Scientists in the US made new brain cells by inserting reprogrammed adult skin cells into fetal mouse brains and then used them to reduce symptoms of Parkinson’s disease in rats. While this is a long way from demonstrating such a method might be effective in humans, it brings that hope a step closer.
The study is published in the early online 7th April issue of PNAS, the Proceedings of the National Academy of Sciences and is the work of lead author Dr Marius Wernig and colleagues.
Wernig is a postdoctoral researcher working with Rudolf Jaenisch, whose team at Whitehead Institute for Biomedical Research first showed last December that adult mouse skin cells could be reprogrammed into a state that resembled embryonic stem cells and then used to treat mice with a human sickle-cell anemia disease trait.
The long term goal of such a process is to create embryonic stem-cell like cells with patient-specific DNA for transplant therapy, because this overcomes the problem of rejection by the recipient’s immune system which is what happens when the donor DNA is different.
Wernig said this latest study was the:
“First demonstration that reprogrammed cells can integrate into the neural system or positively affect neurodegenerative disease.”
“This experiment shows that in vitro reprogrammed cells can in principle be used to treat Parkinson’s disease,” added Jaenisch.
In the experiment, Wernig and colleagues used induced pluripotent stem cells (IPS cells). These behave like embryonic stem cells in that they have the potential to give rise to a range of other cells, including brain cells. They are induced in that they are made by reprogramming adult skin cells, which in this case was done using retroviruses to introduce four genes into the nuclear DNA of the skin cells.
The genes that were introduced were Oct4, Sox2, c-Myc and Klf4, the same ones that were found in the earlier research to change skin cells into pluripotent cells.
The newly reprogrammed IPS cells were then separated into two different types: neural precursor cells and dopamine neurons. To do this the investigators used methods already proven with embryonic stem cells.
The researchers then took the neural precursor cells and transplanted them into the brains of mouse embryos which were then born naturally and examined nine weeks after transplantation.
Wernig and colleagues found new cell clusters around the transplant sites and they noticed quite a significant number had also migrated into the surrounding brain tissue.
They also found that the neural precursor cells had differentiated into several types of brain cells, including new neurons and glia cells, and that these new cells were behaving like mature cells in the host brain (functionally integrated).
In a second experiment, Wernig and colleagues used rats that had had some of the dopamine-producing neurons in their mid-brains destroyed so they showed symptoms of Parkinson’s. The researchers induced some IPS cells to differentiate into dopamine neurons and transplanted them into the rats’ brains.
Four weeks after transplant, the rats’ Parkinson’s symptoms decreased. This was tested using amphetamine injections. When injected with amphetamine, rats with Parkinson’s tend to walk in circles, going to the side where there is less dopamine activity. Eight of the nine rats treated with the IPS cells showed either no circling behaviour or significantly less.
Eight weeks after the transplant, the researchers found that the dopamine neurons had extended into the surrounding brain tissue.
Jaenisch said the experiment showed that in principle, reprogrammed cells could be used to treat Parkinson’s disease:
“It’s a proof of principle experiment that argues, yes, these cells may have the therapeutic promise that people ascribe to them,” he explained.
Wernig and Jaenisch hoped their findings will lead to work on human patients, but they were careful to point out there are many hurdles to overcome first.
For example, one large hurdle will be to find alternatives to retroviruses as a way to introduce the genes that make skin cells into IPS cells. Retroviruses cause cancer.
Another hurdle will be to develop a way to transplant the newly created brain cells into the human brain, and to locate the specific sites in the brain where this will have the highest chance of success.
“Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease.”
Marius Wernig, Jian-Ping Zhao, Jan Pruszak, Eva Hedlund, Dongdong Fu, Frank Soldner, Vania Broccoli, Martha Constantine-Paton, Ole Isacson, and Rudolf Jaenisch.
Proc. Natl. Acad. Sci., Published online on April 7, 2008
Source: Whitehead Institute for Biomedical Research press release, journal abstract.
Written by: Catharine Paddock, PhD