Extracellular Vesicles Derived from Neural Progenitor Cells––a Preclinical Evaluation for Stroke Treatment in Mice

Zheng, Xuan; Zhang, L.; Kuang, Yi; Venkataramani, Vivek; Jin, Fengyan; Hein, Katharina; Zafeiriou, Maria-Patapia; Lenz, Christof; Moebius, Wiebke; Kılıç, Ertuğrul; Hermann, Dirk M.; Weber, Martin; Urlaub, Henning; Zimmermann, Wolfram‐Hubertus; Bähr, Mathias; Doeppner, Thorsten R.

doi:10.1007/s12975-020-00814-z

Cited by 64 publications

(79 citation statements)

References 79 publications

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“…The subsequent characterization of such enriched ADMSC‐EVs included transmission electron microscopy (TEM), nanosight tracking analysis (NTA), and Western blotting. In line with previous reports (Zheng et al., 2020), Western blotting analysis on the expression patterns of so called EV surface markers revealed CD9, CD63, Alix, and TSG101 but not albumin, Histone, and TOMM20 abundance in these ADMSC‐EVs (Figure 1a). The data showed no difference between the UC and the PEG method.…”

Section: Resultssupporting

confidence: 92%

Adipose‐derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR‐25

Kuang¹,

Zheng²,

Zhang³

et al. 2020

J of Extracellular Vesicle

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120

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Grafted mesenchymal stem cells (MSCs) yield neuroprotection in preclinical stroke models by secreting extracellular vesicles (EVs). The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such cargo and its underlying mechanism, primary neurons were exposed to oxygen‐glucose‐deprivation (OGD) and cocultured with adipose‐derived MSCs (ADMSCs) or ADMSC‐secreted EVs. Under such conditions, both ADMSCs and ADMSC‐secreted EVs significantly reduced neuronal death. Screening for signalling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53‐BNIP3 activity in neurons receiving either treatment paradigm. However, the aforementioned effects were reversed when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869 or when Hrs was knocked down. In light of miR‐25‐3p being the most highly expressed miRNA in ADMSC‐EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Indeed, a miR‐25‐3p oligonucleotide mimic reduced cell death, whereas the anti‐oligonucleotide increased autophagic flux and cell death by modulating p53‐BNIP3 signalling in primary neurons exposed to OGD. Likewise, native ADMSC‐EVs but not EVs obtained from ADMSCs pretreated with the anti‐miR‐25‐3p oligonucleotide (ADMSC‐EVsanti‐miR‐25‐3p) confirmed the aforementioned in vitro observations in C57BL/6 mice exposed to cerebral ischemia. The infarct size was reduced, and neurological recovery was increased in mice treated with native ADMSC‐EVs when compared to ADMSC‐EVsanti‐miR‐25‐3p. ADMSCs induce neuroprotection by improved autophagic flux through secreted EVs containing miR‐25‐3p. Hence, our work uncovers a novel key factor in naturally secreted ADMSC‐EVs for the regulation of autophagy and induction of neuroprotection in a preclinical stroke model.

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Section: Resultssupporting

confidence: 92%

Adipose‐derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR‐25

Kuang¹,

Zheng²,

Zhang³

et al. 2020

J of Extracellular Vesicle

Self Cite

120

View full text Add to dashboard Cite

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“…One hypothesized mode of delivery for these factors is via the secretion of membrane fragments (extracellular vesicles, EVs) from transplanted cells (Bang and Kim, 2019;Surugiu et al, 2019). Recent preclinical data in organoids suggest that EVs alone may be sufficient to significantly decrease injury in a hypoxia-starvation model of injury, opening the possibility for future early phase clinical trials of EV delivery for ischemic stroke (Zheng et al, 2020).…”

Section: Mesenchymal Lineagementioning

confidence: 99%

Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke

Sussman

2020

Front. Aging Neurosci.

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Stroke is the leading cause of serious long-term disability, significantly reducing mobility in almost half of the affected patients aged 65 years and older. There are currently no proven neurorestorative treatments for chronic stroke. To address the complex problem of restoring function in ischemic brain tissue, stem cell transplantation-based therapies have emerged as potential restorative therapies. Aligning with the major cell types found within the ischemic brain, stem-cell-based clinical trials for ischemic stroke have fallen under three broad cell lineages: hematopoietic, mesenchymal, and neural. In this review article, we will discuss the scientific rationale for transplanting cells from each of these lineages and provide an overview of published and ongoing trials using this framework.

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“…112 In a rodent model, NPC-EVs administration was identified as improving neurological recovery and neuroregeneration, lasting for three months. 113 Treatment of EVs derived from human cardiosphere-derived cell in a rabbit model did not increase the risk of intracerebral hemorrhage (ICH) or decrease survival rate, and is even better than rt-PA in attenuating behavioral deficits. 114 Microglia activation within minutes of cerebral ischemia, 115 release of pro-inflammatory and neurotoxic factors like IL-1β, TNF-α, IFN-γ, and triggering of cerebral inflammation are significant cascade reactions, 116 in addition to direct ischemia attack after stroke.…”

Section: Cerebrovascular Disease and Traumatic Disease Of The Cns Strokementioning

confidence: 99%

Recent Advances on Extracellular Vesicles in Central Nervous System Diseases

Jin¹,

Gu²,

Li³

et al. 2021

CIA

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Extracellular vesicles (EVs) are particles released by multiple cells, encapsulated by lipid bilayers and containing a variety of biological materials, including proteins, nucleic acids, lipids and metabolites. With the advancement of separation and characterization methods, EV subtypes and their complex and diverse functions have been recognized. In the central nervous system (CNS), EVs are involved in various physiological and pathological processes, such as regulation of neuronal firing, synaptic plasticity, formation and maintenance of myelin sheath, propagation of neuroinflammation, neuroprotection, and spread and removal of toxic protein aggregates. Activity-dependent alteration of constituents enables EVs to reflect the change of cell and tissue states, and the wide distribution of EVs in biological fluids endows them with potential as diagnostic and prognostic biomarkers for CNS diseases, including neurodegenerative disease, cerebrovascular disease, traumatic brain disease, and brain tumor. Favorable biocompatibility, ability of crossing the blood-brain barrier and protecting contents from degradation, give promising therapeutic effects of EVs, either collected from mesenchymal stem cells culture conditioned media, or designed as drug delivery vehicles loaded with specific agents. In this review, we summarized EVs' basic biological properties, and mainly focused on their applications in CNS diseases.

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Extracellular Vesicles Derived from Neural Progenitor Cells––a Preclinical Evaluation for Stroke Treatment in Mice

Cited by 64 publications

References 79 publications

Adipose‐derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR‐25

Adipose‐derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR‐25

Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke

Recent Advances on Extracellular Vesicles in Central Nervous System Diseases

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