U-M scientists reported their research results in two papers published in the Aug.15 issue of Neuron.
"We know that stem cells exist in the adult central nervous system," says Sean J. Morrison, Ph.D., a Howard Hughes Medical Institute assistant investigator and a U-M Medical School assistant professor of internal medicine and of cell and developmental biology. "But this is the first indication that they also remain in the peripheral nervous system – not only after birth, but into adult life."
Morrison explains that the central and peripheral nervous systems develop from two different locations in the early embryo. Stem cells in one area create the central nervous system's brain and spinal cord. Stem cells from another area, called the neural crest, give rise to peripheral neurons and glial cells that control gut function, regulate the fight-or-flight response and make it possible for us to have a sense of touch. Glial cells are supportive cells for the nervous system.
"We don't know what these neural crest stem cells are doing in the gut or whether they persist into adult life in humans, as they do in rats," says Morrison. "The importance of the study is that it provides the first evidence that stem cells persist in the adult peripheral nervous system. Our results will lead to additional research, which could lead to new ways of using stem cells to promote peripheral nervous system repair after injury or disease."
Suzanne Bixby, a research associate in Morrison's laboratory, and Genevieve M. Kruger, a student in the U-M Medical School's Medical Scientist Training Program, used flow cytometry technology to isolate the stem cells described in the Neuron articles. Cited as first authors of the papers, Bixby worked with neural crest stem cells from embryonic rat gut and sciatic nerves, while Kruger focused on stem cells in postnatal and adult rat gut.
"We decided to look for stem cells in postnatal gut tissue, because that's where development of the peripheral nervous system continues the longest," Kruger says.
The stem cells were rare and difficult to find, according to Bixby. Even in embryonic gut tissue, only one to two percent of all cells turned out to be neural crest stem cells.
To demonstrate that they were true stem cells with the ability to self-renew and form new peripheral nervous system cells, Bixby cultured individual neural crest stem cells taken from rat gut at Day 14 of embryonic development, while Kruger used single cells from rats that were 15-to-110 days old.
Whether from embryonic or adult rat gut, individual neural crest stem cells gave rise to thousands of neurons, glia and smooth muscle cells. Even though activity declined with age, stem cells could still be isolated from the oldest rat in the study, which was 110 days old.
One of the most intriguing findings of the U-M study, according to Morrison, was the discovery that neural crest stem cells have the power to control their own developmental destiny.
"One reason why different types of cells exist in different parts of the nervous system is that they develop from different types of stem cells," Morrison explains. "This is the first study to clearly show there are cell-intrinsic differences between stem cells in different parts of the nervous system at the same time in development, and these innate differences have real functional consequences."
Jack T. Mosher, a post-doctoral fellow in Morrison's lab, had the challenging job of transplanting neural crest stem cells from rats into developing peripheral nerves in chick embryos. Mosher used stem cells from rats at identical stages of embryonic development (Day 14), but some of the stem cells were isolated from embryonic rat gut and others from the sciatic nerve.
"Sciatic nerve neural crest stem cells developed into glial cells, while stem cells from the gut became neurons," Morrison says. "Stem cells from different regions of the nervous system differ in their responsiveness to environmental signals that stimulate neural development. Some cells were more responsive to signals promoting neuronal development, while others were more responsive to signals promoting glial development."
Morrison cautions that it's too early to make predictions on whether the new stem cell discovery will have medical applications. "We are just at the stage of imagining new approaches," he says. "Our immediate goal is to understand the function of these cells and find out whether they exist in humans. If so, it could change the way we think about promoting repair in the adult peripheral nervous system."
Sean Morrison was one of 100 young innovators profiled in the June 2002 issue of Technology Review . The honorees work in "hot spot" research areas with the potential to transform existing industries and create new ones.
Morrison's stem cell research is supported by the National Institutes of Health, the Searle Scholars Program and the Howard Hughes Medical Institute. The U-M has filed a patent application on the research findings.
Additional U-M collaborators were Nancy M. Joseph, a student in the Medical School's Medical Scientist Training Program, and Toshihide Iwashita, Ph.D., a post-doctoral fellow. Joseph defined the expression patterns of environmental factors that control stem cell differentiation. Iwashita determined where neural crest stem cells were most likely to be located in the gut.
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Journal
Neuron