Safety evaluation of intra-arterial cell delivery in stroke patients—a framework for future trials

Effective treatments are not yet available for the majority of stroke patients despite the significant advances in acute stroke management and care evident since the advent of therapeutic recanalization in 2015. Unfortunately, even patients who are eligible for recanalization treatment often suffer from residual functional deficits. Hence, there is an unmet demand for additional stroke therapies promoting functional recovery, not only those that can be considered as complementary approaches to recanalization but also for treatments that can be provided beyond its narrow time window. Cell therapies are an emerging paradigm in translational neuroscience and have been widely investigated in experimental stroke models (1). Preclinical evidence collected over the past two decades has revealed that administration of cells can exert robust effects in improving functional outcome when delivered in subacute (2,3) and even in chronic stroke stages (4). These promising findings have promoted small, early phase clinical studies intended to assess the feasibility, safety and efficacy of cell therapy approaches (5)

Cell therapy in stroke—cautious steps towards a clinical treatment

In the future, stroke patients may receive stem cell therapy as this has the potential to restore lost functions. However, the development of clinically deliverable therapy has been slower and more challenging than expected. Despite recommendations by STAIR and STEPS consortiums, there remain flaws in experimental studies such as lack of animals with comorbidities, inconsistent approaches to experimental design, and concurrent rehabilitation that might lead to a bias towards positive results. Clinical studies have typically been small, lacking control groups as well as often without clear biological hypotheses to guide patient selection. Furthermore, they have used a wide range of cell types, doses, and delivery methods, and outcome measures. Although some ongoing and recent trial programs offer hints that these obstacles are now being tackled, the Horizon2020 funded RESSTORE trial will be given as an example of inconsistent regulatory requirements and challenges in harmonized cell production, logistic, and clinical criteria in an international multicenter study. The PISCES trials highlight the complex issues around intracerebral cell transplantation. Therefore, a better understanding of translational challenges is expected to pave the way to more successful help for stroke patients

Microglia is an active player in how glibenclamide improves stroke outcome

The recent review article"Sulfonylurea receptor 1 in central nervous system injury: a focused review"1 is an extensive summary of the current knowledge of the role of the sulfonylurea receptor 1 (SUR-1) and SUR-1-regulated NCCa-ATP channels in acute brain injuries. The review also highlights the potential translational applicability of the use of glibenclamide in treating brain pathologies such as cerebral ischemia or traumatic brain injury......

Behavioral outcome measures to improve experimental stroke research

Functional recovery after an experimental stroke can be assessed by multiple behavioural tests, however, there is no consensus about which test to use in long-term stroke recovery studies or whether the tests are affected by stroke surgery, post-operative care or behavioural compensation due to repeated testing. This review describes the tests most commonly used to assess motor and sensorimotor function, cognition and mood in stroke animals. Although it is difficult to predict the direction of future research, it may be possible to prevent false-positive results by selecting an appropriate task or a battery of tasks. It is also expected that the upcoming stroke recovery recommendations and the improved dialogue between academy, industry and healthcare professionals will further promote translational success

Hypoxia and extracellular vesicles: A review on methods, vesicular cargo and functions

Hypoxia is an essential hallmark of several serious diseases such as cardiovascular and metabolic disorders and cancer. A decline in the tissue oxygen level induces hypoxic responses in cells which strive to adapt to the changed conditions. A failure to adapt to prolonged or severe hypoxia can trigger cell death. While some cell types, such as neurons, are highly vulnerable to hypoxia, cancer cells take advantage of a hypoxic environment to undergo tumour growth, angiogenesis and metastasis. Hypoxia-induced processes trigger complex intercellular communication and there are now indications that extracellular vesicles (EVs) play a fundamental role in these processes. Recent developments in EV isolation and characterization methodology have increased the awareness of the importance of EV purity in functional and cargo studies. Cell death, a hallmark of severe hypoxia, is a known source of intracellular contaminants in isolated EVs. In this review, methodological aspects of studies investigating hypoxia-induced EVs are critically evaluated. Key concerns and gaps in the current knowledge are highlighted and future directions for studies are set. To accelerate and advance research, an in-depth analysis of the functions and cargo of hypoxic EVs, compared to normoxic EVs, is provided with the focus on the altered microRNA contents of the EVs

Glibenclamide enhances neurogenesis and improves long-term functional recovery after transient focal cerebral ischemia

Glibenclamide is neuroprotective against cerebral ischemia in rats. We studied whether glibenclamide enhances long-term brain repair and improves behavioral recovery after stroke. Adult male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 90 minutes. A low dose of glibenclamide (total 0.6mg) was administered intravenously 6, 12, and 24 hours after reperfusion. We assessed behavioral outcome during a 30-day follow-up and animals were perfused for histological evaluation. In vitro specific binding of glibenclamide to microglia increased after pro-inflammatory stimuli. In vivo glibenclamide was associated with increased migration of doublecortin-positive cells in the striatum toward the ischemic lesion 72 hours after MCAO, and reactive microglia expressed sulfonylurea receptor 1 (SUR1) and Kir6.2 in the medial striatum. One month after MCAO, glibenclamide was also associated with increased number of NeuN-positive and 5-bromo-2-deoxyuridine-positive neurons in the cortex and hippocampus, and enhanced angiogenesis in the hippocampus. Consequently, glibenclamide-treated MCAO rats showed improved performance in the limb-placing test on postoperative days 22 to 29, and in the cylinder and water-maze test on postoperative day 29. Therefore, acute blockade of SUR1 by glibenclamide enhanced long-term brain repair in MCAO rats, which was associated with improved behavioral outcome

Concise review : increasing the validity of cerebrovascular disease models and experimental methods for translational stem cell research

Interspecies differences, anatomical and physiological aspects, as wells as simplified study designs contribute to an overestimation of treatment effects and limit the transferability of experimental results into clinical applications. Confounders of cell therapies for cerebrovascular disorders (CVD) include common CVD comorbidities, frequent medications potentially affecting endogenous and transplanted stem cells, as well as age‐ and immune‐system–related effects. All those can contribute to a substantial modeling bias, ultimately limiting the prospective quality of preclinical research programs regarding the clinical value of a particular cell therapy. In this review, we discuss the nature and impact of most relevant confounders. We provide suggestions on how they can be considered to enhance the validity of CVD models in stem cell research. Acknowledging substantial and sometimes surprising effects of housing conditions, chronobiology, and intersex differences will further augment the translational value of animal models. We finally discuss options for the implementation of high‐quality functional and imaging readout protocols. Altogether, this might help to gain a more holistic picture about the therapeutic impact of a particular cell therapy for CVD, but also on potential side and off‐site effects of the intervention

Mental health conditions and bleeding events in patients with incident atrial fibrillation : A Finnish nationwide cohort study

Peer reviewe

Socioeconomic factors and bleeding events in patients with incident atrial fibrillation : A Finnish nationwide cohort study

Background: Low socioeconomic status has been associated with higher risk of ischemic stroke and death in patients with atrial fibrillation (AF). However, whether socioeconomic status affects risk of bleeding events is unknown. We assessed the hypothesis that low income and educational attainment are associated with higher risk of bleeding in patients with AF.Methods: The registry-based FinACAF study covers all patients with AF in Finland during 2007-2018. Patients were divided into income quartiles and three categories based on their educational attainment. Outcomes of interest were the first-ever gastrointestinal (GI), intracranial (IC) and any bleeding.Results: We identified 205 019 patients (50.9 % female; mean age 72.3 (SD 13.4) years) with incident AF without prior bleeding. Mean follow-up time was 4.0 (SD 3.2) years, during which 25 013 (12.2 %) patients experienced first-ever any bleeding (incidence rate 3.07 (95 % CI 3.03-3.10) /100 patient-years). Low income was inde-pendently associated with hazard of any bleeding as well as GI and IC bleeding (adjusted hazard ratios (HRs) comparing lowest vs highest income quartile: 1.13 (1.08-1.17), 1.32 (1.23-1.41) and 1.15 (1.06-1.24), respectively). Income-related bleeding disparities were larger among younger patients under 65 years and among men. Education-related bleeding disparities were smaller than income related-disparities (adjusted HRs comparing lowest vs highest educational category: any bleeding 1.06 (1.02-1.11), GI bleeding 1.16 (1.08-1.24), IC bleeding 1.10 (0.93-1.09))Conclusions: Patients with AF and low income are at higher risk of bleeding, especially GI bleeding.Peer reviewe