Researchers Convert Human Skin Cells Directly into Brain cells

Scientists are transforming human skin cells directly into a specific type of brain cell affected by Huntington’s disease, an ultimately fatal neurodegenerative disorder. Dissimilar to other strategies that turn one cell type into another, this new process does not pass through a stem cell phase, avoiding the production of multiple cell types.

The researchers, from Washington University School of Medicine in St. Louis (MO, USA), demonstrated that these converted cells survived at least six months after injection into the brains of mice and behaved similarly to native cells in the brain.


“Not only did these transplanted cells survive in the mouse brain, they showed functional properties similar to those of native cells,” said senior author Andrew S. Yoo, PhD, assistant professor of developmental biology. “These cells are known to extend projections into certain brain regions. And we found the human transplanted cells also connected to these distant targets in the mouse brain. That’s a landmark point about this paper.”

The research was published October 22, 2014, in the journal Neuron. The investigators produced a specific type of brain cell called medium spiny neurons, which are vital for controlling movement. They are the principal cells affected in Huntington’s disease, an inherited genetic disorder that causes involuntary muscle movements and cognitive decline usually beginning in middle-adulthood.

The research involved adult human skin cells, instead of the more typically studied mouse cells or even human cells at an earlier stage of development. In regard to possible future treatments, the capability to convert adult human cells presents the possibility of using a patient’s own skin cells, which are easily accessible and will not be rejected by the immune system.

To reprogram these cells, Dr. Yoo and his colleagues put the skin cells in a setting that closely mimics the environment of brain cells. They knew from past research that exposure to two small molecules of RNA, a close chemical relative of DNA, could transform skin cells into a combination of different types of neurons.

In a skin cell, the DNA instructions for how to become a brain cell, or any other type of cell, is efficiently bundled away, unused. In past research published in Nature, Dr. Yoo and his colleagues showed that exposure to two microRNAs called miR-9 and miR-124 altered the processes that control packaging of DNA. Although the investigators still are finding out more about the details of this complicated process, these microRNAs appear to be opening up the tightly packaged sections of DNA important for brain cells, allowing expression of genes governing development and function of neurons.

Knowing exposure to these microRNAs by itself could alter skin cells into a combination of neurons, the researchers then started to modify the chemical signals, exposing the cells to additional molecules called transcription factors that the investigators knew were present in the region of the brain where medium spiny neurons are common.

“We think that the microRNAs are really doing the heavy lifting,” said co-first author Matheus B. Victor, a graduate student in neuroscience. “They are priming the skin cells to become neurons. The transcription factors we add then guide the skin cells to become a specific subtype, in this case medium spiny neurons. We think we could produce different types of neurons by switching out different transcription factors.”

Furthermore, Dr. Yoo explained that the microRNAs, but not the transcription factors, are important components for the general reprogramming of human skin cells directly to neurons. His team, including co-first author Michelle C. Richner, senior research technician, revealed that when the skin cells were exposed to only the transcription factors, without the microRNAs, the conversion into neurons was not successful.

The researchers performed comprehensive testing to demonstrate that these newly converted brain cells did definitely look and act like native medium spiny neurons. The converted cells expressed genes specific to native human medium spiny neurons and did not express genes for other types of neurons. When transplanted into the mouse brain, the converted cells showed morphologic and functional properties similar to native neurons.

To evaluate the cellular characteristics tied to the disease, the investigators now are taking skin cells from patients with Huntington’s disease and reprogramming them into medium spiny neurons using this approach. They also plan to inject healthy reprogrammed human cells into mice with a model of Huntington’s disease to see if this has any effect on the symptoms.

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Washington University School of Medicine in St. Louis