Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles

Heras‐Romero, Yessica; Morales-Guadarrama, Axayácatl; Santana-Martínez, Ricardo A.; Ponce, Isaac; Rincón-Heredia, Ruth; Poot-Hernández, Augusto César; Martínez-Moreno, Araceli; Urrieta, Esteban; Bernal‐Vicente, Berenice N.; Campero-Romero, Aura N.; Moreno-Castilla, Perla; Greig, Nigel H.; Escobar, Martha L.; Concha, Luis; Tovar‐y‐Romo, Luis B.

doi:10.1016/j.ymthe.2021.09.023

Cited by 27 publications

(28 citation statements)

References 97 publications

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“…3A). This result overtly contrasts our previous nding that EVs derived from astrocytes facilitate spontaneous recovery in the rat after tMCAo 17 . Therefore we hypothesized that if NPC-EV had any neuroprotective effect, this was being masked by the endogenous process already happening in the in vivo model, so we set out to determine whether a possible neuroprotective effect would become clearer under conditions that impede the proliferation of endogenous NPCs after stroke.…”

Section: Npc-derived Nx-ev Promote Post-ischemic Neurological Recover...contrasting

confidence: 99%

“…The isolated EV pellets were resuspended in 100 µl PBS and stored at -80°C until used. EV size, distribution, and concentrations were determined as previously reported 17 using an NS300 NanoSight nanoparticle tracking analysis system (Malvern Instruments). Data were binned and plotted as a continuous histogram.…”

Section: Ev Isolation and Quantitationmentioning

confidence: 99%

“…An alternative mechanism for this protection is that NPCs secrete neuroprotective factors not as soluble molecules but in more complex structures, like extracellular vesicles (EVs). We have recently shown that EV-mediated intercellular communication between astrocytes and neurons promotes a faster neurological recovery following a stroke by enhancing axon outgrowth in the lesioned brain 17 . In this regard, human NPC-derived EVs have been shown to ameliorate neurological deterioration in experimental stroke 18 .…”

Section: Introductionmentioning

confidence: 99%

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Extracellular vesicles from neural progenitor cells promote functional recovery after stroke in mice with pharmacological inhibition of neurogenesis

Campero-Romero

Real

Santana-Martínez

et al. 2023

Preprint

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Neural progenitor cells (NPCs) of the subventricular zone proliferate in response to ischemic stroke in the adult mouse brain. Newly generated cells have been considered to influence recovery following a stroke. However, the mechanism underlying such protection is a matter of active study since it has been thought that proliferating NPCs mediate their protective effects by secreting soluble factors that promote recovery rather than neuronal replacement in the ischemic penumbra. We tested the hypothesis that this mechanism is mediated by the secretion of multimolecular complexes in extracellular vesicles (EVs). We found that the molecular influence of oxygen and glucose-deprived (OGD) NPCs-derived EVs is very limited in improving overt neurological alterations caused by stroke compared to our recently reported astrocyte-derived EVs. However, when we inhibited the ischemia-triggered proliferation of NPCs with the chronic administration of the DNA synthesis inhibitor Ara-C, the effect of NPC-derived exosomes became evident, suggesting that the endogenous protection exerted by the proliferation of NPC is mainly carried out through a mechanism that involves the intercellular communication mediated by EVs. We analyzed the proteomic content of NPC-derived EVs cargo with label-free relative abundance mass spectrometry and identified several molecular mediators of neuronal recovery within these vesicles. Our findings indicate that NPC-derived EVs are protective against the ischemic cascade activated by stroke and, thus, hold significant therapeutic potential.

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Section: Npc-derived Nx-ev Promote Post-ischemic Neurological Recover...contrasting

confidence: 99%

Section: Ev Isolation and Quantitationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extracellular vesicles from neural progenitor cells promote functional recovery after stroke in mice with pharmacological inhibition of neurogenesis

Campero-Romero

Real

Santana-Martínez

et al. 2023

Preprint

Self Cite

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“…Comparing cellular, EV-enriched preparations, and EV luminal RNAs using miRNA-seq, we identified a selection of miRNAs preferentially secreted and protected from proteinase K and RNase A/T1 treatment, indicating that they are likely transported inside EVs. Even though this should be taken with some caution because the preferentially secreted miRNAs included several miRNAs without experimentally validated targets ( Table S4 ), GO annotations of their target mRNA point to preferentially secreted miRNAs protected inside EVs as being good candidates to drive the reported effects of astrocyte EVs in neuronal processes, such as cell survival and axon regeneration [ 9 , 73 ]; miR-203 has been reported to play a role in neuronal cell death and the regulation of neuronal activity [ 74 ], and miR-205 has been reported to modulate the expression of the leucine-rich repeat kinase 2 (LRRK2) gene which is involved in Parkinson’s disease [ 75 ]. MiR-21, involved, among other roles, in neuronal repair and transferred by EVs in the brain [ 7 , 13 , 76 ] is not significantly different between cells and the EV lumen and miR-23, which is equally distributed in cells, and EVs are involved in myelination and neuronal differentiation [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

Human Adult Astrocyte Extracellular Vesicle Transcriptomics Study Identifies Specific RNAs Which Are Preferentially Secreted as EV Luminal Cargo

Shanthi

Fischer

Sharma

et al. 2023

Genes

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Astrocytes are central nervous system (CNS)-restricted glial cells involved in synaptic function and CNS blood flow regulation. Astrocyte extracellular vesicles (EVs) participate in neuronal regulation. EVs carry RNAs, either surface-bound or luminal, which can be transferred to recipient cells. We characterized the secreted EVs and RNA cargo of human astrocytes derived from an adult brain. EVs were isolated by serial centrifugation and characterized with nanoparticle tracking analysis (NTA), Exoview, and immuno-transmission electron microscopy (TEM). RNA from cells, EVs, and proteinase K/RNase-treated EVs was analyzed by miRNA-seq. Human adult astrocyte EVs ranged in sizes from 50 to 200 nm, with CD81 as the main tetraspanin marker and larger EVs positive for integrin β1. Comparison of the RNA between the cells and EVs identified RNA preferentially secreted in the EVs. In the case of miRNAs, enrichment analysis of their mRNA targets indicates that they are good candidates for mediating EV effects on recipient cells. The most abundant cellular miRNAs were also abundant in EVs, and the majority of their mRNA targets were found to be downregulated in mRNA-seq data, but the enrichment analysis lacked neuronal specificity. Proteinase K/RNase treatment of EV-enriched preparations identified RNAs secreted independently of EVs. Comparing the distribution of cellular and secreted RNA identifies the RNAs involved in intercellular communication via EVs.

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“…Upregulation of the cholesterol-binding sigma-1 receptor in astrocytes is beneficial for axonal sprouting; a sigma-1 receptor agonist enhanced neurite outgrowth, promoting behavioral recovery after stroke [168]. A recent study showed that astrocytes can promote structural remodeling of striato-cortical circuits through the release of extracellular vesicles in the tMCAO mouse model [169]. A meta-analysis of astrocytic EV proteomes revealed that proteins which regulate axon outgrowth and guidance, including TUBB, ACTG1, RTN4, and Rab11A, are upregulated.…”

Section: Neurogenesis and Synaptogenesis: Astrocytes And Neuroblastsmentioning

confidence: 99%

Crosstalk of Astrocytes and Other Cells during Ischemic Stroke

Yang

Zhang

2022

Life

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Stroke is a leading cause of death and long-term disability worldwide. Astrocytes structurally compose tripartite synapses, blood–brain barrier, and the neurovascular unit and perform multiple functions through cell-to-cell signaling of neurons, glial cells, and vasculature. The crosstalk of astrocytes and other cells is complicated and incompletely understood. Here we review the role of astrocytes in response to ischemic stroke, both beneficial and detrimental, from a cell–cell interaction perspective. Reactive astrocytes provide neuroprotection through antioxidation and antiexcitatory effects and metabolic support; they also contribute to neurorestoration involving neurogenesis, synaptogenesis, angiogenesis, and oligodendrogenesis by crosstalk with stem cells and cell lineage. In the meantime, reactive astrocytes also play a vital role in neuroinflammation and brain edema. Glial scar formation in the chronic phase hinders functional recovery. We further discuss astrocyte enriched microRNAs and exosomes in the regulation of ischemic stroke. In addition, the latest notion of reactive astrocyte subsets and astrocytic activity revealed by optogenetics is mentioned. This review discusses the current understanding of the intimate molecular conversation between astrocytes and other cells and outlines its potential implications after ischemic stroke. “Neurocentric” strategies may not be sufficient for neurological protection and recovery; future therapeutic strategies could target reactive astrocytes.

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Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles

Cited by 27 publications

References 97 publications

Extracellular vesicles from neural progenitor cells promote functional recovery after stroke in mice with pharmacological inhibition of neurogenesis

Extracellular vesicles from neural progenitor cells promote functional recovery after stroke in mice with pharmacological inhibition of neurogenesis

Human Adult Astrocyte Extracellular Vesicle Transcriptomics Study Identifies Specific RNAs Which Are Preferentially Secreted as EV Luminal Cargo

Crosstalk of Astrocytes and Other Cells during Ischemic Stroke

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