Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Wang, Lin; Pei, Shuang; Liang, Han; Guo, Bin; Li, Yanfei; Duan, Ranran; Yao, Yaobing; Xue, Bohan; Chen, Xuemei; Jia, Yanjie

doi:10.1159/000494652

Cited by 155 publications

(128 citation statements)

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“…BMSCs-derived exosomes were extracted as previously reported [28], and the morphology and size distribution of exosomes were observed by transmission electron microscopy and dynamic light scattering (DLS) analysis. The exosome markers were assessed by Western blot analysis.…”

Section: Extraction Identification and Labeling Of Exosomesmentioning

confidence: 99%

RETRACTED ARTICLE:Bone mesenchymal stem cell-derived exosomal microRNA-29b-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway

Hou¹,

Li²,

Zhao³

et al. 2020

J Neuroinflammation

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Background: Mesenchymal stem cells (MSCs) are suspected to exert neuroprotective effects in brain injury, in part through the secretion of extracellular vesicles like exosomes containing bioactive compounds. We now investigate the mechanism by which bone marrow MSCs (BMSCs)-derived exosomes harboring the small non-coding RNA miR-29b-3p protect against hypoxic-ischemic brain injury in rats. Methods:We established a rat model of middle cerebral artery occlusion (MCAO) and primary cortical neuron or brain microvascular endothelial cell (BMEC) models of oxygen and glucose deprivation (OGD). Exosomes were isolated from the culture medium of BMSCs. We treated the MCAO rats with BMSC-derived exosomes in vivo, and likewise the OGD-treated neurons and BMECs in vitro. We then measured apoptosis-and angiogenesis-related features using TUNEL and CD31 immunohistochemical staining and in vitro Matrigel angiogenesis assays. Results: The dual luciferase reporter gene assay showed that miR-29b-3p targeted the protein phosphatase and tensin homolog (PTEN). miR-29b-3p was downregulated and PTEN was upregulated in the brain of MCAO rats and in OGD-treated cultured neurons. MCAO rats and OGD-treated neurons showed promoted apoptosis and decreased angiogenesis, but overexpression of miR-29b-3p or silencing of PTEN could reverse these alterations. Furthermore, miR-29b-3p could negatively regulate PTEN and activate the Akt signaling pathway. BMSCs-derived exosomes also exerted protective effects against apoptosis of OGD neurons and cell apoptosis in the brain samples from MCAO rats, where we also observed promotion of angiogenesis.Conclusion: BMSC-derived exosomal miR-29b-3p ameliorates ischemic brain injury by promoting angiogenesis and suppressing neuronal apoptosis, a finding which may be of great significance in the treatment of hypoxic-ischemic brain injury.

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Section: Extraction Identification and Labeling Of Exosomesmentioning

confidence: 99%

RETRACTED ARTICLE:Bone mesenchymal stem cell-derived exosomal microRNA-29b-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway

Hou¹,

Li²,

Zhao³

et al. 2020

J Neuroinflammation

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“…EVs are emerging as a promising tool for therapeutic delivery owing to its favorable intrinsic features of biocompatibility, stability, stealth capacity, and the ability to overcome natural barriers (Dostert et al 2017;Shahjin et al 2019). In other studies, bm-SC-EVs were found to exert immune-suppressive effects by enforcing ARM macrophage polarization and stimulating T-cell induction as well as producing neurotrophic factors and anti-inflammatory cytokines, as a dedicated reaction of environmental vesicles or cytokines from degenerating, malfunctioning cells (Dostert et al 2017;Cizkova et al 2018;Harting et al 2018;Kim et al 2018;Wang et al 2018;Beers and Appel 2019;Shahjin et al 2019). This hypothesis, though, is still a hypothesis, and recently, the possibility that bm-SCs one way or the other might donate healthy mitochondria to neurons that harbor dysfunctional mitochondria has also been raised to explain their positive effects (Babenko et al 2015).…”

Section: Mode Of Action Of Bm-derived Stromal Cellsmentioning

confidence: 99%

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

et al. 2020

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Neurodegenerative disorders share the final degenerative pathway, the inflammation-induced apoptosis and/or necrosis, irrespective of their etiology, be it of acute and chronic traumatic, vascular and idiopathic origin. Although disease-modifying strategies are an unmet need in these disorders, lately, (pre)clinical studies suggested favorable effects after an intervention with bone marrow-derived stromal cells (bm-SC). Recent interventions with intrathecal transplantation of these cells in preclinical rodent models improved the functional outcome and reduced the inflammation, but not anti-inflammatory drugs. The benefit of bm-SCs was demonstrated in rats with an acute (traumatic spinal cord injury, tSCI) and in mice with a chronic [amyotrophic lateral sclerosis (ALS)-like FUS 1-358 or SOD1-G93-A mutation] neurodegenerative process. Bm-SCs, were found to modify underlying disease processes, to reduce final clinical SCI-related outcome, and to slow down ALS-like clinical progression. After double-blind interventions with bm-SC transplantations, Vehicle (placebo), and (non) steroidal anti-inflammatory drugs (Methylprednisolone, Riluzole, Celecoxib), clinical, histological and histochemical findings, serum/spinal cytokines, markers for spinal microglial activation inclusive, evidenced the cell-to-cell action of bm-SCs in both otherwise healthy and immune-deficient tSCI-rats, as well as wild-type and FUS/SOD1-transgenic ALS-like mice. The multi-pathway hypothesis of the cell-to-cell action of bmSCs, presumably using extracellular vesicles (EVs) as carriers of messages in the form of RNAs, DNA, proteins, and lipids rather than influencing a single inflammatory pathway, could be justified by the reported differences of cytokines and other chemokines in the serum and spinal tissue. The mode of action of bm-SCs is hypothesized to be associated with its dedicated adjustment of the pro-apoptotic glycogen synthase kinase-3β level towards an anti-apoptotic level whereas their multi-pathway hypothesis seems to be confirmed by the decreased levels of the pro-inflammatory interleukin (IL)-1β and tumor necrosis factor (TNF) as well as the level of the marker of activated microglia, ionized calcium binding adapter (Iba)-1 level.

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“…A reduction of the inflammatory response was observed by Kim et al too [184,185]. A diminished inflammation was even observed in spinal cord injury, probably via neuronal apoptosis inhibition, angiogenesis stimulation, A1 astrocytes inactivation and up-regulation of anti-inflammatory IL-10 and TGF-β as well as down-regulation of the pro-inflammatory TNF-α and IL-1β [171,[186][187][188][189]]. An essential function after spinal cord injury and brain ischemia was also attributed to the miRNA-113b [184,190].…”

Section: Extracellular Vesicles-based Regenerative Medicinementioning

confidence: 88%

Extracellular Vesicles: The New Frontier of Stem Cell Regenerative Medicine?

Barreca¹,

Geraci²

2020

Preprint

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Regenerative medicine aims to repair damaged or missing cells, tissues or organs for the treatment of various diseases, poorly managed with conventional drugs and medical procedures. To date there are different approaches to obtain these results. Multimodal regenerative methods include transplant of healthy organs, tissues, or cells, body stimulation to activate a self healing response in damaged tissues, as well as the combined use of cells and bio-degradable scaffold to obtain functional tissues. Certainly, stem cells and derived products are promising tools in regenerative medicine due to their ability to induce de novo tissue formation and/or promote tissue and organ repair and regeneration. Currently, several studies have shown that the beneficial stem cell effects in damaged tissue restore are not depending on their engraftment and differentiation on the injury site, but rather to their paracrine activity. It is now well known that paracrine action of stem cells is due to their ability to release Extracellular Vesicles (EVs). EVs play a fundamental role in cell-to cell communication and are directly involved in tissue regeneration. In the present review, we tried to summarize the molecular mechanisms trough which EVs carry out their therapeutic action and their possible application for the treatment of several diseases.

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Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Cited by 155 publications

References 83 publications

RETRACTED ARTICLE:Bone mesenchymal stem cell-derived exosomal microRNA-29b-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway

RETRACTED ARTICLE:Bone mesenchymal stem cell-derived exosomal microRNA-29b-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

Extracellular Vesicles: The New Frontier of Stem Cell Regenerative Medicine?

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