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Therapeutic mechanism of cord blood mononuclear cells via the IL-8-mediated angiogenic pathway in neonatal hypoxic-ischaemic brain injury.

ABSTRACT: In a clinical trial of cerebral palsy, the level of plasma interleukin-8 (IL-8) was increased, correlated with motor improvement, after human umbilical cord blood mononuclear cell (hUCBC) infusion. This study aimed to elucidate the role of IL-8 in the therapeutic effects of hUCBCs in a mouse model of hypoxic-ischaemic brain injury (HI). In P7 HI mouse brains, hUCBC administration at day 7 after HI upregulated the gene expression of Cxcl2, the mouse IL-8 homologue and increased the expression of its receptor, CXCR2. hUCBC administration restored the sequential downstream signalling axis of p-p38/p-MAPKAPK2, NF?B, and angiogenic factors, which were downregulated by HI. An in vitro assay revealed the downregulation of the angiogenic pathway by CXCR2 knockdown and p38 inhibition. In vivo p38 inhibition prior to hUCBC administration in HI mouse brains produced identical results. Behavioural outcomes revealed a therapeutic effect (ps?

SUBMITTER: Cho KH

PROVIDER: S-EPMC7064601 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Therapeutic mechanism of cord blood mononuclear cells via the IL-8-mediated angiogenic pathway in neonatal hypoxic-ischaemic brain injury.

Cho Kye Hee KH Choi Jee In JI Kim Jin-Ock JO Jung Joo Eun JE Kim Dong-Wook DW Kim MinYoung M

Scientific reports 20200310 1

In a clinical trial of cerebral palsy, the level of plasma interleukin-8 (IL-8) was increased, correlated with motor improvement, after human umbilical cord blood mononuclear cell (hUCBC) infusion. This study aimed to elucidate the role of IL-8 in the therapeutic effects of hUCBCs in a mouse model of hypoxic-ischaemic brain injury (HI). In P7 HI mouse brains, hUCBC administration at day 7 after HI upregulated the gene expression of Cxcl2, the mouse IL-8 homologue and increased the expression of ...[more]

PMID: 32157146

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Project description:BackgroundHypoxic ischaemic encephalopathy (HIE) in newborns can cause significant long-term neurological disability. The insult is a complex injury characterised by energy failure and disruption of cellular homeostasis, leading to mitochondrial damage. The importance of individual metabolic pathways, and their interaction in the disease process is not fully understood. The aim of this study was to describe and quantify the metabolomic profile of umbilical cord blood samples in a carefully defined population of full-term infants with HIE.Methods and findingsThe injury severity was defined using both the modified Sarnat score and continuous multichannel electroencephalogram. Using these classification systems, our population was divided into those with confirmed HIE (n = 31), asphyxiated infants without encephalopathy (n = 40) and matched controls (n = 71). All had umbilical cord blood drawn and biobanked at -80 °C within 3 hours of delivery. A combined direct injection and LC-MS/MS assay (AbsolutIDQ p180 kit, Biocrates Life Sciences AG, Innsbruck, Austria) was used for the metabolomic analyses of the samples. Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). 9 of these metabolites were only significantly altered between neonates with Hypoxic ischaemic encephalopathy and matched controls, while 14 were significantly altered in both study groups. Multivariate Discriminant Analysis models developed showed clear multifactorial metabolite associations with both asphyxia and HIE. A logistic regression model using 5 metabolites clearly delineates severity of asphyxia and classifies HIE infants with AUC = 0.92. These data describe wide-spread disruption to not only energy pathways, but also nitrogen and lipid metabolism in both asphyxia and HIE.ConclusionThis study shows that a multi-platform targeted approach to metabolomic analyses using accurately phenotyped and meticulously biobanked samples provides insight into the pathogenesis of perinatal asphyxia. It highlights the potential for metabolomic technology to develop a diagnostic test for HIE.

Project description:BackgroundInterleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action.MethodsThe brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia and treated with IL-33 at a dose of 0.2 μg/day i.p. for 3 days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells and cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes.ResultsThe expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 days after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation.ConclusionsThe activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

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Therapeutic mechanism of cord blood mononuclear cells via the IL-8-mediated angiogenic pathway in neonatal hypoxic-ischaemic brain injury.

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Therapeutic mechanism of cord blood mononuclear cells via the IL-8-mediated angiogenic pathway in neonatal hypoxic-ischaemic brain injury.

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