Researchers at Cima and the Clínica Universidad de Navarra have led an international study in which they have identified the heart cells that are responsible for repairing the damage that occurs in this organ after infarction. These "repair" cells are a subpopulation of cardiac fibroblasts that play a fundamental role in the generation of the collagen scar necessary to prevent rupture of the ventricular wall. The research also reveals the molecular mechanisms involved in the activation of these cells and in the regulation of their function.

This finding, in which basic and clinical researchers have participated, will allow the identification of new therapeutic targets and the development of targeted treatments to control the repair process of the heart after infarction.

The study is published in the latest issue of the journal Circulationthe leading scientific journal of the American Heart Association.

Characterization of reparative cardiac fibroblasts.

Cardiac fibroblasts are one of the fundamental components of the heart. These cells play a key role in maintaining the structure and mechanics of this vital organ. "Recent studies have shown that cardiac fibroblasts do not respond homogeneously to cardiac injury, so the purpose of our study was to determine their heterogeneity during remodeling of the damaged ventricle and to understand the mechanisms that regulate the function of these cells," explains Dr. Felipe Prósper, researcher at Cima and the Clínica Universidad de Navarra and head of the study.

"Using single-cell RNA-seq transcriptomic analysis techniques, we identified a subpopulation within cardiac fibroblasts that we have named Reparative Cardiac Fibroblasts (RCF) for their role after cardiac injury. We have found that when a patient suffers an infarction, these RCFs are activated to provide a fibrotic response that generates a collagen scar that prevents rupture of the cardiac tissue," says Dr. Prósper, also a member of the Cell Therapy Network (TerCel) and the Institute for Health Research of Navarra (IdiSNA).

CTHRC1, a collagen-related protein essential for the regenerative process.

In the detailed study at the molecular level, the researchers have discovered that RCFs are characterized by a unique transcriptional profile, i.e., a specific pattern of information for the expression of genes involved in their cardiac function. "Among the main differential markers of the transcriptome of these cells, we have identified the CTHRC1 (Collagen Triple Helix Repeat Containing 1) protein, a molecule with a fundamental role in the fibrotic response after myocardial infarction. Specifically, this protein participates in the synthesis of collagen in the cardiac extracellular matrix and is crucial in the process of ventricular remodeling," says Adrián Ruiz-Villalba, a researcher in the Cima Regenerative Medicine Program and first author of the article.

These results "suggest that RCFs activate cardiac injury healing through the secretion of the CTHRC1 protein. Therefore, this molecule could be considered as a biomarker associated with the physiological state of the damaged heart and a potential therapeutic target for patients who have suffered a myocardial infarction or who suffer from dilated cardiomyopathy," says Ruiz-Villalba, also a researcher at IdiSNA. In addition to Cima and the Clinic, basic and clinical researchers from the United States, Belgium and Austria have participated in this research.

This work is part of the line of research in regenerative medicine that the Clinic and Cima have underway and is aimed at understanding the regenerative potential of stem cells and their therapeutic application in various diseases such as cardiovascular disease. Specifically, this study is linked to the BRAVƎ project , an international research that combines bioengineering and cardiac stem cells to recover the functionality of an infarcted heart. BRAVƎ is a project funded by the European Union under the H2020 program (H2020-SC1-BHC-07-2019-874827).

• Bibliographic reference:
  Ruiz-Villalba A. et al. Single-Cell RNA-seq Analysis Reveals a Crucial Role for Collagen Triple Helix Repeat Containing 1 (CTHRC1) Cardiac Fibroblasts after Myocardial Infarction. Circulation. 2020 Sep 25.
  Doi: 10.1161/CIRCULATIONAHA.119.044557.