Researchers from Brigham and Women’s Hospital (BWH) have identified what they believe to be the cells responsible for fibrosis, the buildup of scar tissue. Fibrotic diseases, such as chronic kidney disease and failure, lung disease, heart failure and cirrhosis of the liver, are estimated to be responsible for up to 45 percent of deaths in the developed world. The opensource findings are published in the journal Cell Stem Cell.
Previous research indicated that myofibroblasts are the cells responsible for fibrosis. However, there was controversy around the origin of this cell. Identifying the origin could lead to targeted therapies for these very common diseases.
With the knowledge that fibrosis appears to radiate from blood vessels, the team examined the hedgehog signaling pathway, which normally regulates organ development but whose roles in the adult are less clear. They noticed that in adult mice, a hedgehog pathway gene called Gli1 was specifically expressed in a rare group of cells located around blood vessels in all solid organs.
This pattern suggested that the cells might play a role in fibrosis. To test this hypothesis the researchers tagged this protein in tissue with varying forms of fibrosis, and found that these cells proliferated by almost 20-fold under chronic injury and turned into myofibroblasts. The researchers believe that this cell population is responsible for about 60 percent of all organ myofibroblasts.
After identifying these cells the team set out to determine whether removing these cells would lead to improvement in organ function.
Using a genetic strategy in mice, the researchers were able to ablate these Gli1 cells, while leaving other cells unharmed. In mice with kidney and cardiac fibrosis, the ablation of these cells resulted in reduction in fibrosis and rescued heart function. The group found that these Gli1 progenitor cells differentiate into myofibroblasts, and in fibrotic disease, when they are ablated, researchers can rescue organs and organ function.
Researchers note that the genetic strategy employed in the preclinical model is not feasible in humans. For this reason, future research involves the exploration of drugs that could specifically target and shut off these fibrosis-causing stem cells with the hope that either an existing drug or a new drug could translate to a potential therapy for humans.
The team also notes that this cell population plays a role in the aging process stating that most organs develop fibrosis as a person age. Specifically, kidneys lose one percent of kidney function as a result of fibrosis for each year that they age. The group look forward to future research, using human tissue, to confirm their findings in humans and work to develop a potential therapy.
Source: Brigham and Women’s Hospital
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