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Can Small Molecule-Reprogramming of Fibroblasts Create Better Drugs or Be Used to Treat Human Neuronal Disorders?

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A recent move in compound screening dictates the use more biologically relevant cells for drug discovery experiments, but as researchers know, it can be a challenge to obtain enough primary cells. Stem cells have been used to generate biologically relevant cells, but the process is time consuming and expensive.

In a new proof of principle study titled “Direct Conversion of Normal and Alzheimer’s Disease Human Fibroblasts into Neuronal Cells by Small Molecules,” and published in Cell Stem Cell, researchers in China directly converted one mature cell type into another by culturing with a cocktail of small molecules. No genetic manipulation was required. Specifically, they used human fibroblasts from control and Alzheimer’s disease patients and developed functional neuronal cells, bypassing the neural progenitor stage. The chemical cocktail erased fibroblast-specific gene expression of the initial cells, specifically upregulating neuronal gene expression and facilitating the neuronal conversion of human aortic fibroblasts.

The authors’ detailed analysis of the chemically-induced neurons included extensive assessment of ion channel function. They found that chemically-induced human neuronal cells had complex neuron morphology and possessed the electrophysiological properties of neurons, including the ability to fire action potentials (APs), the induction of membrane current and the presence of functional glutamate and GABA receptors. The ability to chemically induce neurons from human primary fibroblasts may represent a simple, rapid source of neurons for use in disease modeling and drug development.

Interestingly, the authors demonstrate the ability to use fibroblasts from Alzheimer patients to create neurons which in fact showed features of the disease including elevated Ab42 levels and higher total and phosphorylated Tau levels. This suggests that chemical induction of neurons from patient fibroblasts could open the door for personalized medicine. The authors also suggest a potential new therapeutic avenue in which small molecules could be given to patients with neurological diseases or injury to reprogram cells.  Moreover, this method of patient-specific neuronal cell production may have a significant impact on the emerging field cell replacement therapy of neurological disorders.