Stroke is the main cause of disability and death in the world within neurological diseases. Despite such a huge impact, enzymatic, and mechanical recanalization are the only treatments available so far for ischemic stroke, but only <20% of patients can benefit from them. The use of stem cells as a possible cell therapy in stroke has been tested for years. The results obtained from these studies, although conflicting or controversial in some aspects, are promising. In the last few years, the recent development of the induced pluripotent stem cells has opened new possibilities to find new cell therapies against stroke. In this review, we will provide an overview of the state of the art of cell therapy in stroke. We will describe the current situation of the most employed stem cells and the use of induced pluripotent stem cells in stroke pathology. We will also present a summary of the different clinical trials that are being carried out or that already have results on the use of stem cells as a potential therapeutic intervention for stroke.

Background and Purpose-Hypothermia is potentially the most effective protective therapy for brain ischemia; however, its use is limited because of serious side effects. Although focal hypothermia (FH) has a significantly lower stress profile than systemic hypothermia (SH), its efficacy in ischemia has been poorly studied. We aimed to compare the therapeutic effects of each treatment on various short-and long-term clinically relevant end points. Methods-Sprague-Dawley rats were subjected to transient (45 minutes) occlusion of the middle cerebral artery. One hour after arterial reperfusion, animals were randomly assigned to groups for treatment with SH or FH (target temperature: 32°C) for 4 or 24 hours. Lesion volume, edema, functional recovery, and histological markers of cellular injury were evaluated for 1 month after ischemic injury. Effects of SH and FH on cerebral temperature were also analyzed for the first time by magnetic resonance thermometry, an approach that combines spectroscopy with gradient-echo-based phase mapping. Results-Both therapeutic approaches reduced ischemic lesion volume (P<0.001), although a longer FH treatment (24 hours) was required to achieve similar protective effects to those induced by 4 hours of SH. In addition, magnetic resonance thermometry demonstrated that systemic hypothermia reduced whole-brain temperature, whereas FH primarily reduced the temperature of the ischemic region. Conclusions-Focal brain hypothermia requires longer cooling periods to achieve the same protective efficacy as SH.However, FH mainly affects the ischemic region, and therefore represents a promising and nonstressful alternative to SH.

RNA-binding motif protein 3 (RBM3) is a molecular marker of hypothermia that has proved neuroprotective in neurodegenerative disease models. However, its relationship to the well-recognized therapeutic effect of hypothermia in ischemic stroke had not been studied. In this work, the expression of RBM3 was investigated in ischemic animal models subjected to systemic and focal brain hypothermia, specifically the effects of RBM3 silencing and overexpression on ischemic lesions. Moreover, the association of RBM3 levels with body temperature and clinical outcome was evaluated in two independent cohorts of acute ischemic stroke patients (n = 215); these levels were also determined in a third cohort of 31 patients derived from the phase III EuroHYP-1 trial of therapeutic cooling in ischemic stroke. The preclinical data confirmed the increase of brain RBM3 levels in ischemic animals subjected to systemic and focal hypothermia; this increase was selectively higher in the cooled hemisphere of animals undergoing focal brain hypothermia, thus confirming the direct effect of hypothermia on RBM3 expression, while RBM3 up-regulation in ischemic brain regions led to functional recovery. Clinically, patients with body temperature &lt;37.5 °C in the first two cohorts had higher RBM3 values at 24 hours and good outcome at 3 months post-ischemic stroke, while RBM3 levels in the cooled third cohort tended to exceed those in placebo-treated patients. These results make RBM3 a molecular marker associated with the effect of hypothermia in ischemic stroke and suggest its potential application as a promising protective target.

Proper occlusion of the medial cerebral artery, as determined by laser Doppler monitoring, during cerebral ischaemia in rat models is an important inclusion criterion in experimental studies. However, successful occlusion of the artery does not always guarantee a reproducible infarct volume, which is crucial for validating the efficacy of new protective drugs. In a rat intraluminal ischaemic model, laser Doppler monitoring alone was compared with laser Doppler monitoring in combination with magnetic resonance angiography (MRA) and diffusion-weighted imaging (DWI). Twenty-eight animals showed successful occlusion and reperfusion determined with Doppler monitoring, with an infarct size at 24 h of 16.7±11.5% (determined as ischaemic damage with respect to the ipsilateral hemisphere volume). However, when arterial occlusion and infarct damage were analysed in these animals using MRA and DWI, respectively, 15 animals were excluded and only 13 animals were included, with an infarct size at 24 h of 21.6±6.1%, showing a variability in the infarct size significantly lower (P<0.05, F-test) than that obtained with Doppler monitoring alone. We also observed that blocking of the pterygopalatine artery (a maxillary artery that is usually occluded in the intraluminal ischaemic model) was not relevant for this model, at least in terms of infarct variability. These results show that laser Doppler monitoring is a necessary procedure, but not sufficient to guarantee a reproducible infarct volume, in a rat ischaemic model. Therefore, laser Doppler monitoring in combination with DWI and MRA represents a reliable inclusion protocol during ischaemic surgery for the analysis of new protective drugs.