[Image courtesy of the MIT researchers]
As the researchers note in the abstract of their paper, the method by which transcription factors (TFs) drive cells to new identities has proven to be elusive historically, given the “sparse and stochastic nature of conversion.” But the MIT researchers were able to transcend this limitations through the development of a bespoke and efficient conversion system that “increases the direct conversion of fibroblasts to motor neurons 100-fold.” To demonstrate the functionality of these converted neurons, the team implanted them into the brains of mice in a region known as the striatum. That region is crucial for motor control. Within two weeks, the implanted neurons not only survived but also integrated with the existing brain tissue. They also showed electrical activity and communication with neighboring neurons.
The development hinges on the researchers’ discovery that by first pushing skin cells into a hyperproliferative state before introducing the transcription factors, they dramatically increased receptivity to conversion. This two-stage approach—proliferation followed by identity transformation—proved crucial to achieving the high yield. The team identified the minimal combination of three transcription factors (NGN2, ISL1, and LHX3) necessary for successful neuronal conversion, as they allow for more efficient delivery through a single viral vector.
“What makes this approach so powerful is that we’re not just improving efficiency incrementally—we’re fundamentally changing the cellular landscape before conversion,” explains Katie Galloway, the study’s senior author, in a press release. “By creating this hyperproliferative cellular state first, we’re essentially preparing the cells to be more receptive to the transcription factors that drive neuronal identity. This is why we can generate more than ten neurons from a single skin cell, which would be impossible with conventional methods.”
While the research is still in an experimental phase, the advance holds potential for several clinical conditions. First, te ability to generate large quantities of motor neurons could lead to cell replacement therapies for patients with spinal cord injuries, and could potentially restore mobility. It could also lead to new therapeutic options for ALS. The researchers mention ALS as a target condition that could benefit from their neuron generation technique. While clinical trials using neurons derived from iPSCs to treat ALS are already underway, this more efficient method could make it easier to test and develop treatments for more widespread use in humans. The MIT press release notes that when implanted in the striatum of mice, the converted neurons survived and formed connections with other brain cells, showing promising functional integration, which could have ramifications for a range of neurological conditions. Finally, the dramatic improvement in conversion efficiency (over 1000% yield) addresses one of the major hurdles in cell therapy—generating sufficient quantities of neurons for clinical treatment.
Filed Under: Cell & gene therapy
