Human skin cells turned directly into motor neurons

Scientists have converted skin cells from healthy adults directly into motor neurons without going through a stem cell state. The technique developed by researchers at Washington University in the US makes it possible to study motor neurons of the human central nervous system in the lab. Scientists working to develop new treatments for neurodegenerative diseases have been stymied by the inability to grow human motor neurons in the lab.

Motor neurons drive muscle contractions, and their damage underlies devastating diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy, both of which ultimately lead to paralysis and early death. Avoiding the stem cell phase eliminates ethical concerns raised when producing what are called pluripotent stem cells, which are similar to embryonic stem cells in their ability to become all adult cell types, researchers said.

Bypassing a stem cell state allows the resulting motor neurons to retain the age of the original skin cells and, therefore, the age of the patient. Maintaining the chronological age of these cells is vital when studying neurodegenerative diseases that develop in people at different ages and worsen over decades. "In this study, we only used skin cells from healthy adults ranging in age from early 20s to late 60s," said Andrew S Yoo, assistant professor at Washington University.

"Our research revealed how small RNA molecules can work with other cell signals called transcription factors to generate specific types of neurons, in this case motor neurons," Yoo said. To convert skin cells into motor neurons, the researchers exposed the skin cells to molecular signals that are usually present at high levels in the brain. Past work by Yoo and his colleagues - then at Stanford University in the US - showed that exposure to two short snippets of RNA turned human skin cells into neurons.

These two microRNAs - called miR-9 and miR-124 - are involved with repackaging the genetic instructions of the cell. In the new study published in the journal Cell Stem Cell, the researchers extensively characterised this repackaging process, detailing how skin cells reprogrammed into generic neurons then can be guided into specific types of neurons. They found that genes involved in this process become poised for expression but remain inactive until the correct combination of molecules is provided. 

After much experimentation with multiple combinations, the researchers found that adding two more signals to the mix - transcription factors called ISL1 and LHX3 - turned the skin cells into spinal cord motor neurons in about 30 days. The combination of signals - microRNAs miR-9 and miR-124 plus transcription factors ISL1 and LHX3 - tells the cell to fold up the genetic instructions for making skin and unfurl the instructions for making motor neurons, researchers said.