Understanding the stiff heart: scientists discover the cells and molecules responsible for cardiac fibrosis. August 12, 2007

August 12, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Boston, MA New research published in the journal Nature Medicine has identified the origins of cardiac fibroblasts, the cells responsible for forming scar tissue in the heart. Scar tissue, or fibrosis, is the body’s response to trauma or microscopic damage. In some cases, such as in the formation of keloids, this process goes awry, or is maladaptive. Fibrosis is a final common pathway of diseases such as chronic hypertension, aortic stenosis, hypertrophic cardiomyopathy, ischemic heart disease, and restrictive or infiltrative heart diseases. When the heart is subjected to increased wall stress, it responds adaptively by cellular hypertrophy, increasing wall thickness. Additionally, a fibrotic extracellular matrix is deposited by fibroblasts. In large part, it is the network of fibrosis that leads to impaired relaxation and diastolic heart failure, which patients experience as exercise intolerance and shortness of breath. Interestingly, the origin of the cardiac fibroblasts was a question of debate, as they are not present in high numbers in a normal heart. Scientists have now identified the origin of these fibroblasts, as well as the molecule which signal the production of these cells. This new research will likely pave the way towards designer therapies for diastolic dysfunction.

The authors found that cardiac fibroblasts are derived from endothelial cells within the heart. This transition in cellular phenotype is called an endothelial to mesenchymal transition, a phenomenon that had not previously been known to occur in adult animals. During ontogeny of the heart, this transition contributes to the formation of the endocardial cushions. The authors noticed that cardiac fibrosis in heart failure is often perivascular and subendocardial; this was their first clue that endothelial cells might be the source of the cardiac fibroblasts. They used two different transgenic mouse models that enabled them to identify cells that were descendents of endothelial cells, as only descendent cells expressed a reporter molecule. In the transgenic mice, this reporter molecule was seen only in endothelial cells, as expected. After the mice were subjected to high cardiac wall stress by aortic banding, however, this reporter molecule was seen in fibroblasts in addition to endothelial cells. Knowing which cell types contribute to cardiac fibrosis, the authors then proceeded to ask what molecules trigger the endothelial to mesenchymal transition. They found that the cytokine TGFbeta was important for this transition. In an exciting next step, they demonstrated that administration of human BMP-7 could reverse the TGFbeta-induced cellular transition. Importantly, this molecule could also prevent the detrimental myocardial fibrosis which occurs following aortic banding in the mice. This work marks a major advance in our understanding of the cellular and molecular biology of cardiac fibrosis. The hope is that these findings will translate into new therapies for treatments of diastolic dysfunction.


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