Wednesday, November 23, 2011

Host neurons obey transplants

Neurons derived from human embryonic stem cells can control native neurons in mice.

Charlotte Schubert

Transplanted human neurons, derived from embryonic stem cells, can integrate with a network of mouse neurons in culture and the mouse brain.

The findings, published today in the Proceedings of the National Academy of Sciences, lay the foundations for potential future treatments of Parkinson's disease, stroke and other conditions.

Transplanted human neurons grown from embryonic stem cells (red) can integrate with, and communicate with, native neurons (green) in a mouse brain.

National Academy of Science

Previous studies have shown that transplanted human neurons derived from stem cells look and act like functional nerve cells. For instance, such cells form connections with host neurons in the mouse brain, and receive signals from them.

But it has been a challenge to show that the transplanted cells can successfully signal to and regulate the behaviour of host neurons. To address this question, Jason Weick and his colleagues at the University of Wisconsin in Madison harnessed a technique known as optogenetic targeting. This involves genetically engineering neurons to produce an ion channel (a protein-lined pore that spans the cell membrane) that opens in response to light, allowing positive ions such as sodium and calcium to flow through it and activate the neuron. In this way the researchers can selectively activate human neurons in a mixture of human and mouse cells.

"It's kind of a neat way to show that you are just activating human neurons," says Clive Svendsen, director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, California. "You have some control over the system."

Full integration

Weick and his colleagues engineered human embryonic stem (ES) cells to express the light-activated ion channel and then turned them into neurons in cell-culture dishes. They then studied these neurons' properties and behaviours when cultured together with mouse neurons, and when transplanted into a region of the mouse brain called the hippocampus.

For their cell-culture experiments, the researchers chose mouse neurons that show a spontaneous synchronized electrical activity called 'bursting' in embryonic mice. Activating the human neurons caused the mouse neurons to fire as well. "If we light up the human cells, then the mouse cells 'burst'," says Weick, "It's this really nice tight coupling, and one precedes the other."

In brain slices from mice into which the human neurons had been transplanted, Weick similarly found that activating the human neurons with light prompted electrical activity in the mouse neurons.

The findings show that transplanted human ES-cell-derived neurons can successfully send signals to host cells — and that they can modulate the activity of a network of host neurons.

"That is pretty exciting," says Hongjun Song, director of the stem cell programme at Johns Hopkins University in Baltimore, Maryland. "You can put in a small number of cells and have a big effect." And while the findings were expected in some ways — transplanted neurons have already been shown to ameliorate disease — the technique provides a platform to answer questions such as which type of host neurons respond, says Song.

Into the brain

Weick and his colleagues are now transplanting light-activatable neurons into the brains of mice with various neurodegenerative diseases. "The gigantic pie-in-the-sky stuff is that essentially we will have the capacity to customize neurons for particular diseases," says Weick, who imagines a fibre-optic cable strung through the brain, activating a set of transplanted cells — such as neurons that release the neurotransmitter dopamine to treat Parkinson's disease.

Svendsen cautions that some regions of the brain may not be as 'plastic' and amenable to neuronal integration as the hippocampus. But he's intrigued. "As a potential therapy, it's very exciting," he says.

Nature

doi :10.1038/nature.2011.9406