MIT researchers have developed a way to convert skin cells directly into neurons, avoiding the need to create stem cells first. This method produces over 10 neurons from a single skin cell in mouse experiments. If replicated in human cells, it could create large quantities of motor neurons for treating mobility-impairing conditions like spinal cord injuries.
These lab-made neurons were successfully integrated into the brains of mice in a preliminary step toward therapy. This breakthrough holds promise for advancing cell replacement therapies.
Katie Galloway, the W. M. Keck Career Development Professor in Biomedical Engineering and Chemical Engineering, said, “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.”
About 20 years ago, scientists discovered that skin cells could be converted into pluripotent stem cells (iPSCs), which can become various cell types. However, this process takes weeks and often faces roadblocks, with cells getting “stuck” in intermediate stages.
MIT researchers, led by Katie Galloway, have now bypassed the iPSC stage. By delivering a specific mix of just three transcription factors (NGN2, ISL1, LHX3) and two proliferation-driving genes (p53DD and mutant HRAS), they directly converted skin cells into motor neurons with significantly higher efficiency.
This method simplifies earlier approaches requiring six or more factors and ensures more consistent gene expression by using fewer viral vectors.
Their breakthrough improved neuron yields by about 1,100% in mouse cells and showed potential for human cells, albeit with lower efficiency (10-30%). This method also works faster—around five weeks—than iPSC-based conversions. It holds promise for producing neurons at scale for therapeutic purposes.
Galloway said, “If you express the transcription factors at really high levels in nonproliferative cells, the reprogramming rates would be low, but hyperproliferative cells are more receptive. It’s like they’ve been potentiated for conversion, and then they become much more receptive to the levels of the transcription factors.”
By refining transcription factors, researchers achieved 10–30% efficiency in converting human cells, a faster alternative to iPSCs, completed in around five weeks. This advancement could enable large-scale neuron production for therapeutic use.
After fine-tuning the gene combination, researchers focused on improving the delivery method. Among three tested viruses, a retrovirus was the most efficient for converting skin cells into motor neurons. They also found that reducing cell density in the culture dish boosted yields, achieving over 1,000% efficiency in just two weeks with mouse cells.
Collaborating with Boston University, they implanted these neurons into the striatum of mice brains—a region tied to motor control. In just two weeks, many neurons survived and successfully connected with the brain’s existing cells, showing great potential for therapeutic use.
Converted neurons demonstrated activity and communication, proving their functionality. Researchers aim to test them for spinal cord therapies while enhancing human cell conversion to generate more neurons for large-scale treatments.
Clinical trials using iPSC-derived neurons show promise for ALS treatment, but scaling neuron production with methods like Galloway’s could fast-track progress. Generating more neurons simplifies testing and development, making these therapies widely available to patients.
Journal References:
- Nathan B. Wang, Brittany A. Lende-Dorn, Adam M. Beitz, Patrick Han, Honour O. Adewumi, Timothy M. O’Shea, Kate E. Galloway. Proliferation history and transcription factor levels drive direct conversion to motor neurons. Cell Systems, 2025; 101205 DOI: 10.1016/j.cels.2025.101205
- Nathan B. Wang1 ∙ Honour O. Adewumi2 ∙ Brittany A. Lende-Dorn1 ∙ Adam M. Beitz1 ∙ Timothy M. O’Shea2 ∙ Kate E. Galloway. Compact transcription factor cassettes generate functional, engraftable motor neurons by direct conversion. Cell Systems. DOI: 10.1016/j.cels.2025.101206
Source: Tech Explorist
