FGF Proteins Maintain Stem Cells in Developing Kidney


The digestion of food and other metabolic processes necessary for the maintenance of our bodies produce waste products that must be routinely removed. Without proper removal of these metabolic waste products, they will build up in concentration and poison the organs and tissues. In the human body, two organs work to dispose of wastes. The liver processes wastes in order to make them more water-soluble. Waste products that are not water soluble are excreted into the bile. Bile is made by the liver and stored in the gall bladder. When we eat fat-soluble food molecules, bile helps solubilize the fatty materials so that enzymes can degrade them. Bile is also used to dump things the body no longer wants into the intestine so that they can be excreted rom the body. The second organ that excreted water-soluble materials is the kidneys. The kidneys filter the blood and concentrate the waste products into a fluid called urine. Urine is excreted by means of the urinary tract.

Kidneys are composed of 800,000 to 1.5 million tiny units called nephrons. Nephrons are small structures that are composed of a series of tubes. The front end of the nephron is inflated into a cup-shaped structure that is fed by a knot of tiny blood vessels. The walls of these blood vessels is very porous and the fluid of the blood and many things dissolved in it move from the blood vessels into the nephron, The long tubules of the nephron recapture water and precious ions while leaving the wastes. Eventually the concentrated fluid, urine, is deposited into a tube called the ureter that connects the kidneys to the urinary bladder.

In the United States, 10% of the population is afflicted with some kind of chronic kidney disease. Regenerative treatments for the kidneys are in their infancy. The developing kidney contains a robust stem cell population, but soon after birth, the stem cells form nephrons and are essentially all used up. However, researchers at Washington University School of Medicine in St. Louis, Missouri have identified two proteins in mice and humans that are required to maintain a supply of stem cells in the developing kidney. Manipulation of these proteins might provide a means to maintain or even renew a stem cell population in the kidney.

These two proteins, Fibroblast Growth Factor-9 (FGF-9) and Fibroblast Growth Factor-20 (FGF-20), allow mouse kidney stem cells to survive in culture longer than previously reported. Though the cells were maintained only five days (up from about two), this work is a small step toward the future goal of growing kidney stem cells in the lab.

In the developing embryo, these early stem cells give rise to adult cells called nephrons, the blood filtration units of the kidneys. Raphael Kopan from Washington University said, “When we are born, we get a certain allotment of nephrons. Fortunately, we have a large surplus. We can donate a kidney – give away 50 percent of our nephrons – and still do fine. But, unlike our skin and gut, our kidneys can’t build new nephrons.”

Herein lies the reason why regenerative medicine in the kidney is behind other tissues: the skin and the gut have small pools of local stem cells that continually renew these organs throughout life. A term used by scientists for such a pool of local stem cells that support a system is a “stem cell niche.” During early development, the embryonic kidney has a stem cell niche, but later in development, possibly shortly before or shortly after birth; all stem cells in the kidney differentiate to form nephrons. This leaves no stem cell niche.

According to Kopan: “In other organs, there are cells that specifically form the niche, supporting the stem cells in a protected environment. But in the embryonic kidney, it seems the stem cells form their own niche, making it a bit more fragile. And the signals and conditions that lead the cells to form this niche have been elusive.”

David M. Ornitz and his laboratory provide a surprising clue to the signals that maintain the embryonic kidney’s stem cell niche. Earlier this year, Ornitz, who studies FGF signaling during the development of the mouse ear, published a paper showing that FGF20 plays an important role in inner ear development. However, even though mice that lack FGF20 “are profoundly deaf,” explained Ornitz, “they are otherwise viable and healthy,” but “in some cases we noticed that their kidneys looked small.”

Past work from his own lab and others suggested that FGF9, a closely-related cousin of FGF20, might also participate in kidney development. In general, members of the FGF family are known to play important and broad roles in embryonic development, tissue maintenance, and wound healing. Mice that lack FGF9 have defects in development of the male urogenital tract and die after birth due to defects in lung development.

Since FGF9 and 20 are so closely related, Ornitz and Sung-Ho Huh, Ph.D., a postdoctoral research associate, and former postdoctoral researcher Hila Barak, Ph.D., thought the two proteins might serve overlapping, redundant functions in the developing kidney. Essentially, the two proteins might compensate for each other if one is missing. The next logical question, according to Ornitz, was what happens when both are missing.

The results confirmed these hypotheses. “When we examined mice lacking both FGF9 and FGF20, we saw that the embryos had no kidneys,” Ornitz said.

In humans, the role of these proteins came from genetic studies in families that showed a marked propensity for their children to have kidney problems. Collaborators in France identified two families that lost more than one pregnancy because the fetuses developed without kidneys (renal agenesis).

Analyses of DNA from the fetuses that had died from renal agenesis showed mutations in four genes known to be involved in kidney development. One of these mutations resulted in the total loss of FGF20. This analysis confirmed the mouse studies, but also underscored an important difference between humans and mice: in mice, FGF9 appears to compensate for a total loss of FGF20, but in humans, fetuses that develop without kidneys had normal FGF9. This suggests that the two genes do not completely compensate for each other in human kidney development.

Now that at least some of the more crucial proteins necessary to support the kidney stem cell niche have been identified, Kopan and Ornitz both look to future work to further extend the life of such cells in the lab. Kopan noted, “The holy grail would be to deliver these cells back to a diseased kidney,” Kopan said. “This is a very small step. But we hope this will be a stimulus to the field, for us and for others to continue thinking about how to convince these cells to stick around longer.”