Chemical-Only Cell Reprogramming Cocktails Direct Converts Skin Cells into Neurons

Two Chinese laboratories have independently transformed skin cells into neurons using only a cocktail of chemicals. One laboratory used skins cells from Alzheimer’s patients and the other used healthy laboratory mice, and therefore, the protocols developed by each laboratory differ. However, the success of these protocols suggests that it might be economically possible to use neurons made a patient’s own cells to test drug regiments for clinical purposes.

These two studies reinforce the idea that a purely chemical approach represents a promising way to scale up cell reprogramming research that might avoid the technical challenges and safety concerns associated with the more popular method of using transcription factors.

One of the challenges of reprogramming cells to change their identity is that you may end up with cells that look normal on the outside, but inside, many of their internal workings are quite different from the cell type you want to make. In these two papers, neurons made from chemically reprogrammed cells showed neuron-specific gene expression, action potentials, and synapse formation, which is strong evidence that these protocols produce fully operational neurons.

In both cases, the protocols employed decreased the expression of skin-specific genes and increased the expression of neuron-specific genes. These chemicals promoted neuronal cell fates by coordinating multiple signaling pathways that worked together to commit the cells to a neuronal fate. This direct reprogramming procedure bypasses the so-called “proliferative intermediate stage” that put cells under stress and increases the mutation rates. Therefore direct conversion protocols are inherently safer than other reprogramming protocols.

The paper from the laboratory of Jian Zhao (Cell Stem Cell 2015;17(2):204) designed a purely chemical protocol to convert skin cells from human Alzheimer’s disease patients into neurons. Direct reprogramming protocols are available for converting human skin cells into neurons, but these protocols require that cells be transfected with genes that encode transcription factors. Such manipulation requires that cells be treated with viruses or subjected to potentially stressful transfection conditions. This purely chemical protocol is a potentially welcome alternative that would be both safer and easier. The chemicals used in these procedures are easy to synthesize, stable, and standardization of the procedures would also be much easier.

The paper that uses a purely chemical protocol to directly reprogram mouse skin cells comes from the laboratory of Hongkui Deng (Cell Stem Cell 2015;17(2):195) is the culmination of four years of work. The main hurdle was suppressing skin-specific gene expression. Then Dong identified a compound called I-BET151 that suppressed skin cell-specific gene expression. This allowed Deng and his colleagues to successfully reprogram mouse cells with a purely chemical protocol.

The next step for both of these laboratories is to show that, in principle, these chemically reprogrammed cells can be used for therapeutic purposes. Such a proof-of-principle experiment will put direct reprogramming on the map for regenerative medicine in a powerful way.