Written by:
Qing-Dong Wang
Senior Principal Scientist, Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D
Regeneration can be considered the “holy grail” for future medicines, allowing us to move from focusing on disease risk factors to directly addressing the underlying causes of disease. The key to regeneration is understanding which cells need to grow and divide to regenerate a desired tissue, organ or body part. In addition, understanding these relationships could lead to new targeted treatments designed to moderate the effects of overactive cells. This research could lead us to life-changing therapies for people living with heart failure, kidney and liver diseases.
New cells are made through proliferation, where one cell divides to produce two new cells. As a result, all cells in the body can be related to each other in a vast family tree. Our cells are not all the same though and different groups of cells undergo differentiation to perform specialised functions. Following the science to learn more about proliferation and differentiation could reveal ways to control these processes, potentially making it possible to regenerate damaged tissues, or to moderate the harmful effects of overzealous biological processes such as fibrosis (thickening or scarring of the tissue).
Our research in this area is supported by a long-term collaboration with Professor Bin Zhou, at the University of Chinese Academy of Sciences, Shanghai, China, a world leader in this field that has contributed extensively to the understanding of heart repair and regeneration. Professor Zhou has created a tool called ProTracer that makes it possible to follow highly specific groups of cells as they proliferate and differentiate.
In 2021, we published research with Professor Zhou in Cell Stem Cell, that made it possible to use ProTracer to study a much larger range of different cell types. In addition to tracing the origins of cells, these enhancements also made it possible to selectively remove genes from target cells to study their role in different illnesses.
Regenerating damaged cells in the liver and heart
The liver has an exceptional capacity for natural regeneration and, with enough time, it is possible for the liver to regrow 70% of its mass over the course of three months.1 However, liver diseases can slow this process and eventually the damage becomes too extensive to repair.
We have published work in Science examining proliferation of different groups of liver hepatocytes in different situations, such as during liver homeostasis, injury repair, and regeneration. The findings are helping to show that different groups of hepatocytes support regeneration in different situations, and this could hold the key to developing effective regenerative therapies.
By contrast to the liver, heart muscle has a limited ability to regenerate naturally and the resulting weakness has long-lasting effects on heart function, this makes it a priority for our regeneration research.2 It had been thought that groups of cells known as c-Kit-positive cells and stem cell antigen-1 (Sca-1)-positive progenitor cells in the heart play an intrinsic role in heart regeneration.3,4
Our work has shown that these cells have no role in producing heart muscle cells (cardiomyocytes) either under physiological conditions or after myocardial infarction. Instead, the healing heart produces most new cardiomyocytes through proliferation of pre-existing cardiomyocytes. These data have been published in several high profile journals; two in Circulation (here and here), Cell Research, Circulation Research and Nature Medicine.
Limiting the effects of heart failure
The lack of regeneration in the heart means that it depends on other mechanisms to respond to damage. Fibrosis is a key part of this response, but excess fibrosis also limits heart function contributing to the chronic symptoms of heart failure.5
Fibrosis is caused by cells called fibroblasts. In the heart there are two notable groups of fibroblasts, epicardium-derived fibroblasts (EpiFb) and endocardium-derived fibroblasts (EndoFb). The different types have very different origins and, like the hepatocytes, each group becomes active in response to different triggers.
In our most recent work, published in Nature Genetics, we examined both groups of fibroblasts in heart failure caused by blood pressure overload. Our results showed that EndoFb cells were responsible for fibrosis that limited heart efficiency, and we were able to reduce the extent of fibrosis by removing the EndoFb population. The loss of EndoFb cells led to a lesser reduction in heart function and this should mean less severe symptoms.
We were also able to show that EndoFb cells have high levels of proteins linked to the Wnt signalling pathway, which has many functions throughout the body including driving harmful fibrosis following heart damage. We went on to show that removing a key component of Wnt signalling, a protein called beta-catenin, from EndoFb cells reduced tissue fibrosis and improved heart function. By following the science we could find ways to target Wnt signalling in the EndoFb cells of people with heart failure, which may lead to new treatments that help to stop or slow the deterioration of heart function.
Lineage tracing for the future of medicine
Our work is bringing us closer to the possibility of regrowing and regenerating damaged tissues as a way to reverse disease damage, with the potential for cure. Supported by a strong collaboration with Professor Zhou and his team, we have investigated the origins of key groups of cells and explored regenerative mechanisms in the liver and heart. Along the way, we have made discoveries with more immediate applications. The identification of Wnt signalling as a driver of fibrosis mediated by EndoFbs presents an exciting avenue for developing novel heart failure treatments based on existing techniques.
