Fuchs also demonstrated that those who think the era of stem cell biology began only recently are more than a century late to the party; the term “stammzelle” was first used in 1877 by Ernst Haeckel. In the early 1900s, Alexander Maximov proposed that blood cells arise from a stem cell. In the mid-1970s, Fuchs’ mentor, Dr. Howard Green at MIT, was the first to culture stem cells. They were epidermal stem cells and Green applied his methods to treat burn victims by using their stem cells to create sheets of cultured skin.
Green’s work repairing burned skin led to a number of new insights: the lab-grown skin never showed any signs of promoting cancer, thus eliminating one worry about this particular stem cell therapy. And the “artificial” sheets of skin were incapable of growing hair or sweating, which eventually resulted in the realization that a niche, or a cell’s neighborhood, sends powerful signals orchestrating normal development; Fuchs’ studies have shown that hair follicles, sebaceous and sweat glands have their own stem cells apart from epidermal stem cells.
In the eye as well, regenerative medicine has already laid down milestones: transplants of corneal epithelial cells have restored vision in at least 100 patients over the past decade, Fuchs said.
Regardless of which epithelial stem cell she interrogates, Fuchs finds that stem cells rely on heterologous neighbors, or their niche, to fulfill function.
“We have discovered more than 700 differences between cancer stem cells and normal stem cells,” said Fuchs. Looking on is NIH director Dr. Francis Collins, who introduced her.
Photos: Ernie Branson
Hair follicle stem cells are particularly abundant in most mammals such as the laboratory mouse. The ability of hair follicles to undergo cycles or spurts of follicle regeneration and hair growth makes it an ideal model for studying how stem cells toggle between resting states when they aren’t making tissue and active states when they are, she explained. Governing that cycle are cues from the microenvironment, or cell signals.
“As we began to delve deeper into how the hair follicle stem cells respond to these cues to become activated,” Fuchs said, “we realized that if we genetically manipulate them to become more responsive, the skin of the mice becomes prone to developing cancer.”
It turns out that stem cells are regulated by both heterologous and progeny niche cells—it’s a continuous feedback loop. “This is why wound repair has a ‘stop’ signal eventually,” Fuchs explained. “This system is perturbed in cancer…Cancer hijacks how stem cells transition from quiescence to activation.”
Fuchs and her team have isolated and characterized cancer stem cells from squamous cell carcinomas of the skin. It turns out that squamous cell carcinoma arises from a niche of its own, she said.
“We have discovered more than 700 differences between cancer stem cells and normal stem cells. The problem we face is similar to that faced by the National Cancer Institute’s human cancer sequencing project, where hundreds of mutations have been found in human squamous cell carcinomas that are not found in normal human skin. Which of these differences is causal to cancer and which are mere bystanders?”
Most exciting, Fuchs’ team has developed a new method to carry out large-scale screens in mice, similar to what makes the worm and fly such amenable organisms for geneticists. In screening the gene alterations in cancer stem cells and those from human head and neck cancers, the group identified seven new tumor suppressor genes, previously unconnected to cancer. They presented their new work at NIH for the first time. It was published recently in Science.
As detailed and complicated as the pathways they are searching turn out to be, Fuchs let a last slide serve as a motto: “Don’t get so engrossed in details that you miss the big picture.”
And, as if niche only played a role in determining cell behavior, Fuchs reminded her audience of the importance of niche in the production of talented scientists: NIH director Dr. Francis Collins (who introduced Fuchs’ talk) inherited his first graduate student (now a professor at Duke) from Fuchs’ lab. And Fuchs’ lab begat NHGRI’s Dr. Julie Segre, who was recently celebrated as federal Employee of the Year.
The full lecture is on view at http://videocast.nih.gov/summary.asp?Live=13556&bhcp=1.