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Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke

ABSTRACT: Background: Increasing evidence indicates stem cell transplantation may be an effective stroke treatment but little is known about the direct impact of transplanted cells on injured brain tissue. We investigated the effects of lineage negative murine hematopoietic stem/progenitor cells (HSPCs) on the cerebral microcirculation following ischemia-reperfusion injury (I/RI). Following subsequent evaluation of the mRNA transcriptome of the explanted HSPCs, we assessed whether metallothionein (MT)-1, (increased in explanted HSPCs from I/R mice) administration was able to evoke similar neuro-protection following cerebral I/RI. Methods and Results: Murine HSPCs administered intravenously 24 hours (h) post cerebral I/R were selectively recruited to the brain of I/RI mice. Mice treated with HSPCs displayed decreased disease severity for up to 2-weeks post cerebral I/R, as evidenced by decreased mortality rate, decreased infarct volume, improved functional outcome, reduced microglial activation and elevated plasma levels of anti-inflammatory interleukin-10. Using confocal intravital microscopy, we found that transplanted cells had emigrated into the brain parenchyma and that RNA-seq analysis of explanted HSPCs indicated significantly increased levels of metallothionein transcripts, in particular MT-1. We further determined that treatment of mice with MT-1 significantly reduced neurological score and IV. Conclusions: These studies provide further evidence for HSPCs as a promising therapeutic strategy in promoting repair following cerebral I/RI, potentially via a MT-1 mechanism.

ORGANISM(S): Mus musculus

PROVIDER: GSE95853 | GEO | 2018/02/21

REPOSITORIES: GEO

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Project description:Cerebral ischemia/reperfusion injury (CI/RI), including neurological behavior deficits, cerebral infarction, blood-brain barrier (BBB) dysfunction, and neuroinflammation, et al. is a severe challenge in treatment of ischemic stroke. Traditional Chinese medicine (TCM) with the characteristics of multi-components and multi-functions for multiple targets/pathways has been historically used in the treatment of stroke and post stroke recovery in China. QiShenYiQi (QSYQ), a representative component-based Chinese medicine, is capable of reducing organ injury caused by ischemia/reperfusion via multiple mechanisms. Recently, we have previously reported that the positive action of QSYQ against the acute phase of CI/RI is partly via modulation of neuroinflammatory response. However, the effects and underlying mechanisms of QSYQ on subacute phase of CI/RI remain unknown, which are aimed to investigate in present study. The pharmacological action of QSYQ treatment on brain damage was estimated in the experimental stroke rats underwent 90 min ischemia and 8 days reperfusion by assessing the neurological and locomotor deficits, cerebral infarction, brain edema, and BBB integrity. Furthermore, we used TMT-based quantitative proteomics technology to identify significantly differentially expressed proteins following QSYQ treatment, which could give important clues for revealing the possible mechanism underlying the positive role of QSYQ in CI/RI. Besides, immunohistochemistry, western blot analysis, RT-qPCR, and rat ELISA kits were executed to further verify the accuracy of proteomics analysis results. As a consequence, we found that treatment with QSYQ (600mg/kg) for 7 days obviously improved neurological and behavioral impairment, attenuated infarct volume and brain edema, and alleviated BBB breakdown in stroke rats. Bioinformatics analysis suggested that differentially expressed protein galectin-3 mediated inflammatory response was closely related to the beneficial effect of QSYQ. Results of immunohistochemistry, western blot analysis and RT-qPCR showed that the model rats treated with QSYQ (600mg/kg) markedly downregulated the mRNA and protein expression level of galectin-3 in brain tissues compared to the untreated stroke rats. In addition, the decrease of mRNA level in brain tissues and contents in serum of TNF-α and IL-6 following QSYQ treatment were also observed. These interesting finding manifested that the effective action of QSYQ against subacute phase of CI/RI was partly via regulating galectin-3 mediated inflammatory reaction.

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Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke

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