Skipping a Step: Turning Brain Cells Directly into Neurons

It was once commonly believed that “what you see is what you get” with the human brain. As in, the brains cells that you are born with are the only ones you’ll have for the rest of your life because they can’t regenerate.

The discovery of brain stem cells in the late 90s disproved this notion and established that the brain can replace old cells and repair damage after injury. The brain’s regenerative capacity is limited, however. Consequently, patients suffering from neurodegenerative diseases like Alzheimer’s and Parkinson’s can’t rely on their brain stem cells to repopulate all of the sick and dying neurons in their brains.

This is where cellular reprogramming technology could come to the rescue. Induced pluripotent stem cells (iPSCs) generated from patient skin cells by cellular reprogramming can be turned into many types of brain cells to study diseases in a petri dish, as well as to test drugs and develop stem cell therapies. Eventually, the hope is to transplant iPSC-derived brain cells back into patient brains to treat or cure degenerative diseases.

Making neurons directly from other brain cells

Another form of cellular reprogramming, offers a more direct approach to generating populations of healthy brain cells. Using a similar technique to iPSCs, scientists can use specific factors to directly reprogram skin cells or other brain cells into neurons without making them go through the pluripotent stem cell state. By skipping a step in the reprogramming process, researchers save time, money, and energy – and it could result in safer cells.

The group used small molecules to directly reprogram human astrocytes into neurons that could be transplanted into mice. (Zhang et al., 2015)

The group used small molecules to directly reprogram human astrocytes into neurons that could be transplanted into mice. (Zhang et al., 2015)

While direct reprogramming of skin and non-neuronal brain cells into neurons has been published before, a study in Cell Stem Cell by a group at Penn State University last week described a new-and-improved method to make properly functioning neurons from brain astrocytes. Astrocytes are a type of glial cell that are abundant in the brain. They provide neurons with support, nutrients, and aid following injury.

Led by senior author Gong Chen, the group bathed human astrocytes in a cocktail of small molecules that turned the astrocytes into neurons in less than 10 days. These neurons survived in a dish for more than 5 months and were able to send electrical signals to each other (a sign that they were functional). Even more exciting was that the directly reprogrammed neurons survived and functioned properly when they were transplanted into the brains of mice.

When they studied the biological mechanism behind their direct reprogramming method, they found that the small molecule cocktail turned off the activity of astrocyte-specific genes in the astrocytes and turned on neuron-specific genes to convert them into neurons.

Human astrocytes (left) were directly reprogrammed into neurons (right). (Zhang et al., 2015)

Human astrocytes (left) were directly reprogrammed into neurons (right). (Zhang et al., 2015)

This discovery is great news for the reprogramming field as using small molecule reprogramming instead of the commonly used transcription-factor based reprogramming (which involves using viruses that can damage or alter the genome) is a more attractive method with broader applications­ for making neurons that can be transplanted into humans.

Direct reprogramming makes new neurons in the brain

But wait, there’s more! An article from TheScientist reported that multiple groups at the Society for Neuroscience (SFN) conference  in Chicago presented results on directly converting glial cells into neurons in mouse brains rather than in a dish.

One group from the Johannes Gutenberg University used two transcription factors, proteins that control which genes are turned on or off in the human genome, to directly reprogram mouse astrocytes into neurons. By producing more of Sox2 and Ascl1 in the cortex of the mouse brain than would normally be found there, they were able to turn 15% of the glial cells in that area into neurons.

The function of these directly reprogrammed neurons remains to be determined, but the lead scientist, Sophie Peron, told TheScientist:

“That’s the next step. Now that we have a system to get these cells converted we are currently studying their connectivity, functionality, and precise characteristics.”

Two other groups also reported similar findings when they worked with a type of glial cell called reactive astrocytes. These cells are specifically activated during injury to jumpstart the healing process. The first group from the University of Texas Southwestern used the factor Sox2 to directly reprogram reactive astrocytes into neurons in mice, while the group from Penn State University – mentioned earlier in this blog – did the same thing, but using a different factor, NeuroD1.

The Penn State group went further to test their direct reprogramming method in a mouse model of stroke and found that NeuroD1-reprogrammed neurons reduced cell death and tissue scarring after stroke.

Lead scientist Yuchen Chen said:

“These findings suggest that direct reprogramming of glial cells into functional neurons may provide a completely new approach for brain repair after stroke. Our next step is to analyze whether the glia-neuron conversion technology can facilitate functional recovery in stroke animals.”

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