Fibrosis is the result of dysfunctional regenerative processes, such as those operating in old tissues. Instead of rebuilding the structures that should exist, instead regeneration is characterized by the formation of scar-like collagen deposits that disrupt normal tissue layout and function. This is particularly important in the age-related decline of organs such as the kidney, lung, liver, and heart: where correct function is absolutely vital, or where precise tissue structure is absolutely vital. Regeneration is a coordinated dance between immune cells, senescent cells, and the cells that will do the work of rebuilding: a mix of stem cells, progenitor cells of various types, and ordinary somatic cells. With age, the immune system becomes inflammatory and disarrayed, stem and progenitor cells are less activity, and growing numbers of persistent senescent cells pump out signals that disrupt the intricate relationships needed for regenerative processes to operate.
Recent research is making it clear that lingering, persistent senescent cells are an important cause of fibrosis. However, it remains the case that most researchers interested in fibrosis are still operating in the paradigm of mapping regulatory genes and proteins throughout a tissue, rather than looking for a set of cells that are at fault. The mapping proceeds in the hope of finding target proteins that can be blocked, enhanced, or otherwise manipulated in order to change cell behavior during regeneration - to dial down fibrosis. In the paper noted here, the authors settle on Wnt/β-catenin signaling as a potential target, and indeed demonstrate that absent this signaling process mice produce less scarring and fibrosis after injury to heart tissue.
If you read through the paper, there isn't any mention given to cellular senescence, but we can look elsewhere to find a number of studies that implicate Wnt/β-catenin signaling in the machinery and reactions that push cells into a senescent state. So what these researchers appear to have demonstrated is that reducing the degree to which heart injury results in increased cellular senescence also reduces fibrosis and scarring - which dovetails nicely with what other researchers are uncovering of the role of senescent cells in this aspect of aging. Suppressing the creation of senescent cells isn't, to my eyes, as desirable as destroying them after the fact with senolytic therapies, however. Senescent cells do have a transient role to play in healing. Continual suppression will make healing less effective overall, even as it reduces fibrosis in older individuals. On the other hand, periodic elimination of lingering senescent cells should allow patients to obtain all of the benefits of reduced inflammation, unimpaired regeneration, and minimal fibrosis.
The Wnt/β-catenin signaling pathway is involved in several of the body's fundamental biological processes. After heart injury, however, Wnt/β-catenin signaling ramps up in cardiac fibroblast cells to cause fibrosis, scarring and harmful enlargement of the heart muscle, according to the researchers. "Our findings provide new insights on what causes cardiac fibrosis and they open the potential for finding new therapeutic approaches to fight it and preserve heart function. Wnt/β-catenin signaling is involved in many normal and disease processes and it's tough to target therapeutically. But the idea that early targeting of fibrotic response in cardiac disease may improve muscle function and stop disease is an exciting new direction."
In the current study, researchers used a newly developed line of genetically bred laboratory mice that allowed them to determine how important Wnt/β-catenin signaling is in cardiac fibroblast cells. Fibroblasts are important to building the connective tissues and structural framework cells that help hold the body together. But in the context of heart disease, researchers are learning resident cardiac fibroblast cells cause a deadly mix of tissue fibrosis, scarring and diminished function.
To simulate cardiac injury in the mice, researchers conducted a procedure called trans-aortic constriction to restrict blood flow through the heart. Some of the mice were bred so that following cardiac injury they did not express cardiac Wnt/β-catenin in fibroblasts. Control mice in the study continued to express Wnt/β-catenin following heart injury. The control mice exhibited extensive fibrosis, scarring, and diminished heart function. Mice not expressing Wnt/β-catenin had diminished fibrosis and scarring and the animals' heart function was preserved.
Cardiac fibrosis, commonly seen with a variety of cardiac injuries, can significantly reduce tissue compliance and disrupt cardiac conduction, thus contributing to morbidity and mortality associated with heart disease. The hallmark of cardiac fibrosis is increased fibrillar collagen, which contributes to reduced cardiac output and can ultimately lead to heart failure. Cardiac fibroblasts (CFs) that arise from epicardial and endothelial progenitors in the developing heart are the predominant collagen-producing cell type in pathologic cardiac fibrosis. Although these resident CFs maintain a quiescent phenotype under physiological conditions, they can be activated in response to various types of cardiac injury. Importantly, the regulatory mechanisms that lead to increased collagen production from resident CFs under pathophysiologic conditions, ultimately leading to heart failure, have not been fully elucidated.
Wnt/β-catenin signaling is induced in areas of inflammation, scar formation, and epicardial activation in mouse models of ischemic injury. However the role of Wnt/β-catenin signaling in myocardial interstitial fibrosis independent from scar formation has not been determined. In addition, the requirement for Wnt/β-catenin signaling specifically in resident CFs and direct downstream targets related to cardiac fibrosis have not been reported previously. Recently developed inducible Cre-expressing mouse lines are effective for manipulation of gene expression in resident CF lineages. Using this approach to specifically target activated CFs is of use in studies of CF-specific regulatory mechanisms in cardiac fibrosis.
The requirements for Wnt/β-catenin signaling specifically in resident and activated CFs after cardiac pressure overload were examined using an engineered loss of β-catenin. Here, we demonstrate that cardiac pressure overload leads to increased Wnt/β-catenin signaling in CFs, while loss of β-catenin results in improved cardiac function, blunted cardiac hypertrophy, reduced interstitial fibrosis and decreased expression of fibrotic extracellular matrix (ECM) protein genes 8 weeks post trans-aortic constriction (TAC). Further, β-catenin loss of function mutation in CFs directly reduces cardiomyocyte hypertrophy. Together, these data support a regulatory role for Wnt/β-catenin signaling in fibrosis due to CFs after cardiac injury.