hUCMSCs Mitigate LPS-Induced Trained Immunity in Ischemic Stroke

Feng, Yiwei; Wu, Chang-Chieh; Liang, Fengyin; Lin, Tuo; Li, Wanqi; Jing, Yinghua; Dai, Pei; Yu, Huixian; Lan, Yue; Pei, Zhong; Xu, Gelin

doi:10.3389/fimmu.2020.01746

Cited by 23 publications

(17 citation statements)

References 25 publications

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“…Our previous study found that MSCs could alleviate trained immunity through the inhibition of H3K4 methylation (Feng et al, 2020). Although MSC therapy shows potential regarding the mitigation of neuropathologies, the main distribution of MSCs after their intravenous injection is mostly restricted to the lungs, indicating that the therapeutic effect of MSCs occurs mainly via a paracrine-mediated mechanism (Gnecchi et al, 2016;Sherman et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Advances in regenerative medicine have revealed the great potential of mesenchymal-stem cells (MSCs) in brain repair based on their remarkable anti-inflammatory and immunomodulatory properties (Galindo et al, 2011;Sherman et al, 2019). Our previous study found that MSCs triggered the remission of trained immunity through the inhibition of H3K4 methylation (Feng et al, 2020). However, concerns regarding their safety as well as their tumor-or microinfarction-inducing potential limit the translational capacity of MSCs (Kunter et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal-Stem-Cell–Derived Extracellular Vesicles Mitigate Trained Immunity in the Brain

Feng

Guo

Zhao

et al. 2020

Front. Bioeng. Biotechnol.

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Trained immunity was recently discovered in innate immune cells and shown to facilitate the clearance of pathogens at the time of occurrence of the second insult. However, it exacerbates several aspects of neuropathologies, and proper therapy is needed to rectify this abnormal immune reaction. Mesenchymal-stem cells (MSCs) exhibit a distinct capability for brain repair but are associated with safety concerns. Extracellular vesicles derived from MSCs are a promising alternative therapy. In this study, we used lipopolysaccharides to activate trained immunity in the brain and examined the therapeutic potential of MSC-derived extracellular vesicles in mitigating the trained-immunity-induced exacerbated neuropathology. We found that MSC-derived extracellular vesicles showed comparable effects to those of MSCs in the mitigation of trained immunity in the brain. Moreover, the administration of MCS-derived extracellular vesicles mitigated the aggregated inflammatory responses in the acute stage of stroke and alleviated the trained-immunity-induced increased load of amyloid-β in APP/PS1 mice. We further investigated the molecular machinery of MSC-derived extracellular vesicles and found that IL-10 is important for the mediation of the therapeutic potential of MSC-derived extracellular vesicles toward the alleviation of trained immunity. Our study indicates that extracellular-vesicle-based regenerative strategies might be useful to mitigate trained immunity in the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mesenchymal-Stem-Cell–Derived Extracellular Vesicles Mitigate Trained Immunity in the Brain

Feng

Guo

Zhao

et al. 2020

Front. Bioeng. Biotechnol.

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“…The bilateral carotid artery stenosis (BCAS) model was performed as described previously (Feng et al, 2020b ). Briefly, the mice were anesthetized using 4% isoflurane in 28% O 2 and 68% N 2 and maintained on 2% isoflurane in 29% O 2 and 69% N 2 by a mask.…”

Section: Methodsmentioning

confidence: 99%

“…From the limited studies on WML, evidence shows that the Dl-NBP could promote the cognitive function in VaD models caused by chronic hypoperfusion (Li et al, 2019 ). The normal cognitive function requires a relatively normal electronic signal and a synaptic signal, which rely on intact myelin, as well as cholinergic neurotransmission (Feng et al, 2020b ). The beneficial effects of Dl-NBP on VaD were demonstrated by improving remyelination and enhancing the function of the cholinergic system (Tian et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Dl-3-n-Butylphthalide Alleviates Demyelination and Improves Cognitive Function by Promoting Mitochondrial Dynamics in White Matter Lesions

Feng

Guo

Zhao

et al. 2021

Front. Aging Neurosci.

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White matter lesions (WMLs) are a type of cerebrovascular disorder accompanied by demyelination and cognitive decline. Dl-3-n-butylphthalide (D1-NBP) is a neuroprotective drug used for the treatment of ischemic cerebrovascular diseases, although the function of DI-NBP on WML is still not clear. This study aims to investigate whether DI-NBP affects cognitive function and ameliorates demyelination in a model of WML. The bilateral carotid artery stenosis (BCAS) mouse model and in vitro brain slice cultures with low glucose and low oxygen (LGLO) treatment were adopted. The Dl-NBP was administered intragastrically for 28 days after BCAS or added at a dose of 50 μm for 48 h after LGLO. Spatial learning and memory were evaluated by an eight-arm radial maze. Demyelination was detected using a TEM. Mitochondrial dynamics were assessed by time-lapse imaging in the cultured brain slices. The function of the synapse was evaluated by the patch clamp technique. In BCAS mice, obvious demyelination and cognitive decline were observed, while both were significantly relieved by a high-dose D1-NBP treatment (100 mg/kg). Along with demyelination, mitochondrial accumulation in the axons was significantly increased in the BCAS mice model, but with the treatment of a high-dose D1-NBP, mitochondrial accumulation was mitigated, and the anterograde/retrograde transport of mitochondria was increased. Following the improved anterograde/retrograde transport of mitochondria, the synapse activity was significantly upregulated while the reactive oxygen species (ROS) generation was remarkably decreased in the cultured brain slices. In addition, we identified syntaphilin (SNPH) as the downstream target of D1-NBP. The overexpression of SNPH mediated the effects of D1-NBP in mitigating axonal mitochondrial accumulation. In conclusion, the D1-NBP treatment significantly relieved demyelination and improved spatial learning and memory in the WML model by promoting mitochondrial dynamics. These neuroprotective effects of D1-NBP were mediated by inhibiting the mitochondrial arching protein, SNPH, which provided a potential therapeutic target for WML.

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“…Also, the secretion of trophic factors and antiapoptotic molecules that promote neurogenesis and angiogenesis is increased. Some studies have also reported the use of human umbilical cord-derived MSCs for ischemic stroke treatment (Feng et al, 2020 ; Noh et al, 2020 ).…”

Section: Stem Cell Types For Treatment Of Ischemic Strokementioning

confidence: 99%

Insight Into the Mechanisms and the Challenges on Stem Cell-Based Therapies for Cerebral Ischemic Stroke

Liu

Reiter

Zhou

et al. 2021

Front. Cell. Neurosci.

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Strokes are the most common types of cerebrovascular disease and remain a major cause of death and disability worldwide. Cerebral ischemic stroke is caused by a reduction in blood flow to the brain. In this disease, two major zones of injury are identified: the lesion core, in which cells rapidly progress toward death, and the ischemic penumbra (surrounding the lesion core), which is defined as hypoperfusion tissue where cells may remain viable and can be repaired. Two methods that are approved by the Food and Drug Administration (FDA) include intravenous thrombolytic therapy and endovascular thrombectomy, however, the narrow therapeutic window poses a limitation, and therefore a low percentage of stroke patients actually receive these treatments. Developments in stem cell therapy have introduced renewed hope to patients with ischemic stroke due to its potential effect for reversing the neurological sequelae. Over the last few decades, animal tests and clinical trials have been used to treat ischemic stroke experimentally with various types of stem cells. However, several technical and ethical challenges must be overcome before stem cells can become a choice for the treatment of stroke. In this review, we summarize the mechanisms, processes, and challenges of using stem cells in stroke treatment. We also discuss new developing trends in this field.

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hUCMSCs Mitigate LPS-Induced Trained Immunity in Ischemic Stroke

Cited by 23 publications

References 25 publications

Mesenchymal-Stem-Cell–Derived Extracellular Vesicles Mitigate Trained Immunity in the Brain

Mesenchymal-Stem-Cell–Derived Extracellular Vesicles Mitigate Trained Immunity in the Brain

Dl-3-n-Butylphthalide Alleviates Demyelination and Improves Cognitive Function by Promoting Mitochondrial Dynamics in White Matter Lesions

Insight Into the Mechanisms and the Challenges on Stem Cell-Based Therapies for Cerebral Ischemic Stroke

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