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Cell Stem Cell. 2015 Dec 3;17(6):735-747. doi: 10.1016/j.stem.2015.09.012. Epub 2015 Oct 17.

Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons.

Author information

1
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
2
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
3
Department of Human Genetics, Emory University School of Medicine, Whitehead Research Building, Room 323, 615 Michael Street, Atlanta, GA 30322, USA.
4
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA; School of Life Science, South China Normal University, Guangzhou 510631, China. Electronic address: gangyiwu1@gmail.com.
5
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA. Electronic address: gongchen@psu.edu.

Abstract

We have recently demonstrated that reactive glial cells can be directly reprogrammed into functional neurons by a single neural transcription factor, NeuroD1. Here we report that a combination of small molecules can also reprogram human astrocytes in culture into fully functional neurons. We demonstrate that sequential exposure of human astrocytes to a cocktail of nine small molecules that inhibit glial but activate neuronal signaling pathways can successfully reprogram astrocytes into neurons in 8-10 days. This chemical reprogramming is mediated through epigenetic regulation and involves transcriptional activation of NEUROD1 and NEUROGENIN2. The human astrocyte-converted neurons can survive for >5 months in culture and form functional synaptic networks with synchronous burst activities. The chemically reprogrammed human neurons can also survive for >1 month in the mouse brain in vivo and integrate into local circuits. Our study opens a new avenue using chemical compounds to reprogram reactive glial cells into functional neurons.

PMID:
26481520
PMCID:
PMC4675726
DOI:
10.1016/j.stem.2015.09.012
[Indexed for MEDLINE]
Free PMC Article

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