Sleep and Circadian Rhythms in Parkinson’s Disease and Preclinical Models

Krishna D Sharma, Danielle Schaal, Rajshekhar A Kore, Rabab N Hamzah, Sahitya Chetan Pandanaboina, Abdallah Hayar, Robert J Griffin, Malathi Srivatsan, Nathan S Reyna, Jennifer Yanhua Xie

Sleep and Circadian Rhythms in Parkinson’s Disease and Preclinical Models

2020

PLoS One (Public Library of Science)

0
9007-58-3
Animals
Astrocytes metabolism physiology
Cell Differentiation physiology
Cell Proliferation
Cells, Cultured
Coculture Techniques
Elastin metabolism
Exosomes metabolism physiology
Gene Expression Regulation genetics
Glioma metabolism
Humans
Index Medicus
Interleukin-6 metabolism
Metallothionein 3
Nerve Tissue Proteins metabolism
Neural Stem Cells metabolism physiology
Neurons metabolism
Primary Cell Culture
Rats
STAT3 Transcription Factor metabolism

English

Exosomes appear to be effective inter-cellular communicators delivering several types of molecules, such as proteins and RNAs, suggesting that they could influence neural stem cell (NSC) differentiation. Our RNA sequencing studies demonstrated that the RNAs related to cell proliferation and astrocyte differentiation were upregulated in human mesenchymal stem cells (hMSC) when co-cultured with exosomes obtained from the culture medium of human glioma cells (U87). Metallothionein 3 and elastin genes, which are related to cell proliferation, increased 10 and 7.2 fold, respectively. Expression of genes for astrocyte differentiation, such as tumor growth factor alpha, induced protein 3 of the NOTCH1 family, colony stimulating factor and interleukin 6 of the STAT3 family and Hes family bHLH transcription factor 1 also increased by 2.3, 10, 4.7 and 2.9 fold, respectively. We further examined the effects of these exosomes on rat fetal neural stem cell (rNSC) differentiation using the secreted exosomes from U87 glioma cells or exosomes from U87 cells that were stimulated with interleukin 1β (IL-1β). The rNSCs, extracted from rat brains at embryonic day 14 (E14), underwent a culture protocol that normally leads to predominant (~90%) differentiation to ODCs. However, in the presence of the exosomes from untreated or IL-1β-treated U87 cells, significantly more cells differentiated into astrocytes, especially in the presence of exosomes obtained from the IL-1β-challenged glioma cells. Moreover, glioma-derived exosomes appeared to inhibit rNSC differentiation into ODCs or astrocytes as indicated by a significantly increased population of unlabeled cells. A portion of the resulting astrocytes co-expressed both CD133 and glial fibrillary acidic protein (GFAP) suggesting that exosomes from U87 cells could promote astrocytic differentiation of NSCs with features expected from a transformed cell. Our data clearly demonstrated that exosomes secreted by human glioma cells provide a strong driving force for rat neural stem cells to differentiate into astrocytes, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type.

Neurodegeneration, vol. 17, no. 1, Jan. 2022, pp. 1–21

Copyright © 2020 Sharma et al
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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