New research from Brigham and Women’s Hospital (BWH) has identified the precursors of the scar forming cells called myofibroblasts. These findings appear online on January 1, in American Journal of Pathology.
“Development of new therapies for kidney diseases has been slow in part because our lack of understanding of the mechanism of the disease,” said corresponding author Jeremy Duffield, MD, PhD, assistant professor of medicine in the Renal Division at BWH. Pericytes, undifferentiated connective tissue cells in blood vessels, have only recently been described in the kidney, but this study has identified these cells as a major source of scar forming myofibroblasts, which contribute to fibrosis in the kidney.
The researchers used genetic manipulation to develop mice that express protein labels exclusively and permanently in renal tubular epithelial cells. They then induced injury in the kidney and, by looking for labeled cells, were able to determine whether any tubular cells had moved into the interstitium or had acquired the ability to behave as myofibroblasts. Contrary to current wisdom in two separate models of human diseases, they did not detect any epithelial cells contributing to the scar forming cells. Next the authors developed mice that express protein labels exclusively in perivascular cells of the capillaries of the kidneys known as pericytes and found that these cells are the precursor of myofibroblasts.
The study not only reverses the currently accepted models for the development of fibrosis in the kidney, but raises the possibility that pericyte migration from the capillaries in response to kidney injury, directly leads to the loss of microvasculature in the kidney. “By targeting the cellular interaction between pericytes and endothelial cells we hope to develop new therapies that target both fibrosis progression and loss of microvasculature,” added Dr. Duffield.
The study was funded by NIH, NIDDK, ARRA Stimulus Challenge Grant, American Society of Nephrology, Harvard Stem Cell Institute and National Science Council, Taiwan.