Skin cells can now be directly converted into neurons

Skin cells can be transformed into other types of cells, but the process is complex.

Traditionally, scientists have used induced pluripotent stem cells (iPSCs) as an intermediate step to reprogram skin cells into neurons, which are nerve cells. However, this method is time-consuming and inefficient, requiring several weeks for full transformation.

In recent research, however, scientists have developed a new technique that bypasses the stem cell stage, and succeeds in converting skin cells directly into neurons.

Transforming skin cells into neurons

Scientists at MIT have devised a streamlined process that significantly increases the efficiency of this delicate process. Using mouse cells, the team achieved a conversion rate where a single skin cell can generate more than ten neurons.

If successfully replicated in human cells, this technique could be a game-changer for treating spinal cord injuries and motor neuron diseases.

Study co-author Katie Galloway is the W. M. Keck Career Development Professor in Biomedical Engineering and Chemical Engineering at MIT.

“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,” said Professor Galloway. “That’s where these types of reprogramming technologies can take us,” she stated.

Direct conversion of skin cells

Nearly two decades ago, scientists discovered that delivering four transcription factors to skin cells could turn them into iPSCs, which were then capable of differentiating into other cell types. While effective, this process takes several weeks and is often inefficient.

“Oftentimes, one of the challenges in reprogramming is that cells can get stuck in intermediate states. 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,” explained Professor Galloway.

Previous attempts at direct conversion had low efficiencies, with yields of less than one percent. Earlier work required six transcription factors and two additional proteins, delivered separately using multiple viral vectors. This made it complex, and difficult to control gene expression levels.

The team optimized the process by identifying a minimal combination of three transcription factors – NGN2, ISL1, and LHX3 – that efficiently convert skin cells into neurons.

Promoting rapid cell division

The experts also included two genes that promote rapid cell division, thus dramatically increasing the yield. By using a single modified virus to deliver all three factors, they ensured precise gene expression in each cell.

Furthermore, the researchers introduced p53DD and a mutated HRAS gene to stimulate cell division before the conversion process began. This enhancement led to a yield increase of over 1,000 percent.

“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,” noted Professor Galloway.

Testing with human skin cells

The team also adapted the process for human cells. While efficiency rates ranged between 10 and 30 percent, the direct conversion method took about five weeks, which was still slightly faster than traditional iPSC-based approaches.

Once the researchers refined their conversion process, they focused on the best methods for gene delivery. They tested three different viruses and found that a retrovirus provided the highest conversion efficiency. Adjusting cell density during growth also improved neuron yield.

In mouse cells, the optimized method produced over 1,000 percent more neurons in just two weeks.

Implanting the neurons

Collaborating with Boston University, the team then examined whether these lab-grown neurons could integrate into living tissue. They implanted the cells into the striatum, a brain region involved in motor control. Two weeks later, many of the neurons had survived and begun forming connections with existing brain cells.

When grown in a dish, these neurons exhibited electrical activity and calcium signaling, indicating their ability to communicate with other neurons.

The next step involves exploring the potential for implanting these neurons into the spinal cord, which could open the door to new treatments for neurodegenerative diseases and injuries affecting motor control.

Treating neurological diseases

The team aims to refine their method for human cells to increase efficiency even further. If successful, this approach could enable large-scale production of neurons, which would offer new possibilities for treating conditions like ALS and spinal cord injuries.

Currently, clinical trials using iPSC-derived neurons to treat ALS are underway. However, increasing the number of available cells through direct conversion could accelerate research and make therapies more widely accessible.

As scientists continue to advance this technology, the hope is that direct cell conversion will become a key tool in regenerative medicine, potentially transforming how neurological diseases and injuries are treated.

The full study was published in the journal Cell Systems.

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