One of the most promising prospects for treatment of a neurodegenerative disorder lies in the use of embryonic stem cells to obtain dopamine for Parkinson’s disease. The goal is ambitious, but scientists are coming closer to reaching it, a panel of researchers from around the world said at the Society for Neuroscience meeting.
This new form of treatment, which so far has not been tested in patients, calls for a graft of embryonic stem cells that would give rise to the correct type of neurons in the portion of the midbrain where the cells affected by Parkinson’s disease would normally exist. In addition, they would have to not only produce the neurotransmitter dopamine in the right amounts at the appropriate times, but deliver it to target neurons in the brain that command all the muscles in the body.
In one advance, Anders Björklund and his colleagues at the Wallenberg Neuroscience Center in Lund, Sweden, have identified two genetic sequences that lead embryonic stem cells to develop into dopamine-producing neurons. These neurons form two distinct populations: A9 cells, which will transmit information about movement to the motor neurons that activate muscles throughout the body, and A10 cells, which are involved in the processing of emotions.
Meanwhile, Harvard Medical School researchers led by Ole Isacson have identified a particular protein found on A9 cells but not on A10 cells. That makes it an important marker for scientists interested in treating Parkinson’s disease, because only the A9 cells are involved in the regulation of movement, the main function that is affected by the disease.
But producing exactly the right type of stem cell is not a simple matter of following a recipe in a petri dish; the timing of each step matters as much as the materials.
“You have to remember that when you grow cells in a dish, you are growing them out of context,” Björklund cautioned. Scientists must attempt to replicate the complex chemicals that would be present in the fetus and that normally are “orchestrated precisely, to within hours,” Björklund said.
All too often the cell grafts to be used for treatment include a number of different cell types because it is almost impossible to capture only the needed A9 cells when preparing a graft for implantation. In addition, in order to survive in the patient’s brain, the cells need to have reached a certain age—ideally, 47 days post-conception—but the timing of their growth in the lab cannot be so precisely synchronized.
Hence it is essential to be able to sort out the cells of the prospective graft by age and cell type, and Björklund’s research team has recently devised a way to do just that.
By isolating cells expressing a gene called Ngn2, they have been able to isolate dopamine neuron precursors at a stage of development when they are able to survive and establish themselves after transplantation.
“It’s important for each neuron to find the right target,” said Hynek Wichterle of Columbia University, so that nerve signals reach the appropriate receptors.
In addition, a cell graft, like any other kind of transplant, raises the risk of rejection by the recipient’s immune system. “Even though brain cells are only mildly immunogenic, there need to be some measures to prevent rejection if there is a serious mismatch between host and donor tissue,” Isacson said.
Despite these potential pitfalls, positive results continue to emerge. The stem-cell grafts that have survived and functioned normally for years in human patients—several for at least 4 years and one for 14—came from aborted fetal tissue; the challenge now is to engineer successful grafts from embryonic stem cells in the laboratory.
In this regard, the researchers expressed optimism about a study published online in October in the journal Stem Cells. In it, Isacson and colleagues document the existence of apparently normal, dopamine-producing neurons in the midbrain of a rodent model of Parkinson‘s disease after a graft of embryonic stem cells.