There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

Interleukin (IL)-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC) transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV) vector using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL-10) at 0 or 3 hr after ischemia reperfusion. Infarct lesions, neurological deficits, and immunological analyses were performed within 7 days after MCAO. 0-hr transplantation of MSCs alone and MSC/IL-10 significantly reduced infarct volumes and improved motor function. Conversely, 3-hr transplantation of MSC/IL-10, but not MSCs alone, significantly reduced infarct volumes (p

Mesenchymal Stem Cells Overexpressing Interleukin-10 Promote Neuroprotection in Experimental Acute Ischemic Stroke.

Stroke is a leading cause of disability and mortality, with limited treatment options. After stroke injury, microglia and CNS-resident macrophages are rapidly activated and regulate neuropathological processes to steer the course of functional recovery. To accelerate this recovery, microglia can engulf dying cells and clear irreparably-damaged tissues, thereby creating a microenvironment that is more suitable for the formation of new neural circuitry. In addition, monocyte-derived macrophages cross the compromised blood-brain barrier to infiltrate the injured brain. The specific functions of myeloid lineage cells in brain injury and repair are diverse and dependent on phenotypic polarization statuses. However, it remains to be determined to what degree the CNS-invading macrophages occupy different functional niches from CNS-resident microglia. In this review, we describe the physiological characteristics and functions of microglia in the developing and adult brain. We also review (a) the activation and phenotypic polarization of microglia and macrophages after stroke, (b) molecular mechanisms that control polarization status, and (c) the contribution of microglia to brain pathology versus repair. Finally, we summarize current breakthroughs in therapeutic strategies that calibrate microglia/macrophage responses after stroke.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.13620

Microglial/Macrophage polarization and function in brain injury and repair after stroke.

http://digital.csic.es/bitstream/10261/206017/1/Molecular%20mechanisms%20and%20cellular%20events%20involved%20in%20the%20neuroprotective%20actions%20of%20estradiol.%20Analysis%20of%20sex%20differences.pdf

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Stroke, a global disease with a high disability rate, has limited options for functional rehabilitation and results in an adverse impact on patients’ lives. In recent years, mesenchymal stem cells (MSCs) have become a new focus of treatment owing to their potential for neuroregeneration. MSCs have demonstrated therapeutic efficacy capable of cell migration, angiogenesis, immunomodulation, neuroprotection and neural circuit reconstruction. The paracrine action of MSCs can also exert neurotrophic effects and improve the functional recovery. This review shows the transplantation protocol for MSCs, discusses the potential therapeutic mechanisms, and summarizes clinical trials on MSCs for treating ischemic stroke. The current proofs show that MSC therapy for ischemic stroke is safe and feasible. The timing and optimal dose of MSC administration are the main challenges in its clinical use. Although still under research, MSC therapy has the potential to be a new therapeutic approach for neurological recovery from ischemic stroke in the future.

Mesenchymal stem cell therapy for ischemic stroke: A look into treatment mechanism and therapeutic potential.

Summary

Aims

Intravenous transplantation of bone marrow mesenchymal stem cells (BMSCs) had been documented to improve functional outcome after ischemic stroke. However, the timing and appropriate cell number of transplantation to achieve better outcome after an episode of stroke remain further to be optimized.



Methods

To determine the optimal conditions, we transplanted different concentrations of BMSCs at different time points in a rat model of ischemic stroke. Infarction volume and neurological behavioral tests were performed after ischemia.



Results

We found that transplantation of BMSCs at 3 and 24 h, but not 7 days after focal ischemia, significantly reduced the lesion volume and improved motor deficits. We also found that transplanted cells at 1 × 106 to 107, but not at 1 × 104 to 105, significantly improved functional outcome after stroke. In addition to inhibiting macrophages/microglia activation in the ischemic brain, BMSC transplantation profoundly reduced infiltration of gamma delta T (γδT) cells, which are detrimental to the ischemic brain, and significantly increased regulatory T cells (Tregs), along with altered Treg-associated cytokines in the ischemic brain.



Conclusions

Our data suggest that timing and cell dose of transplantation determine the therapeutic effects after focal ischemia by modulating poststroke neuroinflammation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.12216

Timing and Dose Regimens of Marrow Mesenchymal Stem Cell Transplantation Affect the Outcomes and Neuroinflammatory Response After Ischemic Stroke

The treatment of ischemic stroke remains a daunting task as few therapeutic strategies have proven effective Systemic thrombolysis with intravenous tissue plasminogen activator (tPA) remains the only proven treatment to improve clinical outcome of patients with acute ischemic stroke But because of increased risk of hemorrhage beyond 4·5 hours post-stroke, few stroke patients (1-2%) benefit from tPA Therefore, new therapies need to be found that protect and repair the damaged brain after stroke The discovery of stem cells holds great promise for the cure of many diseases, including stroke The bone marrow-derived stem cells (BMSCs) have particularly gained a great deal of attention, as BMSCs can differentiate into different lineages under specific conditions In addition, obtaining marrow cells would be easy and using patient's own BMSCs may eliminate the risk of rejection Therapeutic effects have been reported in animal models of stroke after transplantation of BMSCs Initial clinical trials using BMSC transplantation have been performed in patients with ischemic stroke Additional trials are evaluating the impact of BMSCs on safety, feasibility, and efficacy for stroke treatment However, more information about the appropriate cell type, timing of administration, cell delivery route, and optimal dose for translational applications remains largely unexplored This article reviews the recent progress and future perspectives in BMSC-based therapy for ischemic stroke, focusing on cell delivery route and time window of cell transplantation for treatment of ischemic stroke in animal models and clinical trials

Therapeutic applications of bone marrow-derived stem cells in ischemic stroke.

Studies have linked neurogenesis to the beneficial actions of specific antidepressants. However, whether 17β-estradiol (E2), an antidepressant, can ameliorate poststroke depression (PSD) and whether E2-mediated improvement of PSD is associated with neurogenesis are largely unexplored. In the present study, we found that depressive-like behaviors were observed at the first week after focal ischemic stroke in female ovariectomized (OVX) rats, as measured by sucrose preference and open field test, suggesting that focal cerebral ischemia could induce PSD. Three weeks after middle cerebral artery occlusion (MCAO), rats were treated with E2 for consecutive 14 days. We found that E2-treated rats had significantly improving ischemia-induced depression-like behaviors in the forced-swimming test and sucrose preference test, compared to vehicle-treated group. In addition, we also found that BrdU- and doublecortin (DCX)-positive cells in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) were significantly increased in ischemic rats after E2 treatment, compared to vehicle-treated group. Our data suggest that focal cerebral ischemia can induce PSD, and E2 can ameliorate PSD. In addition, newborn neurons in the hippocampus may play an important role in E2-mediated antidepressant like effect after ischemic stroke.

/pdf/17-b-estradiol-attenuates-poststroke-depression-and-2jfx3742i6.pdf

17 β -Estradiol attenuates poststroke depression and increases neurogenesis in female ovariectomized rats

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Timing and Dose Regimens of Marrow Mesenchymal Stem Cell Transplantation Affect the Outcomes and Neuroinflammatory Response After Ischemic Stroke

Therapeutic applications of bone marrow-derived stem cells in ischemic stroke.

17 β -Estradiol attenuates poststroke depression and increases neurogenesis in female ovariectomized rats