Intracerebral transplantation of MRI-trackable autologous bone marrow stromal cells for patients with subacute ischemic stroke.

BACKGROUND: Ischemic stroke is one of the leading causes of death and neurological disability worldwide, and stem cell therapy is highly expected to reverse the sequelae. This phase 1/2, first-in-human study evaluated the safety, feasibility, and monitoring of an intracerebral-transplanted magnetic resonance imaging (MRI)-trackable autologous bone marrow stromal cell (HUNS001-01) for patients with subacute ischemic stroke. METHODS: The study included adults with severe disability due to ischemic stroke. HUNS001-01 cultured with human platelet lysates and labeled with superparamagnetic iron oxide was stereotactically transplanted into the peri-infarct area 47-64 days after ischemic stroke onset (dose: 2 or 5 × 107 cells). Neurological and radiographic evaluations were performed throughout 1 year after cell transplantation. The trial was registered at UMIN Clinical Trial Registry (number UMIN000026130). FINDINGS: All seven patients who met the inclusion criteria successfully achieved cell expansion, underwent intracerebral transplantation, and completed 1 year of follow-up. No product-related adverse events were observed. The median National Institutes of Health Stroke Scale and modified Rankin scale scores before transplantation were 13 and 4, which showed improvements of 1-8 and 0-2, respectively. Cell tracking proved that the engrafted cells migrated toward the infarction border area 1-6 months after transplantation, and the quantitative susceptibility mapping revealed that cell signals at the migrated area constantly increased throughout the follow-up period up to 34% of that of the initial transplanted site. CONCLUSIONS: Intracerebral transplantation of HUNS001-01 was safe and well tolerated. Cell tracking shed light on the therapeutic mechanisms of intracerebral transplantation. FUNDING: This work was supported by the Japan Agency for Medical Research and Development (AMED; JP17bk0104045 and JP20bk0104011).

Intracerebral Transplantation of Mesenchymal Stromal Cell Compounded with Recombinant Peptide Scaffold against Chronic Intracerebral Hemorrhage Model.

Background: Due to the lack of effective therapies, stem cell transplantation is an anticipated treatment for chronic intracerebral hemorrhage (ICH), and higher cell survival and engraftment are considered to be the key for recovery. Mesenchymal stromal cells (MSCs) compounded with recombinant human collagen type I scaffolds (CellSaics) have a higher potential for cell survival and engraftment compared with solo-MSCs, and we investigated the validity of intracerebral transplantation of CellSaic in a chronic ICH model. Methods: Rat CellSaics (rCellSaics) were produced by rat bone marrow-derived MSC (rBMSCs). The secretion potential of neurotrophic factors and the cell proliferation rate were compared under oxygen-glucose deprivation (OGD) conditions. rCellSaics, rBMSCs, or saline were transplanted into the hollow cavity of a rat chronic ICH model. Functional and histological analyses were evaluated, and single-photon emission computed tomography for benzodiazepine receptors was performed to monitor sequential changes in neuronal integrity. Furthermore, human CellSaics (hCellSaics) were transplanted into a chronic ICH model in immunodeficient rats. Antibodies neutralizing brain-derived neurotrophic factor (BDNF) were used to elucidate its mode of action. Results: rCellSaics demonstrated a higher secretion potential of trophic factors and showed better cell proliferation in the OGD condition. Animals receiving rCellSaics displayed better neurological recovery, higher intracerebral BDNF, and better cell engraftment; they also showed a tendency for less brain atrophy and higher benzodiazepine receptor preservation. hCellSaics also promoted significant functional recovery, which was reversed by BDNF neutralization. Conclusion: Intracerebral transplantation of CellSaics enabled neurological recovery in a chronic ICH model and may be a good option for clinical application.

Corrigendum to "Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease".

[This corrects the article DOI: 10.1155/2020/4085617.].

Responses of Immune Organs after Cerebral Ischemic Stroke.

BACKGROUND: Stroke is a leading cause of death and disability worldwide. Recently, secondary damage to the brain has been hypothesized as a key aggravating element in the ischemic cascade. However, the interaction between cerebral infarction and immune organs is not fully understood. In this study, we investigated changes in rat brain, spleen, thymus, mesenteric lymph node, and liver at 3, 7, and 13 days after transient middle cerebral artery occlusion (tMCAO) by immunohistochemistry. METHODS: Rat models of stroke were made by tMCAO. Functional assessment was performed at 3 h and 1, 3, 5, 7, 9, 11, and 13 days after MCAO. Rat organs were harvested for 2,3,5-triphenyltetrazolium chloride staining and immunohistochemistry. RESULTS: The number of CD8α+ T cells decreased in spleen, thymus, mesenteric lymph node, and liver and increased in brain. Numbers of Iba1+ and CD68+ macrophages decreased in spleen, thymus, and mesenteric lymph node and increased in brain and liver. Ki67+ cells exhibited the same characteristics as macrophages, and increased numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) -positive apoptotic cells were present in spleen, mesenteric lymph node, liver, and brain. CONCLUSIONS: The present results indicate that stroke is a systemic disease that, in addition to affecting the brain, also induces responses in immune organs. These results suggest that systemic treatment might be a good strategy for clinical stroke care.

Clinical Trials of Stem Cell Therapy for Cerebral Ischemic Stroke.

Despite recent developments in innovative treatment strategies, stroke remains one of the leading causes of death and disability worldwide. Stem cell therapy is currently attracting much attention due to its potential for exerting significant therapeutic effects on stroke patients. Various types of cells, including bone marrow mononuclear cells, bone marrow/adipose-derived stem/stromal cells, umbilical cord blood cells, neural stem cells, and olfactory ensheathing cells have enhanced neurological outcomes in animal stroke models. These stem cells have also been tested via clinical trials involving stroke patients. In this article, the authors review potential molecular mechanisms underlying neural recovery associated with stem cell treatment, as well as recent advances in stem cell therapy, with particular reference to clinical trials and future prospects for such therapy in treating stroke.

Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease.

Cell therapy for central nervous system (CNS) disorders is beginning to prove its safety and efficiency. Intraparenchymal transplantation can be an option for cell delivery; however, one concern regarding this method is that the transplantation cannula may cause additional brain injuries. These include vessel damage, which results in brain hemorrhage, and clogging of the cannula by brain debris and/or cell clusters, which requires replacement of the cannula or forced injection causing jet flow of the cell suspension. We compared cannulas for cell delivery used in clinical trials, the Pittsburg and Mizuho cannulas, to a newly designed one, MK01, to assess their usability. MK01 has a spherical-shaped tip with a fan-like open orifice on the side of the cannula, which prevents vessel damage, clogging of brain debris, and jet flow phenomenon. We compared the extent of rat cervical and abdominal arterial damage with the cannula, the amount of debris in the cannula, the force needed to cause jet flow, and cell viability. While the viability of cells passed through the cannulas was almost the same among cannulas (approximately 95%), the Pittsburg cannula caused cervical arterial injury and subsequent hemorrhage, as it required a significantly smaller force to penetrate the arterial wall. Moreover, the Pittsburg cannula, but not the Mizuho and MK01 cannulas, showed high frequency of brain debris in the needle tip (approximately 80%) after brain puncture. While jet flow of the injection liquid was observed even when using smaller forces in the Pittsburg and Mizuho cannulas, MK01 constantly showed low jet flow occurrence. Thus, MK01 seems to be safer than the previously reported cannulas, although further investigation is necessary to validate its safety for clinical use.

Human Recombinant Peptide Sponge Enables Novel, Less Invasive Cell Therapy for Ischemic Stroke.

Bone marrow stromal cell (BMSC) transplantation has the therapeutic potential for ischemic stroke. However, it is unclear which delivery routes would yield both safety and maximal therapeutic benefits. We assessed whether a novel recombinant peptide (RCP) sponge, that resembles human collagen, could act as a less invasive and beneficial scaffold in cell therapy for ischemic stroke. BMSCs from green fluorescent protein-transgenic rats were cultured and Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAo). A BMSC-RCP sponge construct was transplanted onto the ipsilateral intact neocortex 7 days after MCAo. A BMSC suspension or vehicle was transplanted into the ipsilateral striatum. Rat motor function was serially evaluated and histological analysis was performed 5 weeks after transplantation. The results showed that BMSCs could proliferate well in the RCP sponge and the BMSC-RCP sponge significantly promoted functional recovery, compared with the vehicle group. Histological analysis revealed that the RCP sponge provoked few inflammatory reactions in the host brain. Moreover, some BMSCs migrated to the peri-infarct area and differentiated into neurons in the BMSC-RCP sponge group. These findings suggest that the RCP sponge may be a promising candidate for animal protein-free scaffolds in cell therapy for ischemic stroke in humans.

[18F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia.

BACKGROUND: The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [18F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [18F]DPA-714 PET. The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [18F]DPA-714 PET was performed 3 and 10 days after MCAO. RESULTS: Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group. CONCLUSIONS: The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [18F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.

Research on advanced intervention using novel bone marrOW stem cell (RAINBOW): a study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke.

BACKGROUND: Stroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke. In this article, we introduce the protocol of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW). METHODS/DESIGN: RAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC product HUNS001-01 when administered to patients with acute ischemic stroke. Estimated enrollment is 6-10 patients suffering from moderate to severe neurological deficits. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset. BMSCs are cultured with allogeneic human platelet lysate (PL) as a substitute for fetal calf serum and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). HUNS001-01 is stereotactically administered around the area of infarction in the subacute phase. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, 18F-fuorodeoxyglucose positron emission tomography, and 123I-Iomazenil single-photon emission computed tomography will be performed for 1 year after the administration. DISCUSSION: This is a first-in-human trial for HUNS001-01 to the patients with acute ischemic stroke. We expect that intraparenchymal injection can be a more favorable method for cell delivery to the lesion and improvement of the motor function than intravenous infusion. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms. TRIAL REGISTRATION: The trial was registered at The University Hospital Medical Information Network on February 22, 2017 (UNIN ID: UMIN000026130 ). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.

Superior Microvascular Perfusion of Infused Liposome-Encapsulated Hemoglobin Prior to Reductions in Infarctions after Transient Focal Cerebral Ischemia.

BACKGROUND: The development of cerebral infarction after transient ischemia is attributed to postischemic delayed hypoperfusion in the microvascular region. In the present study, we assessed the microvascular perfusion capacity of infused liposome-encapsulated hemoglobin (LEH) in a therapeutic approach for transient middle cerebral artery occlusion (tMCAO). METHODS: Two-hour middle cerebral artery occlusion rats were immediately subjected to intra-arterial infusion of LEH (LEH group) or saline (vehicle group) or no treatment (control group), and then to recanalization. Neurological findings, infarct and edema progression, microvascular endothelial dysfunction, and inflammatory reactions were compared between the 3 groups after 24 hours of reperfusion. Microvascular perfusion in the early phase of reperfusion was evaluated by hemoglobin immunohistochemistry and transmission electron microscopy. RESULTS: The LEH group achieved significantly better results in all items evaluated than the other groups. Hemoglobin immunohistochemistry revealed that the number of hemoglobin-positive microvessels was significantly greater in the LEH group than in the other groups (P < .01), with microvascular perfusion being more likely in narrow microvessels (≤5 µm in diameter). An electron microscopic examination revealed that microvessels in the control group were compressed and narrowed by swollen astrocyte end-feet, whereas those in the LEH group had a less deformed appearance and contained LEH particles and erythrocytes. CONCLUSION: The results of the present study demonstrated that the infusion of LEH reduced infarctions after tMCAO with more hemoglobin-positive and less deformed microvessels at the early phase of reperfusion, suggesting that the superiority of the microvascular perfusion of LEH mediates its neuroprotective effects.

Surgical Outcome of Cerebral Aneurysm Clipping Treated with Immunosuppressants: Report of 11 Cases and Review of the Literature.

There are no reports on the outcomes of clippings in patients who receive immunosuppressants, for example, due to connective tissue diseases or following organ transplantation. We thoroughly reviewed these cases focusing on the perioperative management phase. The study included 11 patients with intracranial aneurysms who were taking immunosuppressants; between 2007 and 2014. We performed 12 clipping surgeries. Their clinical records were reviewed for age and gender, aneurysms' location and size, perioperative management of the immunosuppressive drugs, and surgical complications. The study included nine females and two males, aged between 52 and 71 years (mean 60.1 ± 8.5 years). The clinical presentation in five cases was subarachnoid hemorrhage (SAH); the aneurysm was incidentally diagnosed in six patients (7 aneurysms). The reasons for taking immunosuppressants were autoimmune disorder in nine patients and liver transplantation in two patients. Daily intake of oral immunosuppressants for the patients with liver transplantation was discontinued for 2-4 days, and no infectious complications were evidenced. The weekly course of immunosuppressive drugs for the patients with autoimmune disorder was continued in eight of nine patients. Caution must be exercised when considering the suitability of clipping for patients taking immunosuppressants, but surgery outcomes are generally favorable; when operative treatment is required, we believe it to be comparatively safe, if the perioperative management is conducted in close collaboration with the relevant departments.

Application of cell sheet technology to bone marrow stromal cell transplantation for rat brain infarct.

Bone marrow stromal cells (BMSC) transplantation enhances functional recovery after cerebral infarct, but the optimal delivery route is undetermined. This study was aimed to assess whether a novel cell-sheet technology non-invasively serves therapeutic benefits to ischemic stroke. First, the monolayered cell sheet was engineered by culturing rat BMSCs on a temperature-responsive dish. The cell sheet was analysed histologically and then transplanted onto the ipsilateral neocortex of rats subjected to permanent middle cerebral artery occlusion at 7 days after the insult. Their behaviours and histology were compared with those in the animals treated with direct injection of BMSCs or vehicle over 4 weeks post-transplantation. The cell sheet was 27.9 ± 8.0 µm thick and was composed of 9.8 ± 2.4 × 105 cells. Cell sheet transplantation significantly improved motor function when compared with the vehicle-injected animals. Histological analysis revealed that the BMSCs were densely distributed to the neocortex adjacent to the cerebral infarct and expressed neuronal phenotype in the cell sheet-transplanted animals. These findings were almost equal to those for the animals treated with direct BMSC injection. The attachment of the BMSC sheet to the brain surface did not induce reactive astrocytes in the adjacent neocortex, although direct injection of BMSCs profoundly induced reactive astrocytes around the injection site. These findings suggest that the BMSCs in cell sheets preserve their biological capacity of migration and neural differentiation. Cell-sheet technology may enhance functional recovery after ischaemic stroke, using a less invasive method. Copyright © 2014 John Wiley & Sons, Ltd.

Topographic changes in cerebral blood flow and reduced white matter integrity in the first 2 weeks following revascularization surgery in adult moyamoya disease.

OBJECTIVE After revascularization surgery, hyperperfusion and ischemia are associated with morbidity and mortality in adult moyamoya disease (MMD). However, structural changes within the brain following revascularization surgery, especially in the early postsurgical period, have not been thoroughly studied. Such knowledge may enable improved monitoring and clinical management of hyperperfusion and ischemia in MMD. Thus, the objective of this study was to investigate the topographic and temporal profiles of cerebral perfusion and related white matter microstructural changes following revascularization surgery in adult MMD. METHODS The authors analyzed 20 consecutive surgeries performed in 17 adults. Diffusion imaging in parallel with serial measurements of regional cerebral blood flow (rCBF) using SPECT was performed. Both voxel-based and region-of-interest analyses were performed, comparing neuroimaging parameters of postoperative hemispheres with those of preoperative hemispheres at 4 different time points within 2 weeks after surgery. RESULTS Voxel-based analysis showed a distinct topographic pattern of cerebral perfusion, characterized by increased rCBF in the basal ganglia for the first several days and gradually increased rCBF in the lateral prefrontal cortex over 1 week (p < 0.001). Decreased rCBF was also observed in the lateral prefrontal cortex, occipital lobe, and cerebellum contralateral to the surgical hemisphere (p < 0.001). Reduced fractional anisotropy (FA) and axial diffusivity (AD), as well as increased radial diffusivity (RD), were demonstrated in both the anterior and posterior limbs of the internal capsule (p < 0.001). Diffusion parameters demonstrated the greatest changes in both FA and RD on Days 1-2 and in AD on Days 3-6; FA, RD, and AD recovered to preoperative levels on Day 14. Patients with transient neurological deteriorations (TNDs), as compared with those without, demonstrated greater increases in rCBF in both the lateral prefrontal cortex and striatum as well as smaller FAs in the posterior limb of the internal capsule (p < 0.05). CONCLUSIONS The excessively increased rCBF and the recovery process were heterogeneous across brain regions, demonstrating a distinct topographic pattern during the initial 2 weeks following revascularization surgery in MMD. Temporary impairments in the deep white matter tract and immediate postoperative ischemia were also identified. The study results characterized postoperative brain perfusion as well as the impact of revascularization surgery on the brain microstructure. Notably, rCBF and white matter changes correlated to TNDs, suggesting that these changes represent potential neuroimaging markers for tracking tissue structural changes associated with hyperperfusion during the acute postoperative period following revascularization surgery for MMD.

Feasibility and Efficiency of Human Bone Marrow Stromal Cell Culture with Allogeneic Platelet Lysate-Supplementation for Cell Therapy against Stroke.

Currently, there is increasing interest in human bone marrow stromal cells (hBMSCs) as regeneration therapy against cerebral stroke. The aim of the present study was to evaluate the feasibility and validity of hBMSC cultures with allogeneic platelet lysates (PLs). Platelet concentrates (PC) were harvested from healthy volunteers and made into single donor-derived PL (sPL). The PL mixtures (mPL) were made from three different sPL. Some growth factors and platelet cell surface antigens were detected by enzyme-linked immunosorbent assay (ELISA). The hBMSCs cultured with 10% PL were analyzed for their proliferative potential, surface markers, and karyotypes. The cells were incubated with superparamagnetic iron oxide (SPIO) agents and injected into a pig brain. MRI and histological analysis were performed. Consequently, nine lots of sPL and three mPL were prepared. ELISA analysis showed that PL contained adequate growth factors and a particle of platelet surface antigens. Cell proliferation capacity of PLs was equivalent to or higher than that of fetal calf serum (FCS). No contradiction in cell surface markers and no chromosomal aberrations were found. The MRI detected the distribution of SPIO-labeled hBMSCs in the pig brain. In summary, the hBMSCs cultured with allogeneic PL are suitable for cell therapy against stroke.

Cellular Functions and Gene and Protein Expression Profiles in Endothelial Cells Derived from Moyamoya Disease-Specific iPS Cells.

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a slow, progressive steno-occlusive disease, arising in the terminal portions of the cerebral internal carotid artery. However, the functions and characteristics of the endothelial cells (ECs) in MMD are unknown. We analyzed these features using induced pluripotent stem cell (iPSC)-derived ECs. METHODS: iPSC lines were established from the peripheral blood of three patients with MMD carrying the variant RNF213 R4810K, and three healthy persons used as controls. After the endothelial differentiation of iPSCs, CD31+CD144+ cells were purified as ECs using a cell sorter. We analyzed their proliferation, angiogenesis, and responses to some angiogenic factors, namely VEGF, bFGF, TGF-ß, and BMP4. The ECs were also analyzed using DNA microarray and proteomics to perform comprehensive gene and protein expression analysis. RESULTS: Angiogenesis was significantly impaired in MMD regardless of the presence of any angiogenic factor. On the contrary, endothelial proliferation was not significant between control- and MMD-derived cells. Regarding DNA microarray, pathway analysis illustrated that extracellular matrix (ECM) receptor-related genes, including integrin ß3, were significantly downregulated in MMD. Proteomic analysis revealed that cytoskeleton-related proteins were downregulated and splicing regulation-related proteins were upregulated in MMD. CONCLUSIONS: Downregulation of ECM receptor-related genes may be associated with impaired angiogenic activity in ECs derived from iPSCs from patients with MMD. Upregulation of splicing regulation-related proteins implied differences in splicing patterns between control and MMD ECs.

Transarterial regional hypothermia provides robust neuroprotection in a rat model of permanent middle cerebral artery occlusion with transient collateral hypoperfusion.

The robust neuroprotective effects of transarterial regional hypothermia have been demonstrated in the typical transient middle cerebral artery occlusion (tMCAO) model, but have not yet been tested in other ischemic stroke models, even though clinical ischemic conditions are diverse. In order to clarify these effects in a different ischemic stroke model, we employed a rat model of permanent MCAO (pMCAO) with transient collateral hypoperfusion (tCHP), which was achieved by direct MCA ligation through craniotomy and 1-h bilateral common carotid artery occlusion at the beginning of pMCAO. The infusion of 20ml/kg of 4°C cold saline (CS) or 37°C warm saline (WS) into the ipsilateral internal carotid artery (ICA) was performed for 15min in intra- or post-tCHP. Neurological scores, infarct/edema volumes, and neuronal apoptosis and reactive gliosis were compared between the CS and WS groups and a non-infusion control group after 48h of reperfusion. Although brain temperatures were only reduced by 2-3°C for 15min, the CS group had significantly better neurological scores, smaller infarct/edema volumes, and less penumbral neuronal apoptosis and reactive gliosis than the control and WS groups. The post-tCHP CS group exhibited prominent neuroprotective effects, even though infarct volumes and neuronal apoptosis were reduced less than those in the intra-tCHP CS group. In conclusion, we demonstrated the neuroprotective effects of transarterial regional hypothermia in an ischemic model of pMCAO with tCHP. Even though MCAO is persistent, cold infusion via the ICA is neuroprotective for the penumbra, suggesting the wider therapeutic application of this therapy.

Increased Blood Viscosity in Ischemic Stroke Patients with Small Artery Occlusion Measured by an Electromagnetic Spinning Sphere Viscometer.

BACKGROUND AND PURPOSE: High blood viscosity causes blood stagnation and subsequent pathological thrombotic events, resulting in the development of ischemic stroke. We hypothesize that the contribution of blood viscosity may differ among ischemic stroke subtypes based on specific pathological conditions. We tried to verify this hypothesis by measuring blood viscosity in acute ischemic stroke patients using a newly developed electromagnetic spinning sphere (EMS) viscometer. METHODS: Measurements in acute ischemic stroke patients were performed 4 times during admission and data were compared with those obtained from 100 healthy outpatient volunteers. RESULTS: We enrolled 92 patients (cardioembolism: 25, large artery atherosclerosis: 42, and small artery occlusion [SAO]: 25) in this study. Comparisons of blood viscosity between the ischemic stroke subgroups and control group revealed that blood viscosity at the date of admission was significantly higher in the SAO group (5.37 ± 1.11 mPa⋅s) than in the control group (4.66 ± .72 mPa⋅s) (P < .01). Among all subtype groups showing a reduction in blood viscosity after 2 weeks, the SAO group showed the highest and most significant reduction, indicating that SAO patients had the most concentrated blood at the onset. CONCLUSIONS: Blood viscosity was significantly increased in the SAO group at the date of admission, which indicated the contribution of dehydration to the onset of ischemic stroke. The importance of dehydration needs to be emphasized more in the pathogenesis of SAO. The clinical application of the EMS viscometer is promising for understanding and differentiating the pathogenesis of ischemic stroke.

Cell Therapy for Stroke: Review of Previous Clinical Trials and Introduction of Our New Trials.

Stroke is still a leading cause of death and disability, and despite intensive research, few treatment options exist. A recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for the treatment of stroke have been reported, certain problems still remain unsolved. We investigated the use of autologous bone marrow stromal cell (BMSC) transplantation for the treatment of stroke, to develop it as the next-generation cell therapy. In this study, we introduce the preparation of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrow stem cell (RAINBOW) study. The trial will start in 2016, and we hope that it will not only be helpful for treating patients but also for clarifying the therapeutic mechanisms. Moreover, we review stem cell therapeutics as an emerging paradigm in stroke (STEPS) and the guidelines for the development of cell therapy for stroke in the United States as well as introduce the development of new guidelines in Japan. These guidelines are expected to encourage the development of cell therapy for stroke management.