Mesenchymal stromal cell-derived extracellular vesicles modulate microglia/macrophage polarization and protect the brain against hypoxia-ischemic injury in neonatal mice by targeting delivery of miR-21a-5p

Xin, Danqing; Li, Tingting; Chu, Xili; Ke, Hongfei; Yu, Zhuoya; Cao, Lili; Bai, Xuemei; Liu, Dexiang; Wang, Zhen

doi:10.1016/j.actbio.2020.06.037

Cited by 51 publications

(63 citation statements)

References 48 publications

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“…Nevertheless, Iba-1 and GFAP immunoreactivity provide only limited information about astro-and microglia phenotype and function. Recent work indicates that MSC-EVs modulate the ratio of typical pro-inflammatory/neurotoxic M1 and anti-inflammatory/neuroprotective M2 markers (Xin et al, 2020). Here, we demonstrate that HI-related alterations of typical M1/M2 markers was counter-regulated by MSC-EV therapy.…”

Section: Discussionsupporting

confidence: 57%

“…The neuroprotective potential of MSC-EVs has been shown in different models of adult and neonatal brain injury (Doeppner et al, 2015;Drommelschmidt et al, 2016;Sisa et al, 2019;Wang et al, 2020). However, for neonatal HI, only limited data are available with partially discrepant study results (e.g., microglia activation; Ophelders et al, 2016;Sisa et al, 2019;Xin et al, 2020). Furthermore, common to the majority of studies was a major focus on the early phase after injury.…”

Section: Discussionmentioning

confidence: 99%

“…Considering that TNFα released from activated microglia is one of the strongest A1 inducers , our observations of a simultaneous downregulation of TNFα and C3 indicate that MSC-EVs modulated microglia with a consequent modulation of astrocyte phenotype and function. In contrast, MSC-EVs may directly affect both, micro-and astroglia, involving similar molecular mechanisms, e.g., through miRNAs targeting astrocytes (Xin et al, 2013(Xin et al, , 2017 and microglia (Xin et al, 2020). To differentiate between direct in indirect effects of MSC-EVs, appropriate in vitro models with purified cells, but also in vivo tracking analyses of systemically administered EVs will be indispensable.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to regenerative capacities, MSC-EVs have been suggested to reduce neuroinflammatory responses in different models of adult and perinatal brain injury (Drommelschmidt et al, 2016;Sisa et al, 2019;Wang et al, 2020;Xin et al, 2020). A major hallmark of HI-induced neuroinflammation is the activation of astrocytes and microglia, associated FIGURE 1 | MSC-EVs reduce HI-induced striatal tissue injury.…”

Section: Msc-evs Decrease Astro-and Microgliosis and Modulate Inflammmentioning

confidence: 99%

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Mesenchymal Stromal Cell-Derived Extracellular Vesicles Reduce Neuroinflammation, Promote Neural Cell Proliferation and Improve Oligodendrocyte Maturation in Neonatal Hypoxic-Ischemic Brain Injury

Kaminski

Köster

Mouloud

et al. 2020

Front. Cell. Neurosci.

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Background: Neonatal encephalopathy caused by hypoxia-ischemia (HI) is a major cause of childhood mortality and disability. Stem cell-based regenerative therapies seem promising to prevent long-term neurological deficits. Our previous work in neonatal HI revealed an unexpected interaction between mesenchymal stem/stromal cells (MSCs) and the brains' microenvironment leading to an altered therapeutic efficiency. MSCs are supposed to mediate most of their therapeutic effects in a paracrine mode via extracellular vesicles (EVs), which might be an alternative to cell therapy. In the present study, we investigated the impact of MSC-EVs on neonatal HI-induced brain injury.Methods: Nine-day-old C57BL/6 mice were exposed to HI through ligation of the right common carotid artery followed by 1 h hypoxia (10% oxygen). MSC-EVs were injected intraperitoneally 1, 3, and 5 days after HI. One week after HI, brain injury was evaluated by regional neuropathological scoring, atrophy measurements and immunohistochemistry to assess effects on neuronal, oligodendrocyte and vessel densities, proliferation, oligodendrocyte maturation, myelination, astro-, and microglia activation. Immunohistochemistry analyses were complemented by mRNA expression analyses for a broad set of M1/M2- and A1/A2-associated molecules and neural growth factors.Results: While total neuropathological scores and tissue atrophy were not changed, MSC-EVs significantly protected from HI-induced striatal tissue loss and decreased micro- and astroglia activation. MSC-EVs lead to a significant downregulation of the pro-inflammatory cytokine TNFa, accompanied by a significant upregulation of the M2 marker YM-1 and the anti-inflammatory cytokine TGFb. MSC-EVs significantly decreased astrocytic expression of the A1 marker C3, concomitant with an increased expression of neural growth factors (i.e., BDNF, VEGF, and EGF). These alterations were associated with an increased neuronal and vessel density, coinciding with a significant increase of proliferating cells in the neurogenic sub-ventricular zone juxtaposed to the striatum. MSC-EV-mediated neuroprotection went along with a significant improvement of oligodendrocyte maturation and myelination.Conclusion: The present study demonstrates that MSC-EVs mediate anti-inflammatory effects, promote regenerative responses and improve key developmental processes in the injured neonatal brain. The present results suggest different cellular target mechanisms of MSC-EVs, preventing secondary HI-induced brain injury. MSC-EV treatment may be a promising alternative to risk-associated cell therapies in neonatal brain injury.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Msc-evs Decrease Astro-and Microgliosis and Modulate Inflammmentioning

confidence: 99%

See 2 more Smart Citations

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Reduce Neuroinflammation, Promote Neural Cell Proliferation and Improve Oligodendrocyte Maturation in Neonatal Hypoxic-Ischemic Brain Injury

Kaminski

Köster

Mouloud

et al. 2020

Front. Cell. Neurosci.

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“…MSCs-Exo had a neuroprotective effect on hypoxic-ischemia injury in newborn mice, and this outcome was partly because of a decrease in neuron apoptosis and neuroinflammation. Within the injured brain, the miR-21a-5p was upregulated in neurons and microglia via uptake of MSCs-Exo (Xin et al, 2020). IV injection of exosomes improved the brain microenvironment by inducing vascular remodeling and promoting regeneration of damaged neurons in a stroke rat model (Han et al, 2018).…”

Section: Mechanism Of Exosome-mediated Stroke Treatmentmentioning

confidence: 99%

Native and Bioengineered Exosomes for Ischemic Stroke Therapy

Khan

Pan

et al. 2021

Front. Cell Dev. Biol.

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Exosomes are natural cells-derived vesicles, which are at the forefront toward clinical success for various diseases, including cerebral ischemia. Exosomes mediate cell-to-cell communication in different brain cells during both physiological and pathological conditions. Exosomes are an extensively studied type of extracellular vesicle, which are considered to be the best alternative for stem cell–based therapy. They can be secreted by various cell types and have unique biological properties. Even though native exosomes have potential for ischemic stroke therapy, some undesirable features prevent their success in clinical applications, including a short half-life, poor targeting property, low concentration at the target site, rapid clearance from the lesion region, and inefficient payload. In this review, we highlight exosome trafficking and cellular uptake and survey the latest discoveries in the context of exosome research as the best fit for brain targeting owing to its natural brain-homing abilities. Furthermore, we overview the methods by which researchers have bioengineered exosomes (BioEng-Exo) for stroke therapy. Finally, we summarize studies in which exosomes were bioengineered by a third party for stroke recovery. This review provides up-to-date knowledge about the versatile nature of exosomes with a special focus on BioEng-Exo for ischemic stroke. Standard exosome bioengineering techniques are mandatory for the future and will lead exosomes toward clinical success for stroke therapy.

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Dynamic release of neuronal extracellular vesicles containing miR‐21a‐5p is induced by hypoxia

Korvenlaita

Gómez-Budia

Scoyni

et al. 2023

J of Extracellular Vesicle

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Hypoxia induces changes in the secretion of extracellular vesicles (EVs) in several non‐neuronal cells and pathological conditions. EVs are packed with biomolecules, such as microRNA(miR)‐21‐5p, which respond to hypoxia. However, the true EV association of miR‐21‐5p, and its functional or biomarker relevance, are inadequately characterised. Neurons are extremely sensitive cells, and it is not known whether the secretion of neuronal EVs and miR‐21‐5p are altered upon hypoxia. Here, we characterised the temporal EV secretion profile and cell viability of neurons under hypoxia. Hypoxia induced a rapid increase of miR‐21a‐5p secretion in the EVs, which preceded the elevation of hypoxia‐induced tissue or cellular miR‐21a‐5p. Prolonged hypoxia induced cell death and the release of morphologically distinct EVs. The EVs protected miR‐21a‐5p from enzymatic degradation but a remarkable fraction of miR‐21a‐5p remained fragile and non‐EV associated. The increase in miR‐21a‐5p secretion may have biomarker potential, as high blood levels of miR‐21‐5p in stroke patients were associated with significant disability at hospital discharge. Our data provides an understanding of the dynamic regulation of EV secretion from neurons under hypoxia and provides a candidate for the prediction of recovery from ischemic stroke.

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Mesenchymal stromal cell-derived extracellular vesicles modulate microglia/macrophage polarization and protect the brain against hypoxia-ischemic injury in neonatal mice by targeting delivery of miR-21a-5p

Cited by 51 publications

References 48 publications

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Reduce Neuroinflammation, Promote Neural Cell Proliferation and Improve Oligodendrocyte Maturation in Neonatal Hypoxic-Ischemic Brain Injury

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Reduce Neuroinflammation, Promote Neural Cell Proliferation and Improve Oligodendrocyte Maturation in Neonatal Hypoxic-Ischemic Brain Injury

Native and Bioengineered Exosomes for Ischemic Stroke Therapy

Dynamic release of neuronal extracellular vesicles containing miR‐21a‐5p is induced by hypoxia

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