A team of US researchers have managed to convert skin cells directly into neurons that could be used for cell therapy that could be used to treat patients with spinal cord injuries or diseases that affect mobility, such as Amyotrophic lateral sclerosis (ELA).
Research, which is published in ‘Cell Systems‘, has managed to optimize the process of converting skin cells into neurons. Until now, the conversion of a cell type into another – for example, from a skin cell to a neuron – was achieved by means of a process that requires the skin cell to become a pluripotent stem cell and then differentiate in a neuron. But researchers from Massachusetts Technological Institute (MIT) have simplified this process omitting the intermediate stage, that of stem cell, turning the skin cell directly into a neuron.
Working with mouse cells, the team developed an efficient conversion method that can produce more than 10 neurons from a single skin cell. If it is replicated in human cells, this approach could allow the generation of large amounts of motor neurons.
“We hope these cells can be viable candidates for cell replacement therapies,” says Katie Galloway, author of the study.
As a first step towards the development of these cells as therapy, researchers have shown that they could generate motor neurons and graft them in mice brains, where they were integrated with the host tissue.
Almost 20 years ago, Japanese scientists showed that, by administering four transcription factors to skin cells, they could induce their transformation into induced pluripotent stem cells (IPSC). Like embryonic stem cells, IPSC can differentiate in many other cell types. This technique works well, but it takes several weeks, and many cells do not achieve full transition to mature cell types.
The direct conversion had already been obtained, but with very poor results: less than 1%. In previous works, Galloway used a combination of six transcription factors and two additional proteins that stimulate cell proliferation. Each of these eight genes was administered by an independent viral vector, which made it difficult to guarantee its correct expression in each cell.
The researchers, led by Galloway, developed a method to convert skin cells into motor neurons using only three transcription factors (NNG2, ISL1 and LHX3) and two additional genes that induce cell proliferation. Using mouse cells, they optimized the delivery of these genes by means of a modified virus, achieving a 1100 % larger neuronal production. They also adapted the process to human cells, although with less efficiency (10-30 %).
In mice
In a second study, they identified a retrovirus as the most efficient method to administer genes, improving conversion into mouse cells in just two weeks with a performance greater than 1000 %. Finally, they successfully tested the implementation of these neurons in mice, where they survived, formed connections and showed electrical activity, which opens the possibility of future transplants in the spinal cord.
The MIT team also hopes to increase the efficiency of this process for human cell conversion, which could allow the generation of large amounts of neurons that could be used to treat spinal cord injuries or diseases that affect motor control, such as ELA.
Currently, clinical trials with induced pluripotent stem cells (IPSC) are being performed to treat the ELA, but expand the number of cells available for these treatments could facilitate their test and development for more widespread use in humans.
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