Researchers at MIT have now devised a simplified process that bypasses the stem cell stage, converting a skin cell directly into a neuron.
A new technique developed at the Massachusetts Institute of Technology helps convert skin cells into neurons without needing to transform them first into stem cell s. As demonstrated in mouse cells, this method makes it easier and more efficient to produce large-scale quantities of neurons.
If introduced into humans, it could be revolutionary in treating diseases associated with spinal cord injuries and neurodegenerative changes.“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 Katie Galloway, one of the study authors.From skin to neurons: Skipping the stem cell stageTraditional methods of converting one type of cell into another require an intermediate step: reprogramming the cell into an induced pluripotent stem cell before differentiating it into the desired type.“Oftentimes, one of the challenges in reprogramming is that cells can get stuck in intermediate states,” Galloway says. “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 team from MIT pioneered a method that eliminates the stem cell phase with direct conversion. By using just three transcription factors, along with two other genes that assist in proliferation, they were able to turn mouse skin cells into motor neurons. This resulted in over ten neurons being generated from a single skin cell, which is a 1,100% increase based on other techniques.“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. It’s like they’ve been potentiated for conversion, and then they become much more receptive to the levels of the transcription factors,” Galloway says.Efficient gene delivery for maximum neuron productionA major hurdle in achieving direct cell conversion is ensuring that all the required genes are delivered at the necessary thresholds. In prior research, each gene needed a different viral vector, which made expression difficult to control. Now, researchers worked around the problem by combining all three transcription factors into one modified virus, which resulted in proper expression levels and transformed the entire process.To enhance efficacy even more, a different virus was used to put in two other genes, which facilitate faster cell division. Those cells that went through this hyper-proliferation phase became considerably easier to convert and, as a result, greatly increased the neuron yield.After trying a variety of viral delivery systems, the team found retroviruses to be the most effective. Also, reducing cell density in the culture already improved conversion rates even more enabling the rapid production of large numbers of neurons in merely two weeks.Although clinical trials are already underway using iPSC-derived neurons for ALS treatment, generating sufficient quantities of high-quality neurons remains a challenge. This new direct conversion method could provide a more efficient alternative, potentially accelerating the development of neuron-based therapies.The study has been published in Cell Systems.
Neurological Disorders Neuron Skin Cells Somatic Cells Stem Cell
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