Exosomes regulate neurogenesis and circuit assembly

Exosomes are thought to be released by all cells in the body and to be involved in intercellular communication. We tested whether neural exosomes can regulate the development of neural circuits. We show that exosome treatment increases proliferation in developing neural cultures and in vivo in denta...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 32; pp. 16086 - 16094
Main Authors:	Sharma, Pranav, Mesci, Pinar, Carromeu, Cassiano, McClatchy, Daniel R., Schiapparelli, Lucio, Yates, John R., Muotri, Alysson R., Cline, Hollis T.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 06-08-2019
Series:	PNAS Plus
Subjects:	Action Potentials Animals Biological activity Biological Sciences Brain Cell Count Cell Differentiation Cell interactions Cell Proliferation Cell signaling Cells, Cultured Circuits Dentate gyrus Dentate Gyrus - cytology Exosomes Exosomes - metabolism Humans Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism MeCP2 protein Methyl-CpG binding protein Methyl-CpG-Binding Protein 2 - deficiency Methyl-CpG-Binding Protein 2 - metabolism Mice Nerve Net - metabolism Neural networks Neurodevelopmental disorders Neurogenesis Neurons - cytology Neurons - metabolism PNAS Plus Rett syndrome Signal Transduction Signaling Spheroids, Cellular - cytology Synapses - metabolism Synaptogenesis neuronal development extracellular vesicle synaptogenesis exosomes Rett syndrome
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Summary:	Exosomes are thought to be released by all cells in the body and to be involved in intercellular communication. We tested whether neural exosomes can regulate the development of neural circuits. We show that exosome treatment increases proliferation in developing neural cultures and in vivo in dentate gyrus of P4 mouse brain. We compared the protein cargo and signaling bioactivity of exosomes released by hiPSC-derived neural cultures lacking MECP2, a model of the neurodevelopmental disorder Rett syndrome, with exosomes released by isogenic rescue control neural cultures. Quantitative proteomic analysis indicates that control exosomes contain multiple functional signaling networks known to be important for neuronal circuit development. Treating MECP2-knockdown human primary neural cultures with control exosomes rescues deficits in neuronal proliferation, differentiation, synaptogenesis, and synchronized firing, whereas exosomes from MECP2-deficient hiPSC neural cultures lack this capability. These data indicate that exosomes carry signaling information required to regulate neural circuit development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 2A.R.M. and H.T.C. contributed equally to this work. Edited by Richard L. Huganir, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved June 19, 2019 (received for review February 16, 2019) 1P.S. and P.M. contributed equally to this work. Author contributions: P.S. and H.T.C. designed research; P.S., P.M., C.C., D.R.M., and L.S. performed research; P.S., J.R.Y., and A.R.M. contributed new reagents/analytic tools; P.S. and L.S. analyzed data; and P.S. and H.T.C. wrote the paper.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1902513116