Scientists rupture code converts skin cells directly into neurons

In the development of spinal cord injury methods and neurodegenerative diseases such as ALS, which may significantly change the treatment approach, MIT researchers have revealed a simplified approach that can directly convert skin cells into neurons—bypassing the lengthy stem cell phase and achieving a conversion rate of more than 10 times higher than previous methods.

The team led by Katie Galloway is a career development professor in MIT Biomedical Engineering and Chemical Engineering, whose technology shows that their technology can produce functional motor neurons and is successfully synthesized with brain tissue when implanted in mice.

“We were able to succumb, where we could raise questions about whether these cells could be viable candidates for cell replacement therapy, and we hope they could be. “That’s where these types of reprogramming techniques can take us,” Galloway said.

The new approach marks a significant improvement in existing cellular conversion methods, with success rates below 1% historically. By comparison, the MIT team’s optimization process achieves an extraordinary 1,100% yield—which means that each skin cell produces multiple neurons.

For nearly two decades, scientists have been able to convert skin cells into induced pluripotent stem cells (IPSCs), which can then be differentiated into other cell types, including neurons. However, this process usually takes several weeks and often leads to complete immaturity of cells.

“Generally, one of the challenges of reprogramming is that the cells can get stuck in the middle,” Galloway explained. “So we use direct conversion, rather than through IPSC intermediates, but directly from somatic cells to motor neurons.”

This is a key innovation when MIT graduate student Nathan Wang (leading author of two papers) determined that only three transcription factors (NGN2, ISL1 and LHX3) were sufficient to drive conversions when delivered at precise levels. The team designed a modified virus while providing all three factors to ensure consistent expression in each cell.

Key insights from the study suggest that the history of cell proliferation plays a crucial role in the way cells respond to these transcription factors. By delivering genes that stimulate cell division before transformation begins, researchers have created cells that are more readily receptive to transformation.

“If you are expressing transcription factors at very high levels in nonproliferative cells, the reprogramming rate is indeed very low, but highly proliferative cells are more receptive,” Galloway said. “It’s like they’ve been enhanced for the conversion, and then they become more receptive to the level of transcription factors.”

The researchers tested various delivery methods and found that retroviruses achieved the most effective conversion rate. They also found that reducing cell density during growth significantly increases neuronal yield. In mouse cells, the optimization process takes about two weeks.

To test the functions of neurons created by these labs, the team worked with Boston University researchers to implant cells into the striatum regions of the mouse brain. Two weeks later, many neurons survived and appear to be making connections with existing brain cells. When cultured in a Petri dish, neurons showed electrical activity and calcium signaling, indicating that they could communicate with other neurons.

Although the process is also used with human cells, it is currently inefficient (10% to 30%), although still faster than traditional methods involving stem cell intermediates. Researchers are now working to improve the efficiency of human cells’ transformation, which can enable a large number of neurons to be used in therapeutic applications.

These meanings range beyond the laboratory. Clinical trials using inducing pluripotent stem cells to treat neurons that treat ALS are already underway, but the limited number of cells limits the size of these trials. The MIT approach may overcome this hurdle.

For patients with spinal cord injury or neurodegenerative diseases that affect motor control, these advances represent promising pathways for future treatment. The ability to generate a large number of functional motor neurons can accelerate the development and testing of cell replacement therapies that restore movement and function.

Now, researchers plan to implant these neurons directly into the spinal cord to explore, bringing a step closer to potential clinical applications.

As Galloway and her team continue to refine their technology, the goal remains clear: Transform the promise of cell therapy into a practical reality for patients with limited treatment options. With each skin cell potentially producing multiple functional neurons, the target now seems closer than ever.