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B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.

ABSTRACT: Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendritic arborization after oxygen-glucose deprivation. Whole-brain volumetric serial two-photon tomography (STPT) and a custom-developed image analysis pipeline visualized and quantified poststroke B cell diapedesis throughout the brain, including remote areas supporting functional recovery. Stroke induced significant bilateral B cell diapedesis into remote brain regions regulating motor and cognitive functions and neurogenesis (e.g., dentate gyrus, hypothalamus, olfactory areas, cerebellum) in the whole-brain datasets. To confirm a mechanistic role for B cells in functional recovery, rituximab was given to human CD20+ (hCD20+) transgenic mice to continuously deplete hCD20+-expressing B cells following tMCAo. These mice experienced delayed motor recovery, impaired spatial memory, and increased anxiety through 8 wk poststroke compared to wild type (WT) littermates also receiving rituximab. B cell depletion reduced stroke-induced hippocampal neurogenesis and cell survival. Thus, B cell diapedesis occurred in areas remote to the infarct that mediated motor and cognitive recovery. Understanding the role of B cells in neuronal health and disease-based plasticity is critical for developing effective immune-based therapies for protection against diseases that involve recruitment of peripheral immune cells into the injured brain.

SUBMITTER: Ortega SB

PROVIDER: S-EPMC7060723 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.

Ortega Sterling B SB Torres Vanessa O VO Latchney Sarah E SE Whoolery Cody W CW Noorbhai Ibrahim Z IZ Poinsatte Katie K Selvaraj Uma M UM Benson Monica A MA Meeuwissen Anouk J M AJM Plautz Erik J EJ Kong Xiangmei X Ramirez Denise M DM Ajay Apoorva D AD Meeks Julian P JP Goldberg Mark P MP Monson Nancy L NL Eisch Amelia J AJ Stowe Ann M AM

Proceedings of the National Academy of Sciences of the United States of America 20200212 9

Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendr ...[more]

PMID: 32051245

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Project description:Ischemic stroke remains a serious threat to human life. Generation of neuronal and vascular cells is an endogenous regenerative mechanism in the adult brain, which may contribute to tissue repair after stroke. However, the regenerative activity is typically insufficient for significant therapeutic effects after brain injuries. Pyruvate kinase isoform M2 (PKM2) is a key regulator for energy metabolism. PKM2 also has nonmetabolic roles involving regulations of gene expression, cell proliferation, and migration in cancer cells as well as noncancerous cells. In a focal ischemic stroke mouse model, recombinant PKM2 (rPKM2) administration (160 ng/kg, intranasal delivery) at 1 h after stroke showed the significant effect of a reduced infarct volume of more the 60%. Delayed treatment of rPKM2, however, lost the acute neuroprotective effect. We then tested a novel hypothesis that delayed treatment of PKM2 might show proregenerative effects for long-term functional recovery and this chronic action could be mediated by its downstream STAT3 signaling. rPKM2 (160 ng/kg) was delivered to the brain using noninvasive intranasal administration 24 h after the stroke and repeated every other day. Western blot analysis revealed that, 7 days after the stroke, the levels of PKM2 and phosphorylated STAT3 and the expression of angiogenic factors VEGF, Ang-1, and Tie-2 in the peri-infarct region were significantly increased in the rPKM2 treatment group compared with those of the stroke vehicle group. To label proliferating cells, 5-bromo-2'-deoxyuridine (BrdU, 50 mg/kg, i.p.) was injected every day starting 3 days after stroke. At 14 days after stroke, immunohistochemistry showed that rPKM2 increased cell homing of doublecortin (DCX)-positive neuroblasts to the ischemic cortex. In neural progenitor cell (NPC) cultures, rPKM2 (0.4-4 nM) increased the expression of integrin β1 and the activation/phosphorylation of focal adhesion kinase (FAK). A mediator role of FAK in PKM2-promoted cell migration was verified in FAK-knockout fibroblast cultures. In the peri-infarct region of the brain, increased numbers of Glut-1/BrdU and NeuN/BrdU double-positive cells indicated enhanced angiogenesis and neurogenesis, respectively, compared to stroke vehicle mice. Using Laser Doppler imaging, we observed better recovery of the local blood flow in the peri-infarct region of rPKM2-treated mice 14 days after stroke. Meanwhile, rPKM2 improved the sensorimotor functional recovery measured by the adhesive removal test. Inhibiting the STAT3 phosphorylation/activation by the STAT3 inhibitor, BP-1-102 (3 mg/kg/day, o.g.), abolished all beneficial effects of rPKM2 in the stroke mice. Taken together, this investigation provides the first evidence demonstrating that early treatment of rPKM2 shows an acute neuroprotective effect against ischemic brain damage, whereas delayed rPKM2 treatment promotes regenerative activities in the poststroke brain leading to better functional recovery. The underlying mechanism involves activation of the STAT3 and FAK signals in the poststroke brain.

Project description:Background: The clinical outcome of patients suffering from stroke is dependent on multiple factors. The features of the lesion itself play an important role but clinical recovery is remarkably influenced by the plasticity mechanisms triggered by the stroke and occurring at a distance from the lesion. The latter translate into functional and structural changes of which cortical thickness might be easy to quantify one of the main players. However, studies on the changes of cortical thickness in brain areas beyond stroke lesion and their relationship to sensory-motor recovery are sparse. Objectives: To evaluate the effects of cerebral stroke on cortical thickness (CT) beyond the stroke lesion and its association with sensory-motor recovery. Materials and Methods: Five electronic databases (PubMed, Embase, Web of Science, Scopus and the Cochrane Library) were searched. Methodological quality of the included studies was assessed with the Newcastle-Ottawa Scale for non-randomized controlled trials and the Risk of Bias Cochrane tool for randomized controlled trials. Results: The search strategy retrieved 821 records, 12 studies were included and risk of bias assessed. In most of the included studies, cortical thinning was seen at the ipsilesional motor area (M1). Cortical thinning can occur beyond the stroke lesion, typically in regions anatomically connected because of anterograde degeneration. Nonetheless, studies also reported cortical thickening of regions of the unaffected hemisphere, likely related to compensatory plasticity. Some studies revealed a significant correlation between changes in cortical thickness of M1 or somatosensory (S1) cortical areas and motor function recovery. Discussion and Conclusions: Following a stroke, changes in cortical thickness occur both in regions directly connected to the stroke lesion and in contralateral hemisphere areas as well as in the cerebellum. The underlying mechanisms leading to these changes in cortical thickness are still to be fully understood and further research in the field is needed. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020200539; PROSPERO 2020, identifier: CRD42020200539.

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B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.

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B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.

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