In a development that could dramatically alter treatment approaches for spinal cord injuries and neurodegenerative diseases like ALS, MIT researchers have unveiled a streamlined method to convert skin cells directly into neurons — bypassing the lengthy stem cell stage and achieving conversion rates more than 10 times higher than previous approaches.
The team, led by Katie Galloway, the W. M. Keck Career Development Professor in Biomedical Engineering and Chemical Engineering at MIT, has demonstrated that their technique can produce functioning motor neurons that successfully integrate with brain tissue when implanted in mice.
“We were able to get to yields where we could ask questions about whether these cells can be viable candidates for the cell replacement therapies, which we hope they could be. That’s where these types of reprogramming technologies can take us,” says Galloway, whose group published their findings in two papers in the journal Cell Systems on March 13.
The new approach marks a significant improvement over existing cell conversion methods, which have historically yielded success rates below 1 percent. By contrast, the MIT team’s optimized process achieves an extraordinary 1,100 percent yield — meaning each skin cell can produce 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 typically takes several weeks and often results in cells that don’t fully mature.
“Oftentimes, one of the challenges in reprogramming is that cells can get stuck in intermediate states,” Galloway explains. “So, we’re using direct conversion, where instead of going through an iPSC intermediate, we’re going directly from a somatic cell to a motor neuron.”
The key innovation came when MIT graduate student Nathan Wang, lead author on both papers, identified that just three transcription factors — NGN2, ISL1, and LHX3 — were sufficient to drive the conversion when delivered at precise levels. The team engineered a single modified virus to deliver all three factors simultaneously, ensuring consistent expression in each cell.
A critical insight from the research revealed that cell proliferation history plays a crucial role in how cells respond to these transcription factors. By delivering genes that stimulate cell division before conversion begins, the researchers created cells more receptive to transformation.
“If you were to express the transcription factors at really high levels in nonproliferative cells, the reprogramming rates would be really low, but hyperproliferative cells are more receptive,” says Galloway. “It’s like they’ve been potentiated for conversion, and then they become much more receptive to the levels of the transcription factors.”
The researchers tested various delivery methods, finding that retroviruses achieved the most efficient conversion rates. They also discovered that reducing cell density during growth significantly improved neuron yield. The optimized process takes about two weeks in mouse cells.
To test the functionality of these lab-created neurons, the team collaborated with Boston University researchers to implant the cells into the striatum region of mouse brains. After two weeks, many neurons had survived and appeared to be forming connections with existing brain cells. When cultured in dishes, the neurons displayed electrical activity and calcium signaling, suggesting they could communicate with other neurons.
While the process works with human cells too, the efficiency is currently lower — between 10 and 30 percent — though still faster than traditional methods involving stem cell intermediates. The researchers are now working to improve the human cell conversion efficiency, which could enable production of large quantities of neurons for therapeutic applications.
The implications extend beyond the laboratory. Clinical trials using neurons derived from induced pluripotent stem cells to treat ALS are already underway, but the limited cell quantities have restricted the scale of these trials. The MIT approach could potentially overcome this hurdle.
For patients with spinal cord injuries or neurodegenerative diseases affecting motor control, these advances represent a promising avenue for future treatments. The ability to generate large numbers of functioning motor neurons could accelerate the development and testing of cell replacement therapies that restore movement and function.
The researchers now plan to explore implanting these neurons directly into the spinal cord, moving one step closer to potential clinical applications.
As Galloway and her team continue refining their techniques, the goal remains clear: transforming the promise of cell therapy into a practical reality for patients with currently limited treatment options. With each skin cell potentially yielding multiple functional neurons, that goal now seems closer than ever.
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