Ting Xie didn’t set out to discover what governs the fate of stem cells—or to show how these cells might be harnessed to treat disease. Instead, growing up surrounded in rural China, his first big interest was the plant world. That’s why Xie entered the Beijing Agricultural University to learn how to create new varieties of crops. When Xie came to the US to continue his training in plant science, he enrolled in a Ph.D. program at Rutgers in horticulture. But his interest changed after being exposed to developmental genetics and cell biology. “In less than a year, I realized that creating new crops wasn’t for me,” he says. It was too practical, too narrowly focused. “Although producing better vegetables, or making better looking flowers is interesting and useful,” he explains. “I was more attracted to mechanisms—how things happen.”
A developing Drosophila ovariole.
Stem cells at the tip of the germarium continuously assemble egg chambers connected to one another like a string of different sizes of pearls. Germline cells, including GSCs and differentiated germ cells, are labeled green for Vasa, while germline specific structures, spectrosomes and fusomes, as well as follicle cells surrounding differentiated germ cells are labeled red for Hu-li tai-shao. Nuclei are shown in blue.
Image: Courtesy of Xie Lab
Then he discovered the growing body of research using the fruit fly, Drosophila, to probe the intricate biological dance of development—how a single-celled embryo can give rise to a complex creature with a heart, eyes, and wings. Here was an exciting problem worth studying, Xie thought. At that time, Richard Padgett just moved to Rutgers University to start his laboratory working on Drosophila embryonic development. Xie joined the laboratory and began exploring the biological signals that govern the patterns of development. “Once I started on fly research, I decided to pursue science as a career. That was my true interest,” he says.
When Xie moved to the Carnegie Institution of Washington to work with Allan Spradling as a post-doc, he began thinking about stem cells—those cells that are capable of transforming into many types of tissues and organs. Spradling established the Drosophila ovary as an adult stem cell system at that time. It’s hard to imagine now, but “back in 1996, not everyone really appreciated Drosophila stem cells,” Xie says. He realized that adult stem cells in fruit fly ovaries are easy to find, and that they could be used to ask a fundamental question: What tells a stem cell to differentiate into a specialized cell, such as the oocyte (or egg cell) in the fruit fly ovary? The conventional wisdom was that the trigger was inside the stem cell itself.
Not so. In Science in 2000, Xie and Spradling turned the prevailing idea upside down. “Stem cells by themselves don’t exactly know what to do,” he explains. Instead, their fate is determined by what’s around them. Each of these niches contains two or three stem cells, and looks like a hat composed of “cap” cells. Normally, a stem cell divides into two daughter cells, one of which remains a stem cell while the other eventually becomes an oocyte. But in what Xie describes as a “very simple and yet insightful experiment,” he demonstrated that a stem cell’s fate was determined by its proximity to the cap cells. When both daughter cells of a stem cell interact with the cap cells, both become stem cells. When moved away from the cap cells, the daughters become differentiated oocytes. The finding “really changed the field,” says Xie. Other labs quickly showed that this type of niche control of stem cells was the rule, not the exception.
In 2000, Xie moved to the newly established Stowers Institute, and forged ahead with a string of new discoveries. He pinpointed the chemical signals that the cap cells use to tell the stem cells what to do. He identified the glue known as E-cadherin that tethers stem cells in the niche, preventing their loss. In addition, he also learned how to build the niche from scratch during early development. He was surprised by the finding that the niche degenerates with time in the absence of stem cells, pretty much like an abandoned house. In a way, stem cells and their niche are mutually dependent on each other. This may be informative for future stem cell therapy. Transplantation of both stem cells and niche cells may be required for treating degenerative diseases because degenerative tissues may lose both stem cells and niche cells.
Although the niche sufficiently maintains the stem cell fate, not any cell can become a stem cell when put in the niche. Xie went ahead to discover a number of different classes of factors, which work inside stem cells for responding properly to niche instructions or for preventing fate-decision mistakes. For instance, he found a gene involved in stem cell regulation that’s virtually the same as a human gene that causes a disease named lissencephaly (literally ‘smooth brain”), where neurons don’t migrate correctly. This gene is important for stem cells to interact with the niche and understand niche instruction. “It’s very exciting,” says Xie. The revelation of its link to signaling and adhesion in the fly could provide key insights into the human disease.
After he learned much about the relationship between stem cells and their niche, he was curious about the relationship among the stem cells in each niche. “Like siblings in a family, they sometimes work together, or compete for their parents’ attention,” he says. The stem cells in the same niche can back up each other and regenerate a new stem cell when one of them is accidentally lost. On the other hand, their competition for the niche occupancy serves as a quality control mechanism ensuring that stem cells in the niche are not differentiated. If one of them is differentiated and no longer qualified as a stem cell, it can be quickly pushed out of the niche by its siblings and be replaced by a new functional stem cell. In a way, the niche is always occupied by “good” stem cells. But the bad news is that cancer stem cells, which drive tumor growth, take advantage of competition to push “good” stem cells out of the niche, leading to tissue destruction. Just like in the market economy, competition is a two-edge sword for stem cells.
Xie was even able to reverse aging—at least in fruit fly stem cells. Stem cells are vital to keeping the body functioning, since they create the new cells that replace worn out ones. But the stem cells themselves age. Why? Xie discovered that the aging of the entire niche is to blame. The number of cap cells declines, and their ability to make the right chemical signals diminishes. But when Xie jacked up the niche cells’ production of an enzyme, superoxide dismutase, that fights harmful free radicals, he discovered that aging stem cells magically behave young again. “If we rejuvenate the niche, we can stop stem cell aging,” says Xie. Given the complexities of biology, Xie’s aging research isn’t about to produce a Fountain of Youth elixir, of course.
Xie is launching a quest to tackle human diseases. For that, he’s jumping from fruit flies to mice. “The fly system is so powerful and reveals exciting aspects of stem cell regulation, but Drosophila stem cells cannot directly be used to treat diseases,” he explains.
The great promise of stem cells is that, injected into patients, the cells could fix an ailing heart or repair a broken spinal cord by differentiating into the right kind of cells. While that promise has yet to be realized, Xie is working on mice. Xie hopes that they can generate photoreceptors, retinal ganglion cells and pigmented epithelial cells in the Petri dish, which are frequently lost in retinal degenerative diseases. They can be transplanted into mouse retinal degeneration models to test their potential in treating degenerative eye diseases, including glaucoma, retinitis pigmentosa and macular degeneration. “We first need to prove the approach in mice, and then we can start working with human cells and, eventually, patients,” says Xie. So after his many discoveries of mechanisms and how things happen, his research may end up having practical results after all.