Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons.
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.
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Lei
L
Zhang
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Jiu-Chao
JC
Yin
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Hana
H
Yeh
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Ning-Xin
NX
Ma
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Grace
G
Lee
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Xiangyun Amy
XA
Chen
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Yanming
Y
Wang
Department of Human Genetics, Emory University School of Medicine, Whitehead Research Building, Room 323, 615 Michael Street, Atlanta, GA 30322, USA.
Li
L
Lin
Department of Human Genetics, Emory University School of Medicine, Whitehead Research Building, Room 323, 615 Michael Street, Atlanta, GA 30322, USA.
Li
L
Chen
Department of Human Genetics, Emory University School of Medicine, Whitehead Research Building, Room 323, 615 Michael Street, Atlanta, GA 30322, USA.
Peng
P
Jin
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.
Gang-Yi
GY
Wu
Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA. Electronic address: gongchen@psu.edu.
Gong
G
Chen
D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology*; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; C093970:NEUROD1 protein, human; C491183:NEUROG2 protein, human; C501008:Neurod1 protein, mouse; C102938:Neurog2 protein, mouse