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Science Brief: Investigators Develop Technique to bypass iPSCs

Researchers have developed a technique to convert mouse and human fibroblasts directly into dopaminergic neurons without having to first generate induced pluripotent stem cells (iPSCs).

They claim a set of 3 transcription factors is sufficient to transform prenatal and adult fibroblasts from healthy donors and Parkinson disease patients into functional dopaminergic neurons that release dopamine and show spontaneous electrical activity mirroring that of brain dopaminergic neurons.

  • Vania Broccoli, Ph.D., and colleagues at the San Raffaele Scientific Institute, describe their approach in Nature. The paper,  “Direct generation of functional dopaminergic neurons from mouse and human fibroblasts” demonstrated that fibroblasts can be directly converted into neuronal cells (iNs) by the forced expression of three neurodevelopmental factors, Mash1, Brn2 (also known as Pou3f2), and Myt1l.  However, it’s not yet clear whether specific neuronal subtypes can be preferentially induced by direct reprogramming of these heterologous cells.

The Bottom Line: Generation of functional dopaminergic neuronal cells by direct reprogramming opens new possibilities for regenerative therapies for Parkinson’s disease and related disorders. Their process does not pass through proliferative progenitors that also might be tumorigenic. Thus, these procedures might avoid a dangerous drawback of stem cell therapies while providing a sufficient number of functional dopaminergic neurons amenable for autologous cell replacement therapies. Dr. Broccoli’s team does note that other studies published within the last few months described the use of a different gene cocktail to induce the formation of dopaminergic-like neurons directly from human fibroblasts. This opens the intriguing possibility that different molecular fate determinants reach a similar endpoint even though they rely on different transcriptional cascades.