The findings, and their clinical significance, were presented at the Experimental Biology 2002 meetings in New Orleans last month.
This study is the first to identify the signal that instructs stem/progenitor cells to become dopamine neurons, the cells that degenerate in the brain of patients with Parkinson's disease.
The research team found that the primary signal responsible for determining that a progenitor cell will become a neuron is Interleukin 1, a member of the general class of molecules called cytokines, which are responsible for determining when blood stem cells differentiate into blood cells.
Being able to read the stem cells' intention enabled Carvey to select cells already committed to becoming neurons and to clone only those stem cells for transplantation. "We let the body do its own thing," he says. "We watched while it ran these stem cells down the lineage restriction pathways until the cells were almost neurons. Then we grabbed those cells, and only those cells, for our cloning activity."
Such specificity is important for two reasons, he adds. First, you want to produce large quantities of cells that will become the cells you need as quickly as possible. Second, you want to avoid including in your cloning process even one cell that has not yet firmly committed to becoming a neuron but will instead develop into a tumor or other troublesome cell once implanted.
Carvey said that many people do not always recognize the difference between the various types of stem cells. The defining hallmark of the different type of stem cells is not where they come from but how far along the lineage restriction pathway they are.
Many people confuse all types of stem cells with embryonic stem cells, which are taken from the earliest stages of an embryo, generally at 32 cells or less. Such cells have the potential to turn into dopamine neurons when implanted in the brains of humans with Parkinson's disease. Carvey's group did not want to work with this type cell, however, not because of the political difficulties but because it is only at the beginning of the lineage restriction pathway. There are basically three types of stem cells: embryonic stem cells which can become any cell in the body, stem cells for a specific organ that can become any cell in that particular organ (such as brain stem cells that can become any kind of brain cell), and then a more specialized group of stem cells called progenitor cells that are committed to becoming a certain type of cell, such as a dopamine neuron.
"Embryonic stem cells can literally develop into any cells," he said. "We wanted stem cells right at the point of becoming the cells we wanted and therefore unlikely to become cells we didn't want."
They also did not want to work with central nervous system (CNS) stem cells, one of the various types of stem cells taken from an organ and which already have committed to becoming very specific types of cells in that organ. These cells might turn into dopamine neurons but they also might turn into other types of neurons or into any of dozens of brain or nervous system cells. Carvey says it would take years to identify the different signals determining which of hundreds of possible routes the individual CNS stem cells would take. Instead, he and his team went as far down the lineage pathway as possible, right to the progenitor stem cells at the point of committing to a particular cells.
"These results are very encouraging," says Carvey, "because they are proof that it is possible to identify progenitor cells in well developed brains, stem cells that can be selected for the type of cell needed for clinical treatment, and cloned with very little chance of including cells you don't want. We took progenitor stem cells from the midbrain of a fetal rat, but many scientists believe it may be possible to find progenitor cells in adult brains using needle biopsy of living patients (a procedure already being done in humans for different reasons). Cells about to become the needed neurons would be selected, cloned, and placed back in the patient's brain, like an autograft. We know these cells have the capacity to develop into healthy neurons. If the results resembled those we found in our rats, this process could provide stunning new treatments for Parkinson's, Alzheimer's and other diseases."
Rush-Presbyterian-St. Luke's Medical Center is an academic medical center that encompasses the 824-bed Presbyterian-St. Luke's Hospital (including Rush Children's Hospital), the 110-bed Johnson R. Bowman Health Center and Rush University. Rush University, with more than 1,200 students, is home to one of the first medical schools in the Midwest, one of the nation's top-ranked nursing colleges, as well as graduate programs in allied health and the basic sciences. Rush is noted for bringing together clinical care and research to address major health problems, including arthritis and orthopedic disorders, cancer, heart disease, mental illness neurological disorders and diseases associated with aging.