A microscope image of cardiac calcification in a mouse showing cardiac fibroblasts (red) expressing the ENPP1 protein (green and yellow). Image: Courtesy of UCLA Broad Stem Cell Research Center/Cell Stem Cell
UCLA researchers have discovered that calcification of heart-muscle tissue is caused when a type of cell called cardiac fibroblasts goes awry. The scientists also found that blocking a molecular pathway in cardiac fibroblasts prevents heart calcification in mice.
In bones, cells called osteoblasts create a strong, dense matrix out of calcium and phosphate. The calcification of soft tissues — known as ectopic calcification — is abnormal and occurs with common diseases such as diabetes and chronic kidney disease, as well as with aging. But soft tissues don’t have osteoblasts, and scientists have for years sought to understand which type of cells contribute to ectopic calcification.
Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA genetically labeled cardiac fibroblasts, the most plentiful type of cell in the heart, with a fluorescent red dye and followed the cells in mice after a heart injury. When calcification began one-to-four weeks later, the fibroblasts had clustered at the spots where calcification was occurring. The cells adopted characteristics of cardiac-tissue stem cells that then created bone-forming osteoblasts. The researchers transplanted some of these fibroblasts into healthy mice and observed calcium deposits forming around the clumps of cells.
Scientists compared the genes of mice that were prone to ectopic calcification with those that didn’t get it. They discovered that the levels of a protein called ENPP1 were especially high in fibroblasts during calcification. And when they blocked ENPP1 with a drug, they were able to prevent heart calcification.
The study, led by Arjun Deb, MD, associate professor of cardiology and of molecular, cell and developmental biology, identifies for the first time both a cell type and a molecular pathway linked to heart calcification. If the findings hold true in humans, they could lead to a pharmaceutical treatment for ectopic calcification. The researchers are collaborating with other UCLA scientists to study whether or not other types of ectopic calcification can be treated in this manner. Their findings also may help advance the understanding of other types of ectopic calcification.
“Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification,” Cell Stem Cell, November 17, 2016