen and fibrin, which indicates that these cells might contribute to collagen deposition instead of epicardium-derived myofibroblasts. The researchers show that runx1 mutant animals also have increased myocardial cell survival and proliferation following heart injury, and increased expression of fibrin degradation (fibrinolysis) genes through upregulation of the plasminogen receptor Annexin 2A. Conversely, wild type fish strongly upregulate serpine1 upon injury, which inhibits fibrinolysis.

This research demonstrates that Runx1 negatively regulates regenerative responses in the heart, providing a new therapeutic target for heart regeneration.

What we found so interesting was that zebrafish, that have a natural ability to regenerate their hearts after injury, are not even doing this optimally. Absence of Runx1 further speeds up regeneration in these fish. This finding can help us understand what mechanisms improve heart regeneration and, in the future, apply this to patients after a heart attack to improve heart repair. We now first need to further find out what exactly Runx1 is doing during heart regeneration, but drugs that block Runx1 are already being tested in patients with leukaemia, making it a very promising target for treatment. - Prof Mommersteeg

The full paper "Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration" can be read in Development.

Credit to Development for their Research Highlight outlined in this article.

The DPAG team who have contributed to this paper include William Stockdale, Helen Potts and Professor Paul Riley.

Image Legend (above right): Adult regenerating zebrafish heart recreated with cell clusters from single cell sequencing data of runx1 mutant and wild-type hearts.

 

Similar stories

Being "in the zone": how waking activity controls sleep need

Publication Research Vyazovskiy Group News

A new study from the Vyazovskiy group suggests that how and where we spend our time while awake impacts how much we need to sleep - it does not only depend on how long we are awake.

New target identified to develop treatment for Abdominal Aortic Aneurysm

Cardiac Theme Publication Research

A new study from the Smart group has shed light on a key regulatory step in the initiation and progression of Abdominal Aortic Aneurysm by revealing the protective role of a previously little known small protein.

New research grant to Pawel Swietach to further understanding of propionic acidemia

Awards and Honours Cardiac Theme

A new collaborative project led by the Swietach group funded by the Propionic Acidemia Foundation will investigate the disease mechanisms and risk factors for cardiac disease caused by a severe inherited disorder.

Researcher publishes children's book of the brain

Postdoctoral Publication

Betina Ip, a Royal Society Dorothy Hodgkin Research Fellow based in NDCN, formerly a postdoctoral research scientist in DPAG, has written a book for children: The Usborne Book of the Brain and How it Works.

Drug trial that could improve respiratory recovery from COVID-19 now underway

Research

A clinical trial has commenced this week to test whether a drug called almitrine can help people who are seriously ill with COVID-19 to recover from the disease.