Mechanosensing-Based Approach Offers Promising Strategy to Treat Cardiovascular Fibrosis

Cardiac fibrosis, which involves the stiffening and scarring of heart tissue, is a fundamental feature of nearly every type of heart disease, from acute ischemic injuries to genetic cardiomyopathies. Over time, this stiffening restricts the heart's ability to both contract and relax, leading to progressive dysfunction and, eventually, heart failure. Despite its widespread presence, fibrosis has been notoriously difficult to treat, and currently, no effective therapies are available for millions of affected patients. Now, a new study published in Nature has unveiled an innovative approach to treating cardiovascular fibrosis, offering hope for better treatment.

This new method, developed by researchers at the Stanford Cardiovascular Institute (Stanford, CA, USA), takes a dual approach. It aims to not only reprogram the biochemical signals that trigger the activation of fibroblasts—the cells responsible for scar tissue formation—but also addresses the mechanical signals that sustain fibrotic remodeling over time. Once fibroblasts are activated and begin depositing excessive protein fibers to repair damaged heart tissue, it becomes exceedingly difficult to turn them off. The increasing stiffness of the heart tissue further stimulates these cells, perpetuating the scarring process even after the initial pro-inflammatory signals have subsided. To overcome this, the Stanford team analyzed a combination of public and in-house single-cell sequencing data, which led them to discover a key mechanosensory protein named SRC, primarily expressed in stromal cells, particularly fibroblasts, in the heart. SRC, as a critical mechanosensor, presents an excellent target for potential treatments. It functions as a molecular switch that enables cells to sense and react to their mechanical environment.

The researchers found that SRC is not only abundant in cardiac fibroblasts but is also highly activated in diseased hearts. To find drugs capable of inhibiting SRC, the team conducted a virtual screen of over 10,000 compounds and identified saracatinib, an orphan drug originally developed for cancer treatment, as a promising candidate. Through a series of in vitro and in vivo experiments, the team demonstrated that inhibiting SRC activity helped reduce fibrosis, particularly when combined with suppressing the TGFβ pathway, a major driver of fibroblast activation. The results showed that treatment with this drug combination reversed the activation of cardiac fibroblasts, resembling the effects of growing them on a soft, healthy heart-like hydrogel.

Most importantly, this dual treatment not only reduced fibrosis in cultured cells but also restored contractile function in more complex experimental models, including 3D engineered heart tissues and a pre-clinical mouse model of heart failure. The findings suggest that targeting SRC-driven mechanosensing, along with inhibiting upstream signals like TGFβ, could offer a novel strategy for treating cardiovascular fibrosis. By disrupting both the mechanical and biochemical cues promoting fibrotic remodeling—specifically in stromal cells—this dual approach represents a promising blueprint for future “mechanotherapies” aimed at reversing fibrosis, rather than just slowing its progression in the heart. The researchers are also optimistic about applying this approach to other fibrotic diseases, such as those affecting the lungs, skin, or liver.

“The pathological feedback loop of cardiac fibrosis is often overlooked in drug development and is one of the many reasons why anti-fibrotic therapies to date have not been very successful,” said Joseph Wu, MD, PhD, the study’s senior author and Director of Stanford CVI. “We want to break this vicious cycle – but until now, there’s been no reliable way to do so selectively in fibroblasts without affecting other essential heart cell types, such as cardiomyocytes.”

Related Links:
Stanford Cardiovascular Institute