MicroRNA-based conversion of human fibroblasts into striatal medium spiny neurons

Developers

Michelle Richner, Matheus B. Victor, Daniel Abernathy, Andrew Yoo, etc.

Description of the technology

The ability to generate human neurons of specific subtypes of clinical importance offers experimental platforms that may be instrumental for disease modeling.

In order to support this technology its authors carried out a study demonstrating the use of neuronal microRNAs (miRNAs) and transcription factors to directly convert human fibroblasts to a highly enriched population of striatal medium spiny neurons (MSNs), a neuronal subpopulation that has a crucial role in motor control and harbors selective susceptibility to cell death in Huntington’s disease. On the basis of this study, the developers created a stepwise protocol for the generation of striatal medium spiny neurons by direct neuronal conversion of human fibroblasts in 30 d. The protocol provides descriptions of cellular behaviors during reprogramming and crucial steps involved in gene delivery, cell adhesion and culturing conditions that promote cell survival. The protocol offers a unique approach to combine microRNAs and transcription factors to guide the neuronal conversion of human fibroblasts toward a specific neuronal subtype.

The technology is the first to show that, when transplanted into the murine striatum, the reprogrammed striatal medium spiny neurons functionally integrated into the host circuit and showed electrophysiological properties similar to those of native striatal medium spiny neurons

Practical application

The technology will be beneficial to researchers interested in studying molecular mechanisms governing the cell fate specification of striatal medium spiny neurons. In particular, the microRNA-based approach may be a useful tool for studying the synergism between microRNA and neural transcription factors during neuronal reprogramming, specific for striatal medium spiny neurons. Because of the high efficiency in generating human striatal medium spiny neurons, microRNA-based reprogramming approach may also be highly attractive to investigators interested in developing tissue culture models of neurodegenerative disorders including Huntington’s disease, although the feasibility of modeling Huntington’s disease using directly reprogrammed cells remains to be further evaluated.

Laboratories

• Department of Developmental Biology, Washington University School of Medicine, St. Louis (USA)
• Program in Neuroscience, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis (USA)
• Program in Developmental, Regenerative and Stem Cell Biology, Division of Biology and Biomedical Sciences, Washington University, St. Louis (USA)

Links

Publications

• Richner, M. et al. «MicroRNA-based conversion of human fibroblasts into striatal medium spiny neurons." 10 Nature Protocols (2015): 1543–1555.
• Yoo, A.S. et al. «MicroRNA-mediated conversion of human fibroblasts to neurons." 476 Nature (2011): 228–231.
• Yoo, A.S. et al. «MicroRNA-mediated switching of chromatin-remodelling complexes in neural development." 460 Nature (2009): 642–646.