Olfactory Mucosa Mesenchymal Stem Cells Alleviate Cerebral Ischemia/Reperfusion Injury Via Golgi Apparatus Secretory Pathway Ca2+ -ATPase Isoform1

He, Jialin; Liu, Jianyang; Huang, Yan; Zhuo, Yi; Chen, Wei; Duan, Da; Tang, Xiangqi; Lu, Ming

doi:10.3389/fcell.2020.586541

Cited by 25 publications

(27 citation statements)

References 67 publications

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“…Although we suggested that hypoxic OM-MSCs inhibited microglial pyroptosis in ICH, the specific mechanism of the inflammatory response of microglia regulated by hypoxic OM-MSCs after ICH injury is still unclear. Previously, we demonstrated that OM-MSCs exerts neuroprotective effects on cerebral ischemia/reperfusion injury (47,48,50). We also revealed that hypoxia-preconditioned OM-MSCs inhibit pyroptotic death of microglial cells by activating the hypoxia inducible factor-1α (HIF-1α) in vitro model of ischemic stroke (49).…”

Section: Effects Of Mscs On Microglial Pyroptosis Post-ichmentioning

confidence: 97%

“…Olfactory mucosa MSCs (OM-MSCs) localized in the nasal lamina propria have recently been recognized as an ideal source of MSCs, as they are easily accessible and situated for autologous transplantation (46). Previously, we demonstrated that OM-MSCs exerts neuroprotective effects in ischemic stroke (47,48). We also revealed that hypoxia-preconditioned OM-MSCs inhibited microglial pyroptosis in an in vitro model (49) and affirmed that hypoxic preconditioning enhanced the therapeutic efficacy of OM-MSCs in an in vivo model (50).…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia-preconditioned mesenchymal stem cells attenuate microglial pyroptosis after intracerebral hemorrhage

Liu¹,

He²,

Huang³

et al. 2021

Ann Transl Med

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Background: Microglia plays a vital role in neuroinflammation, contributing to the pathogenesis of intracerebral hemorrhage (ICH)-induced brain injury. Mesenchymal stem cells (MSCs) hold great potential for treating ICH. We previously revealed that MSCs ameliorate the microglial pyroptosis caused by an ischemic stroke. However, whether MSCs can modulate microglial pyroptosis after ICH remains unknown.This study aimed to investigate the neuroprotective effects of hypoxia-preconditioned olfactory mucosa MSCs (OM-MSCs) on ICH and the possible mechanisms.Methods: ICH was induced in mice via administration of collagenase IV. At 6 h post-ICH, 2-4×10 5 normoxic/hypoxic OM-MSCs or saline were intracerebrally administered. To evaluate the neuroprotective effects, the behavioral outcome, apoptosis, and neuronal injury were measured. Microglia activation and proinflammatory cytokines were applied to detect neuroinflammation. Microglial pyroptosis was determined by western blotting, immunofluorescence staining, and transmission electron microscopy (TEM). Results:The two OM-MSC-transplanted groups exhibited significantly improved functional recovery and reduced neuronal injury, especially the hypoxic OM-MSCs group. Hypoxic OM-MSCs attenuated microglial activation as well as the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Moreover, we found that hypoxia-preconditioned OM-MSCs ameliorated pyroptosis by diminishing the levels of pyroptosis-associated proteins in peri-hematoma brain tissues, decreasing the expression of the microglial nod-like receptor family protein 3 (NLRP3) and caspase-1, and reducing the membrane pores on microglia post-ICH.Conclusions: Our study showed that hypoxic preconditioning augments the therapeutic efficacy of OM-MSCs, and hypoxia-preconditioned OM-MSCs alleviate microglial pyroptosis in the ICH model.

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Section: Effects Of Mscs On Microglial Pyroptosis Post-ichmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Hypoxia-preconditioned mesenchymal stem cells attenuate microglial pyroptosis after intracerebral hemorrhage

Liu¹,

He²,

Huang³

et al. 2021

Ann Transl Med

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“…Li et al (2012a) have found that adipose-derived mesenchymal stem cells (ADMSCs) attenuated cerebral ischemia-reperfusion injury through suppressing iNOS. Another two interesting findings indicated that olfactory mucosa mesenchymal stem cells (OM-MSCs) exert neuroprotective effects by rescuing the function of mitochondria and Golgi apparatus and enhancing antioxidation via upregulation of UBIAD1 and SPCA1 (He et al, 2020;Liu et al, 2020b). Moreover, that MSCs modified with diverse molecules exhibited antioxidative stress effects on ischemic stroke models have also been reported, such as C-C motif chemokine receptor 2 (CCR-2), brain-derived neurotrophic factor (BDNF), and circRNA-Akap7 (Lu et al, 2016;Huang et al, 2018b;Xu et al, 2020).…”

Section: Mscs Inhibit the Production Of Ros And Rnsmentioning

confidence: 99%

Oxidative Stress, Inflammation, and Autophagy: Potential Targets of Mesenchymal Stem Cells-Based Therapies in Ischemic Stroke

Liu

Huang

et al. 2021

Front. Neurosci.

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Ischemic stroke is a leading cause of death worldwide; currently available treatment approaches for ischemic stroke are to restore blood flow, which reduce disability but are time limited. The interruption of blood flow in ischemic stroke contributes to intricate pathophysiological processes. Oxidative stress and inflammatory activity are two early events in the cascade of cerebral ischemic injury. These two factors are reciprocal causation and directly trigger the development of autophagy. Appropriate autophagy activity contributes to brain recovery by reducing oxidative stress and inflammatory activity, while autophagy dysfunction aggravates cerebral injury. Abundant evidence demonstrates the beneficial impact of mesenchymal stem cells (MSCs) and secretome on cerebral ischemic injury. MSCs reduce oxidative stress through suppressing reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation and transferring healthy mitochondria to damaged cells. Meanwhile, MSCs exert anti-inflammation properties by the production of cytokines and extracellular vesicles, inhibiting proinflammatory cytokines and inflammatory cells activation, suppressing pyroptosis, and alleviating blood–brain barrier leakage. Additionally, MSCs regulation of autophagy imbalances gives rise to neuroprotection against cerebral ischemic injury. Altogether, MSCs have been a promising candidate for the treatment of ischemic stroke due to their pleiotropic effect.

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“…Olfactory mucosa MSCs (OM-MSCs), located in the nasal lamina propria, are an attractive source of stem cells as they are relatively easy to obtain and ideally suited for autologous transplantation [ 10 ]. Previously, we demonstrated that OM-MSCs exert neuroprotective effects in cerebral ischemia/reperfusion injury [ 11 , 12 ], but no study has explored the neuroprotective effects of OM-MSC therapy in ICH.…”

Section: Introductionmentioning

confidence: 99%

Hypoxic preconditioning rejuvenates mesenchymal stem cells and enhances neuroprotection following intracerebral hemorrhage via the miR-326-mediated autophagy

Liu

et al. 2021

Stem Cell Res Ther

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Background Intracerebral hemorrhage (ICH) is a major public health concern, and mesenchymal stem cells (MSCs) hold great potential for treating ICH. However, the quantity and quality of MSCs decline in the cerebral niche, limiting the potential efficacy of MSCs. Hypoxic preconditioning is suggested to enhance the survival of MSCs and augment the therapeutic efficacy of MSCs in ICH. MicroRNAs (miRNAs) are known to mediate cellular senescence. However, the precise mechanism by which miRNAs regulate the senescence of hypoxic MSCs remains to be further studied. In the present study, we evaluated whether hypoxic preconditioning enhances the survival and therapeutic effects of olfactory mucosa MSC (OM-MSC) survival and therapeutic effects in ICH and investigated the mechanisms by which miRNA ameliorates hypoxic OM-MSC senescence. Methods In the in vivo model, ICH was induced in mice by administration of collagenase IV. At 24 h post-ICH, 5 × 105 normoxia or hypoxia OM-MSCs or saline was administered intracerebrally. The behavioral outcome, neuronal apoptosis, and OM-MSC survival were evaluated. In the in vitro model, OM-MSCs were exposed to hemin. Cellular senescence was examined by evaluating the expressions of P16INK4A, P21, P53, and by β-galactosidase staining. Microarray and bioinformatic analyses were performed to investigate the differences in the miRNA expression profiles between the normoxia and hypoxia OM-MSCs. Autophagy was confirmed using the protein expression levels of LC3, P62, and Beclin-1. Results In the in vivo model, transplanted OM-MSCs with hypoxic preconditioning exhibited increased survival and tissue-protective capability. In the in vitro model, hypoxia preconditioning decreased the senescence of OM-MSCs exposed to hemin. Bioinformatic analysis identified that microRNA-326 (miR-326) expression was significantly increased in the hypoxia OM-MSCs compared with that of normoxia OM-MSCs. Upregulation of miR-326 alleviated normoxia OM-MSC senescence, whereas miR-326 downregulation increased hypoxia OM-MSC senescence. Furthermore, we showed that miR-326 alleviated cellular senescence by upregulating autophagy. Mechanistically, miR-326 promoted the autophagy of OM-MSCs via the PI3K signaling pathway by targeting polypyrimidine tract-binding protein 1 (PTBP1). Conclusions Our study shows that hypoxic preconditioning delays OM-MSC senescence and augments the therapeutic efficacy of OM-MSCs in ICH by upregulating the miR-326/PTBP1/PI3K-mediated autophagy.

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Olfactory Mucosa Mesenchymal Stem Cells Alleviate Cerebral Ischemia/Reperfusion Injury Via Golgi Apparatus Secretory Pathway Ca2+ -ATPase Isoform1

Cited by 25 publications

References 67 publications

Hypoxia-preconditioned mesenchymal stem cells attenuate microglial pyroptosis after intracerebral hemorrhage

Hypoxia-preconditioned mesenchymal stem cells attenuate microglial pyroptosis after intracerebral hemorrhage

Oxidative Stress, Inflammation, and Autophagy: Potential Targets of Mesenchymal Stem Cells-Based Therapies in Ischemic Stroke

Hypoxic preconditioning rejuvenates mesenchymal stem cells and enhances neuroprotection following intracerebral hemorrhage via the miR-326-mediated autophagy

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