Current status of ischemic stroke treatment: From thrombolysis to potential regenerative medicine.

Stroke remains a major cause of long-term disability and mortality worldwide. The immune system plays an important role in determining the condition of the brain following stroke. As the resident innate immune cells of the central nervous system, microglia are the primary responders in a defense network covering the entire brain parenchyma, and exert various functions depending on dynamic communications with neurons, astrocytes, and other neighboring cells under both physiological or pathological conditions. Microglia activation and polarization is crucial for brain damage and repair following ischemic stroke, and is considered a double-edged sword for neurological recovery. Microglia can exist in pro-inflammatory states and promote secondary brain damage, but they can also secrete anti-inflammatory cytokines and neurotrophic factors and facilitate recovery following stroke. In this review, we focus on the role and mechanisms of microglia-mediated neuroinflammation and neuroplasticity after ischemia and relevant potential microglia-based interventions for stroke therapy.

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Microglia-mediated neuroinflammation and neuroplasticity after stroke

Ischemic stroke is defined as an infarction in the brain, caused by impaired cerebral blood supply, leading to local brain tissue ischemia, hypoxic necrosis, and corresponding neurological deficits. At present, revascularization strategies in patients with acute ischemic stroke include intravenous thrombolysis and mechanical endovascular treatment. However, due to the short treatment time window (<4.5 h) and method restrictions, clinical research is focused on new methods to treat ischemic stroke. Exosomes are nano-sized biovesicles produced in the endosomal compartment of most eukaryotic cells, containing DNA, complex RNA, and protein (30–150 nm). They are released into surrounding extracellular fluid upon fusion between multivesicular bodies and the plasma membrane. Exosomes have the characteristics of low immunogenicity, good innate stability, high transmission efficiency, and the ability to cross the blood–brain barrier, making them potential therapeutic modalities for the treatment of ischemic stroke. The seed sequence of miRNA secreted by exosomes is base-paired with complementary mRNA to improve the microenvironment of ischemic tissue, thereby regulating downstream signal transduction activities. With exosome research still in the theoretical and experimental stages, this review aims to shed light on the potential of exosomes derived from mesenchymal stem cells in the treatment of ischemic stroke.

Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.

Cell Therapy for Neurological Disorders: The Perspective of Promising Cells.

The lack of regenerative capacity of neurons leads to poor prognoses for some neurological disorders. The use of small molecules to directly reprogram somatic cells into neurons provides a new therapeutic strategy for neurological diseases. In this review, the mechanisms of action of different small molecules, the approaches to screening small molecule cocktails, and the methods employed to detect their reprogramming efficiency are discussed, and the studies, focusing on neuronal reprogramming using small molecules in neurological disease models, are collected. Future research efforts are needed to investigate the in vivo mechanisms of small molecule-mediated neuronal reprogramming under pathophysiological states, optimize screening cocktails and dosing regimens, and identify safe and effective delivery routes to promote neural regeneration in different neurological diseases.

Application of Small Molecules in the Central Nervous System Direct Neuronal Reprogramming

Transplantation of various types of stem cells as a possible therapy for stroke has been tested for years, and the results are promising. Recent investigations have shown that the administration of the conditioned media obtained after stem cell cultivation can also be effective in the therapy of the central nervous system pathology (hypothesis of their paracrine action). The aim of this study was to evaluate the therapeutic effects of the conditioned medium of hiPSC-derived glial and neuronal progenitor cells in the rat middle cerebral artery occlusion model of the ischemic stroke. Secretory activity of the cultured neuronal and glial progenitor cells was evaluated by proteomic and immunosorbent-based approaches. Therapeutic effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis- and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration and the numbers of formed blood vessels in the affected area of the brain. As a result, 31% of the protein species discovered in glial progenitor cells-conditioned medium and 45% in neuronal progenitor cells-conditioned medium were cell type specific. The glial progenitor cell-conditioned media showed a higher content of neurotrophins (BDNF, GDNF, CNTF and NGF). We showed that intra-arterial administration of glial progenitor cells-conditioned medium promoted a faster decrease in neurological deficit compared to the control group, reduced microglia/macrophage infiltration, reduced expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13) and promoted the formation of blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. The results indicate pronounced cytoprotective, anti-inflammatory and angiogenic properties of soluble factors secreted by glial progenitor cells.

Therapeutic Effects of hiPSC-Derived Glial and Neuronal Progenitor Cells-Conditioned Medium in Experimental Ischemic Stroke in Rats

This study's aim was to investigate CT (computed tomography) pattern dynamics differences within surviving and deceased adult patients with COVID-19, revealing new prognostic factors and reproducing already known data with our patients' cohort: 635 hospitalized patients (55.3% of them were men, 44.7%-women), of which 87.3% had a positive result of RT-PCR (reverse transcription-polymerase chain reaction) at admission. The number of deaths was 53 people (69.8% of them were men and 30.2% were women). In total, more than 1500 CT examinations were performed on patients, using a GE Optima CT 660 computed tomography (General Electric Healthcare, Chicago, IL, USA). The study was performed at hospital admission, the frequency of repetitive scans further varied based on clinical need. The interpretation of the imaging data was carried out by 11 radiologists with filling in individual registration cards that take into account the scale of the lesion, the location, contours, and shape of the foci, the dominating types of changes, as well as the presence of additional findings and the dynamics of the process-a total of 45 parameters. Statistical analysis was performed using the software packages SPSS Statistics version 23.0 (IBM, Armonk, NY, USA) and R software version 3.3.2. For comparisons in pattern dynamics across hospitalization we used repeated measures general linear model with outcome and disease phase as factors. The crazy paving pattern, which is more common and has a greater contribution to the overall CT picture in different phases of the disease in deceased patients, has isolated prognostic significance and is probably a reflection of faster dynamics of the process with a long phase of progression of pulmonary parenchyma damage with an identical trend of changes in the scale of the lesion (as recovered) in this group of patients. Already known data on typical pulmonological CT manifestations of infection, frequency of occurrence, and the prognostic significance of the scale of the lesion were reproduced, new differences in the dynamics of the process between recovered and deceased adult patients were also found that may have prognostic significance and can be reflected in clinical practice.

Gevorg Akopyan

Papers

Therapeutic Effects of hiPSC-Derived Glial and Neuronal Progenitor Cells-Conditioned Medium in Experimental Ischemic Stroke in Rats

Differences in Dynamics of Lung Computed Tomography Patterns between Survivors and Deceased Adult Patients with COVID-19.