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Single-Cell Transcriptome Maps Reveal Details of Cardiac Fibrosis

NEW YORK – By bringing together single-cell transcriptomic data for healthy and injured heart samples from humans and mouse models, an Australian research team has spelled out the cell types and processes involved in cardiac fibrosis. The heart muscle scarring is caused by heart attacks, high blood pressure, or other heart conditions that affect tissue contractibility and can, in turn, lead to heart failure.

"Fibrosis is an essential part of the body's way of healing. But in the heart, if the disease triggers are not resolved, the process can go too far, causing scarring that is incredibly harmful to heart function and a major cause of heart failure," Richard Harvey, a researcher affiliated with the Victor Chang Cardiac Research Institute and the University of New South Wales Sydney, said in a statement.

He noted that there remains "an urgent need to develop novel treatments that could arrest or even reverse cardiac fibrosis, benefiting millions."

With that in mind, Harvey and colleagues from the Victor Chang Cardiac Research Institute, UNSW Sydney, the University of Queensland, and other centers in Australia brought together single-cell RNA sequencing data for 100,000 individual cells. The cells came from the heart ventricles of mouse models or humans with myocardial infarction or heart injury. Described in a paper in Science Advances on Friday, the study also included control groups analyzed for several prior projects.

"Integrated single-cell data maps pave the way for generation of multispecies, multilineage, and multidimensional tissue atlases that will drive forward better understanding of human and animal biology and treatment of disease," the authors explained.

With these data, the team highlighted five groups of cardiac fibroblasts in healthy control individuals, together with several more cardiac fibroblast cell clusters that turned up specifically in samples from mouse models of cardiac fibrosis or from affected humans.

Along with resting and progenitor cells, the team flagged activated and inflammatory cell subgroups as well as specialized myofibroblasts and matrifibrocytes that turned up in mouse models of heart attack and appeared to contribute to scarring and a lack of scar resolution, respectively, in the days after the heart attack.

"Our data on diverse [cardiovascular] disease models should inform current efforts to reconstruct 3D tissue context through spatial transcriptomics," the authors wrote, "and will add a deeper perspective to development of novel therapeutics."

With a series of follow-up analyses, they looked at everything from transcription factor network activity, transcript isoform patterns, and cell differentiation over time to the specific effects of heart injury, myocardial infarction, or hypertension.

"We found a surprising similarity in fibrosis progression in very different types of heart disease," coauthor Vaibhao Janbandhu, a researcher with the Victor Chang Cardiac Research Institute and the UNSW Sydney, said in a statement, noting that "[m]yofibroblasts were abundant early on during hypertension and then resolved into matrifibrocytes, just as they are after a heart attack."

Together, the results are expected to provide clues to future treatment strategies, Janbandhu noted, adding that the study also emphasized the importance of controlling treatable conditions such as high blood pressure, which can lead to cardiac fibrosis.

Using data from the study, the team put together a CardiacFibroAtlas, along with analytical and visualization tools to help other investigators interrogate gene expression, cell type, and other changes that accompany cardiac fibrosis in ventricle tissues.

"We uncover insights that consolidate our understanding of cardiac fibrosis progression and resolution in diverse [cardiovascular] disease models, providing a stronger framework for knowledge-based therapeutics," the authors wrote.