Rescue of Brain Function Using Tunneling Nanotubes Between Neural Stem Cells and Brain Microvascular Endothelial Cells

Wang, Xiaoqing; Yu, Xiaowen; Xie, Chong; Tan, Zijian; Tian, Qi; Zhu, Desheng; Liu, Mingyuan; Guan, Yangtai

doi:10.1007/s12035-015-9225-z

Cited by 28 publications

(23 citation statements)

References 31 publications

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“…mNTs are long and thin cytoplasmic projections involved in direct contact-dependent intercellular communication between eukaryotic cells. mNTs were shown to support cell-to-cell transfer of small molecules, proteins, prions, viral particles, vesicles and organelles in a variety of cell types (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Here we demonstrate that mNTs can also transfer mRNA molecules and identify mRNAs encoding a wide variety of proteins that undergo intercellular transfer in in vitro culture conditions.…”

Section: Introductionmentioning

confidence: 63%

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Intercellular mRNA trafficking via membrane nanotubes in mammalian cells

Haimovich

Ecker

Dunagin

et al. 2017

Preprint

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RNAs have been shown to undergo transfer between mammalian cells, though the mechanism behind this phenomenon and its overall importance to cell physiology is not well understood. Numerous publications have suggested that RNAs (microRNAs and incomplete mRNAs) undergo transfer via extracellular vesicles (e.g. exosomes). However, in contrast to a diffusion-based transfer mechanism, we find that fulllength mRNAs undergo direct cell-cell transfer via cytoplasmic extensions, called membrane nanotubes (mNTs), which connect donor and acceptor cells. By employing a simple co-culture experimental model and using single-molecule imaging, we provide quantitative data showing that mRNAs are transferred between cells in contact. Examples of mRNAs that undergo transfer include those encoding GFP, mouse β-actin, and human Cyclin D1, BRCA1, MT2A, and HER2. We show that intercellular mRNA transfer occurs in all co-culture models tested (e.g. between primary cells, immortalized cells, and in co-cultures of immortalized human and murine cells). Rapid mRNA transfer is dependent upon actin, but independent of de novo protein synthesis, and is modulated by stress conditions and gene expression levels. Hence, this work supports the hypothesis that full-length mRNAs undergo transfer between cells through a refined structural connection. Importantly, unlike the transfer of miRNA or RNA fragments, this process of communication transfers genetic information that could potentially alter the acceptor cell proteome. This phenomenon may prove important for the proper development and functioning of tissues, as well as host-parasite or symbiotic interactions. SignificanceMessenger RNA (mRNA) molecules convey genetic information within cells, beginning from genes in the nucleus to ribosomes in the cell body, where they are translated into proteins. Here, we show a novel mode of transferring genetic information from one cell to another. Contrary to previous publications suggesting that mRNAs transfer via extracellular vesicles, we provide visual and quantitative data showing that mRNAs transfer via membrane nanotubes and direct cell-to-cell contact. We predict that this process has a major role in regulating local cellular environments with respect to tissue development and maintenance, cellular responses to stress, interactions with parasites, tissue transplants, and the tumor microenvironment.

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Section: Introductionmentioning

confidence: 63%

“…diffusion or gap junctions), we suspected that mRNA transfer might occur via membrane nanotubes (mNTs). mNTs are long (up to ~200µm), thin (0.05-0.5µm), cellular protrusions that can transfer many types of components from one cell to another (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Section: Mrna Transfer Occurs Via Membrane Nanotubesmentioning

confidence: 99%

Intercellular mRNA trafficking via membrane nanotubes in mammalian cells

Haimovich

Ecker

Dunagin

et al. 2017

Preprint

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“…Nissl assays were performed following a previously described protocol (16). Briefly, samples were rehydrated using decreasing ethanol concentrations and endogenous peroxidase activity was quenched with 2% H 2 O 2 .…”

Section: Methodsmentioning

confidence: 99%

Protective effects of primary neural stem cell treatment in ischemic stroke models

Wang

Zeng

et al. 2018

Exp Ther Med

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Strokes are a major cause of neurological disability. Stem cell replacement therapy is a potential novel strategy of treating patients that have experienced strokes. The present study examined the protective role of neural stem cell (NSC) administration in oxygen-glucose deprivation (OGD) injury and ischemic stroke animal models. Primary cultured embryonic NSCs and brain microvascular endothelial cells were indirectly co-cultured for in vitro testing. A rat model of embolic middle cerebral artery occlusion (MCAO) was used to assess the morphological and functional changes that occur following treatment with NSCs. The role of the phosphoinositide 3-kinase/protein kinase b/glycogen synthase kinase 3β (PI3K/Akt/GSK-3β) signaling pathway in the neuroprotective effects of NSC treatment was also determined. It was demonstrated in vivo and in vitro that NSC administration may attenuate the brain injury caused by stroke. Furthermore, the results suggest that activation of PI3k/Akt/GSK-3β signaling pathway serves a role in attenuating OGD injury. Inflammation, synaptic remodeling and autophagy may be improved following NSC treatment and behavioral testing suggests that treatment with NSCs improves functional recovery in rats following MCAO.

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“…Similarly, the regulation of TNTs between neural stem cells and brain microvascular endothelial cells could rescue brain function (Wang et al, 2016). TNTs facilitate peripheral nerve regeneration through the regulation of neural cell communications (Zhu et al, 2016), the same do EVs (Ching and Kingham, 2015; Lopez-Leal and Court, 2016).…”

Section: Tnts and Evs: Implications In Regenerative/repair Processesmentioning

confidence: 99%

Extracellular Vesicles, Tunneling Nanotubes, and Cellular Interplay: Synergies and Missing Links

Nawaz

Fatima

2017

Front. Mol. Biosci.

104

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The process of intercellular communication seems to have been a highly conserved evolutionary process. Higher eukaryotes use several means of intercellular communication to address both the changing physiological demands of the body and to fight against diseases. In recent years, there has been an increasing interest in understanding how cell-derived nanovesicles, known as extracellular vesicles (EVs), can function as normal paracrine mediators of intercellular communication, but can also elicit disease progression and may be used for innovative therapies. Over the last decade, a large body of evidence has accumulated to show that cells use cytoplasmic extensions comprising open-ended channels called tunneling nanotubes (TNTs) to connect cells at a long distance and facilitate the exchange of cytoplasmic material. TNTs are a different means of communication to classical gap junctions or cell fusions; since they are characterized by long distance bridging that transfers cytoplasmic organelles and intracellular vesicles between cells and represent the process of heteroplasmy. The role of EVs in cell communication is relatively well-understood, but how TNTs fit into this process is just emerging. The aim of this review is to describe the relationship between TNTs and EVs, and to discuss the synergies between these two crucial processes in the context of normal cellular cross-talk, physiological roles, modulation of immune responses, development of diseases, and their combinatory effects in tissue repair. At the present time this review appears to be the first summary of the implications of the overlapping roles of TNTs and EVs. We believe that a better appreciation of these parallel processes will improve our understanding on how these nanoscale conduits can be utilized as novel tools for targeted therapies.

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Rescue of Brain Function Using Tunneling Nanotubes Between Neural Stem Cells and Brain Microvascular Endothelial Cells

Cited by 28 publications

References 31 publications

Intercellular mRNA trafficking via membrane nanotubes in mammalian cells

Intercellular mRNA trafficking via membrane nanotubes in mammalian cells

Protective effects of primary neural stem cell treatment in ischemic stroke models

Extracellular Vesicles, Tunneling Nanotubes, and Cellular Interplay: Synergies and Missing Links

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