Neural regeneration by regionally induced stem cells within post-stroke brains: Novel therapy perspectives for stroke patients

Tanaka

et al. 2020

IJMS

Self Cite

Ischemic stroke caused by cerebral artery occlusion induces neurological deficits because of cell damage or death in the central nervous system. Given the recent therapeutic advances in reperfusion therapies, some patients can now recover from an ischemic stroke with no sequelae. Currently, reperfusion therapies focus on rescuing neural lineage cells that survive in spite of decreases in cerebral blood flow. However, vascular lineage cells are known to be more resistant to ischemia/hypoxia than neural lineage cells. This indicates that ischemic areas of the brain experience neural cell death but without vascular cell death. Emerging evidence suggests that if a vascular cell-mediated healing system is present within ischemic areas following reperfusion, the therapeutic time window can be extended for patients with stroke. In this review, we present our comments on this subject based upon recent findings from lethal ischemia following reperfusion in a mouse model of stroke.

Section: Findings After Early Reperfusion Under Lethal Ischemia Inmentioning

confidence: 99%

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

Tanaka

et al. 2020

IJMS

Self Cite

“…This study examines the ability of EOC2 microglial cells to support the viability, proliferation, neurogenesis, and survival of primary cortical cells outside of the classic neurogenic niche during homeostasis and following mechanical injury. Stem cell progenitors outside of the classic neurogenic niches have the capacity for neurogenesis during normal homeostasis and following injury or disease given exposure to the proper combination of neurogenic cues [47,[48][49][50]. Cortical microglial cells are a potential source of neurogenic signaling molecules [4,[39][40][41][42][51][52][53][54][55][56].…”

Section: Discussionmentioning

confidence: 99%

“…Outside the classic neural stem cell niches, CNS stem cells have the potential to generate neurons and glial cells following ischemia or traumatic injury [35,[47][48][49][50]. Microglial-derived soluble cues are potentially important for local endogenous neurogenesis, migration, and neuronal survival [51].…”

Section: Introductionmentioning

confidence: 99%

Microglia induce neurogenesis by stimulating PI3K/AKT intracellular signaling in vitro

Lorenzen

Mathy

Whiteford

et al. 2020

Preprint

Background: Emerging evidence suggests that microglia can support neuronal survival, synapse development, and neurogenesis in classic neurogenic niches. Little is known about the ability of microglia to regulate the cortical environment and stimulate cortical neurogenesis outside classic neurogenic niches. We used an in vitro co-culture model system to investigate the hypothesis that microglia respond to soluble signals from cortical cells, particularly following injury, by altering the cortical environment to promote cortical cell proliferation, differentiation, and survival. Results: Analyses of cell proliferation, apoptosis, protein expression, and intracellular signaling were performed on uninjured and injured cortical cells in co-culture with an EOC2 microglial cell line. Microglia soluble cues enhanced cortical cell viability and proliferation of uninjured and injured cortical cells. Co-culture of injured cortical cells with microglial cells significantly reduced cortical cell apoptosis. Microglial significantly increased Nestin+ and a-internexin+ cells within and outside the injury site. NeuN+ cells increased in injured cortical cultures with microglia. Multiplex ELISA assays showed decreased levels of inflammatory cytokines in conditioned media collected from injured cortical cell and microglial co-culture. RTPCR analysis of microglial mRNA was performed. AKT phosphorylation in uninjured, and particularly injured cortical cells, significantly increased when co-cultured with EOC2 microglia. Inhibition of AKT phosphorylation in cortical cells blocked the microglial-enhanced cortical cell viability and expression of neurogenic markers in vitro . Conclusion: This in vitro model system allows for assessment of the effect of microglial-derived soluble signals on cortical cell viability, proliferation, and stages of differentiation during homeostasis or following injury. These data suggest that EOC2 microglia downregulate inflammatory cytokine production following activation by acute cortical injury to enhance proliferation of new cells capable of neurogenesis. Inhibition of AKT signaling in cortical cells blocks the microglial-derived enhanced proliferation and expression of neurogenic markers in injured cortical cultures. This in vitro system is useful for continued studies with other microglial cell lines and primary microglial cells. Increasing our understanding of the mechanisms that drive cortical neurogenesis stimulated by microglial cells during homeostasis and following injury will provide insight into the potential mechanisms of the neuroprotective role of immune activity in the central nervous system (CNS).

“…Studies have shown that cells of the adult mammalian central nervous system have destructive repair capabilities, especially the proliferation and differentiation of endogenous neural stem cells that can promote neurogenesis ( Shinozuka et al, 2014 ; Nakagomi et al, 2019 ). The endogenous neural stem cells of the adult brain are mainly present in the subventricular zone (SVZ) region of the lateral ventricle and the subgranular zone (SGZ) region of the hippocampus ( Péron and Berninger, 2015 ; Boldrini et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Electro-Acupuncture Promotes the Differentiation of Endogenous Neural Stem Cells via Exosomal microRNA 146b After Ischemic Stroke

Zhang

Jin

Wang

et al. 2020

Front. Cell. Neurosci.

Background: Evidences indicate that exosomes-mediated delivery of microRNAs (miRNAs or miRs) is involved in the neurogenesis of stroke. This study was to investigate the role of exosomal miRNAs in non-drug therapy of electro-acupuncture (EA) regulating endogenous neural stem cells for stroke recovery. Methods: The model of focal cerebral ischemia and reperfusion in rats were established by middle cerebral artery occlusion (MCAO) and treated by EA. The exosomes were extracted from peri-ischemic striatum and identified by exosomal biomarkers, and detected differentially expressed miRNAs with microarray chip. Primary stem cells were cultured, and oxygen-glucose deprivation and reperfusion (OGD/R) was used to mimic vitro ischemic injury. Results: The levels of exosomal biomarkers TSG101 and CD81 were increased in peri-ischemic striatum after EA treatment, and we revealed 25 differentially expressed miRNAs in isolated exosomes, of which miR-146b was selected for further analysis, and demonstrated that EA increased miR-146b expression and its inhibitors could block the effects. Subsequently, we confirmed that EA upregulated miR-146b expression to promote neural stem cells differentiation into neurons in peri-ischemic striatum. In vitro, it was verified that OGD/R hindered neural stem cells differentiation, and miR-146b inhibitors furtherly suppressed its differentiation, simultaneously NeuroD1 was involved in neural stem cells differentiation into neurons. Moreover, in vivo we found EA promoted NeuroD1-mediated neural stem cells differentiation via miR-146b. In addition, EA also could improve neurological deficits through miR-146b after ischemic stroke. Conclusion: EA promotes the differentiation of endogenous neural stem cells via exosomal miR-146b to improve neurological injury after ischemic stroke.