Neonatal Subventricular Zone Neural Stem Cells Release Extracellular Vesicles that Act as a Microglial Morphogen

Morton, Mary C.; Neckles, Victoria N.; Seluzicki, Caitlin M.; Feliciano, David M.

doi:10.2139/ssrn.3155657

Cited by 11 publications

(17 citation statements)

References 65 publications

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“…However, it has not been clarified whether NPC‐derived EVs or exosomes influence microglia in CNS disorders. In the present study, we found that grafted exosomes recruited microglia to the site of injection and activated microglia, which presented as a rounded shape that was consistent with that reported by Morton et al [35]. Interestingly, Morton et al observed rounded microglia up to day 7, while we found that the rounded microglia returned to ramified shape at day 7 post‐injection of mNPC‐exos (48 hours incubation of exosomes in vitro ), and the density of microglia in the ONL and SRS decreased in our model.…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have reported that NPC‐EVs were taken up by microglia and regulated microglial morphology and function during brain development [35]. It has also been reported that microglial activation and associated inflammatory responses impact the progression of RD [54,55].…”

Section: Discussionmentioning

confidence: 99%

“…And Agilent Bioanalyzer small RNA assay kit (Novogene) was used to quantify the samples. And libraries were prepared according to manufacturer's protocol (Illumina small RNA preparation kit), as previously described [35]. Three experimental replicates per group were performed.…”

Section: Methodsmentioning

confidence: 99%

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Exosomes derived from neural progenitor cells preserve photoreceptors during retinal degeneration by inactivating microglia

Bian

Zhao

et al. 2020

J of Extracellular Vesicle

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Retinal degeneration (RD) is one of the most common causes of visual impairment and blindness and is characterized by progressive degeneration of photoreceptors. Transplantation of neural stem/progenitor cells (NPCs) is a promising treatment for RD, although the mechanisms underlying the efficacy remain unclear. Accumulated evidence supports the notion that paracrine effects of transplanted stem cells is likely the major approach to rescuing early degeneration, rather than cell replacement. NPC-derived exosomes (NPC-exos), a type of extracellular vesicles (EVs) released from NPCs, are thought to carry functional molecules to recipient cells and play therapeutic roles. In present study, we found that grafted human NPCs (hNPCs) secreted EVs and exosomes in the subretinal space (SRS) of RCS rats, an RD model. And direct administration of mouse neural progenitor cell-derived exosomes (mNPC-exos) delayed photoreceptor degeneration, preserved visual function, prevented thinning of the outer nuclear layer (ONL), and decreased apoptosis of photoreceptors in RCS rats. Mechanistically, mNPC-exos were specifically internalized by retinal microglia and suppressed their activation in vitro and in vivo. RNA sequencing and miRNA profiling revealed a set of 17 miRNAs contained in mNPC-exos that markedly inhibited inflammatory signal pathways by targeting TNF-α, IL-1β, and COX-2 in activated microglia. The exosomes derived from hNPC (hNPC-exos) contained similar miRNAs to mNPC-exos that inhibited microglial activation. We demonstrated that NPC-exos markedly suppressed microglial activation to protect photoreceptors from apoptosis, suggesting that NPC-exos and their contents may be the mechanism of stem cell therapy for treating RD.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Exosomes derived from neural progenitor cells preserve photoreceptors during retinal degeneration by inactivating microglia

Bian

Zhao

et al. 2020

J of Extracellular Vesicle

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“…Despite this, the biological response of MC to CPP transfer of fibroblast cytoplasm in our separate work (1,18,34), seems more similar to the published response of cells to uptake of exosomes, than to TNT mediated transfer. For example, exosome uptake alters cell morphology (14,15,42), but we find no literature of TNT mediating this effect. Similarly, while exosomes from a variety of sources can increase migration of several cell types (16,(43)(44)(45)(46), there is less evidence for a similar effect for cellular contents transferred via TNT (17).…”

Section: Discussionmentioning

confidence: 68%

Potential hydrodynamic cytoplasmic transfer between mammalian cells: Cell-projection pumping

Zoellner

Paknejad

Cornwell

et al. 2019

Preprint

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We earlier reported cytoplasmic fluorescence exchange between cultured human fibroblasts (Fib) and malignant cells (MC). Others report similar transfer via either tunneling nanotubes (TNT) or shed membrane vesicles and this changes the phenotype of recipient cells. Our current time-lapse microscopy showed most exchange was from Fib into MC, with less in the reverse direction. Although TNT were seen, we were surprised transfer was not via TNT, but was instead via fine and often branching cell projections that defied direct visual resolution because of their size and rapid movement. Their structure was revealed nonetheless, by their organellar cargo and the grooves they formed indenting MC. Discrete, rapid and highly localized transfer events, evidenced against a role for shed vesicles. Transfer coincided with rapid retraction of the cell-projections, suggesting a hydrodynamic mechanism. Increased hydrodynamic pressure in retracting cell-projections normally returns cytoplasm to the cell body. We hypothesize 'cellprojection pumping' (CPP), where cytoplasm in retracting cell-projections partially equilibrates into adjacent recipient cells via micro-fusions that form temporary inter-cellular cytoplasmic continuities. We tested plausibility for CPP by combined mathematical modelling, comparison of predictions from the model with experimental results, and then computer simulations based on experimental data. The mathematical model predicted preferential CPP into cells with lower cell stiffness, expected from equilibration of pressure towards least resistance. Predictions from the model were satisfied when Fib were cocultured with MC, and fluorescence exchange related with cell stiffness by atomic force microscopy. When transfer into 5000 simulated recipient MC or Fib was studied in computer simulations, inputting experimental cell stiffness and donor cell fluorescence values generated transfers to simulated recipient cells similar to those seen by experiment. We believe CPP is a novel mechanism in mammalian inter-cellular cytoplasmic transfer and communication.

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“…As major immune-competent cells in the brain, microglia exert multiple functions under various physiological and pathological conditions (Wolf, Boddeke, & Kettenmann, 2017). Notably, recent studies have demonstrated that microglia regulate proliferation and differentiation of NSCs and OPCs either positively or negatively depending on conditions, thereby affecting the cellular dynamics of the postnatal brain in both the VZ-SVZ and DG (Kreisel, Wolf, Keshet, & Licht, 2018;Morton, Neckles, Seluzicki, Holmberg, & Feliciano, 2018;Naruse, Shibasaki, Shimauchi-Ohtaki, & Ishizaki, 2018;Vay et al, 2018;Walton et al, 2006). Yet, what impact microglia have on normal brain development remains to be further investigated.…”

Section: Box 1 Impacts Of Non-neuronal/glial Cell Types On Postnatal mentioning

confidence: 99%

Developmental dynamics of neurogenesis and gliogenesis in the postnatal mammalian brain in health and disease: Historical and future perspectives

Nakafuku

Águila

2019

WIREs Developmental Biology

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The mature mammalian brain has long been thought to be a structurally rigid, static organ since the era of Ramón y Cajal in the early 20th century. Evidence accumulated over the past three decades, however, has completely overturned this long‐held view. We now know that new neurons and glia are continuously added to the brain at postnatal stages, even in mature adults of various mammalian species, including humans. Moreover, these newly added cells contribute to structural plasticity and play important roles in higher order brain function, as well as repair after damage. A major source of these new neurons and glia is neural stem cells (NSCs) that persist in specialized niches in the brain throughout life. With this new view, our understanding of normal brain physiology and interventional approaches to various brain disorders has changed markedly in recent years. This article provides a brief overview on the historical changes in our understanding of the developmental dynamics of neurogenesis and gliogenesis in the postnatal and adult mammalian brain and discusses the roles of NSCs and other progenitor populations in such cellular dynamics in health and disease of the postnatal mammalian brain. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease

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Neonatal Subventricular Zone Neural Stem Cells Release Extracellular Vesicles that Act as a Microglial Morphogen

Abstract: Highlights d Neonatal SVZ neural stem cells release extracellular vesicles d SVZ neural stem cell extracellular vesicles are targeted to microglia d Neural stem cell extracellular vesicles and RNA content regulate microglia morphology

Cited by 11 publications

References 65 publications

Exosomes derived from neural progenitor cells preserve photoreceptors during retinal degeneration by inactivating microglia

Exosomes derived from neural progenitor cells preserve photoreceptors during retinal degeneration by inactivating microglia

Potential hydrodynamic cytoplasmic transfer between mammalian cells: Cell-projection pumping

Developmental dynamics of neurogenesis and gliogenesis in the postnatal mammalian brain in health and disease: Historical and future perspectives

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