Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats

Abstract

Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-β polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke.

Crosstalk between stressed brain cells: direct and indirect effects of ischemia and aglycemia on microglia

“…Interestingly, metabolic stress by OGD or aglycemia alone did not affect primary microglia function or their expression of inflammatory markers. In the literature, pro-inflammatory effects of OGD on primary microglia in culture have been described [14,15], albeit sometimes in a shallow range [16] and with a heterogeneous response of different pro-inflammatory markers [17]. In line with our results, another study also did not observe significant changes in inflammatory markers in primary microglia after OGD [18].…”

“…In line with our results, another study also did not observe significant changes in inflammatory markers in primary microglia after OGD [18]. Taken together, literature data on microglia OGD is contradictory, which may be attributed to the heterogeneity of primary microglia and methodical differences in the OGD setting [14][15][16][17][18] as well as species differences [19]. Studies on aglycemia in microglia are scarce, and thus far only two studies focused on this topic, finding an increased proinflammatory response of microglia after aglycemia [20,21].…”

Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy

“…Mac-1 is a β2 integrin that is constitutively expressed on the surface of microglia. Mac-1 upregulation after oxygen-glucose deprivation (OGD) preconditioning has been found to enable microglia to cross the BBB and reach the rat brain parenchyma [69]. In addition, a study in C57BL/6 mice revealed that M2-like macrophages were able to infiltrate the ischaemic hemisphere via the choroid plexus-cerebrospinal fluid (CSF) route, thus suggesting that autologous transplantation of M2-like microglia into the CSF might be a promising treatment strategy for ischaemic stroke [158].…”

“…Ekdahl et al [162] found that microglia pre-conditioned to a protective phenotype could support neurogenesis, progenitor proliferation and survival, migration and differentiation of newly formed neurons in the adult brain following stroke. Kanazawa et al [69] found that intrathecal administration of primary microglia preconditioned in OGD conditions promoted the secretion of remodelling factors into the brain parenchyma, e.g., vascular endothelial growth factor (VEGF), TGF-β and MMP-9, thus facilitating axonal outgrowth and angiogenesis in the ischaemic cortex of rats. Administration of M1-polarised microglia has exacerbated OGD-induced neuronal death, manifested by reduced microtubule-associated protein-2 (MAP2) expression and increased lactate dehydrogenase (LDH) release, compared to microglia expressing differing inflammatory profiles.…”

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

“…In macrophages, the two different subsets-M1 and M2-express different MMPs [95]. MMP-9-which depicts pro-inflammatory roles in BBB opening and cytokine activation-is secreted by M2 microglia and involved as a remodeling factor during repair [96,97]. Kohkha et al further suggest that MMPs-apart from being differentially expressed in M1 and M2 subsets-might also contribute to phenotype polarization by regulating cytokine and growth factor availability [15].…”