Intra-Arterial Bone Marrow Mononuclear Cells in Ischemic Stroke A Pilot Clinical Trial

Department of Neurology, Hospital Universitario Virgen del Rocío, Seville, Spain.
Stroke (Impact Factor: 5.72). 07/2012; 43(8):2242-4. DOI: 10.1161/STROKEAHA.112.659409
Source: PubMed


Bone marrow mononuclear cell (BM-MNC) intra-arterial transplantation improves recovery in experimental models of ischemic stroke. We aimed to assess the safety, feasibility, and biological effects of autologous BM-MNC transplantation in patients with stroke.
A single-blind (outcomes assessor) controlled Phase I/II trial was conducted in patients with middle cerebral artery stroke. Autologous BM-MNCs were injected intra-arterially between 5 and 9 days after stroke. Follow-up was done for up to 6 months and blood samples were collected for biological markers. The primary outcome was safety and feasibility of the procedure. The secondary outcome was improvement in neurological function.
Ten cases (BM-MNC-treated) and 10 control subjects (BM-MNC-nontreated) were consecutively included. Mean National Institutes of Health Stroke Scale before the procedure was 15.6. Mean BM-MNCs injected were 1.59×10(8). There was no death, stroke recurrence, or tumor formation during follow-up, although 2 cases had an isolate partial seizure at 3 months. After transplantation, higher plasma levels of beta nerve growth factor (β-nerve growth factor) were found compared with control subjects (P=0.02). There were no significant differences in neurological function at 180 days. A trend to positive correlation between number of CD34+ cells injected and Barthel Index was found (r=0.56, P=0.09).
Intra-arterial BM-MNC transplantation in subacute ischemic stroke is feasible and seems to be safe. Larger randomized trials are needed to confirm the safety and elucidate the efficacy of BM-MNC transplantation. CLINICAL TRIAL REGISTRATION URL: Unique identifier: NCT00761982.

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Available from: Aurelio Cayuela, Jan 29, 2015
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    • "A Phase I/II clinical trial has been initiated by researchers at University of California San Diego with other collaborators in which allogenic BMSCs are being evaluated to treat ischemic stroke (NCT01297413). A Phase I/II clinical trial in Spain revealed feasibility, safety, and improved neurological outcome in stroke patients transfused intra-arterially at 5 and 9 days after stroke with autologous bone marrow mononuclear cells (Moniche et al., 2012). During the follow up period of 6 months, no adverse effects, deaths, tumor formation, or stroke recurrence were reported, except for two isolated partial seizures at 3 months post treatment. "
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    ABSTRACT: Ischemic stroke is responsible for many deaths and long-term disability world wide. Development of effective therapy has been the target of intense research. Accumulating preclinical literature has shown that substantial functional improvement after stroke can be achieved using subacutely administered cell-based and pharmacological therapies. This review will discuss some of the latest findings on bone marrow-derived mesenchymal stem cells (BMSCs), human umbilical cord blood cells, and off-label use of some pharmacological agents, to promote recovery processes in the sub-acute and chronic phases following stroke. This review paper also focuses on molecular mechanisms underlying the cell-based and pharmacological restorative processes, which enhance angiogenesis, arteriogenesis, neurogenesis, and white matter remodeling following cerebral ischemia as well as an analysis of the interaction/coupling among these restorative events. In addition, the role of microRNAs mediating the intercellular communication between exogenously administered cells and parenchymal cells, and their effects on the regulation of angiogenesis and neuronal progenitor cell proliferation and differentiation, and brain plasticity after stroke are described.
    Frontiers in Human Neuroscience 06/2014; 8:382. DOI:10.3389/fnhum.2014.00382 · 3.63 Impact Factor
    • "Several studies showed that grafting of BM MSCs in the peripheral circulation improved functional neurological outcome and reduced infarct volume (Honmou et al., 2012). Most of these studies used BM MSCs but feasibility and safety in clinical trials was also shown for the bone marrow mononuclear cells (BM MNCs) (Hermann and Chopp, 2012; Moniche et al., 2012). A conclusive result on optimal timing and dosing is, however, still missing. "
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    ABSTRACT: Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (106 cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the “islet of regeneration.” However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.
    Frontiers in aging series 06/2014; 6. DOI:10.3389/fnagi.2014.00130
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    • "In fact, phase I and II clinical trials using intracerebral transplantation of an immature neuron cell line [22], or intravenous transplantation of autologous mesenchymal stem cells [23] have already been conducted in stroke patients. Other studies have already confirmed that the intra-arterial administration of autologous bone marrow-MNCs days or months after stroke was also safe and feasible [24], [25]. However, to date, no study has proven the efficacy of these treatments on motor function or functional dependency in stroke patients. "
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    ABSTRACT: Cell therapy with endothelial progenitor cells (EPCs) has emerged as a promising strategy to regenerate the brain after stroke. Here, we aimed to investigate if treatment with EPCs or their secreted factors could potentiate angiogenesis and neurogenesis after permanent focal cerebral ischemia in a mouse model of ischemic stroke. BALB/C male mice were subjected to distal occlusion of the middle cerebral artery, and EPCs, cell-free conditioned media (CM) obtained from EPCs, or vehicle media were administered one day after ischemia. Magnetic resonance imaging (MRI) was performed at baseline to confirm that the lesions were similar between groups. Immunohistochemical and histological evaluation of the brain was performed to evaluate angio-neurogenesis and neurological outcome at two weeks. CM contained growth factors, such as VEGF, FGF-b and PDGF-bb. A significant increase in capillary density was noted in the peri-infarct areas of EPC- and CM-treated animals. Bielschowsky's staining revealed a significant increase in axonal rewiring in EPC-treated animals compared with shams, but not in CM-treated mice, in close proximity with DCX-positive migrating neuroblasts. At the functional level, post-ischemia forelimb strength was significantly improved in animals receiving EPCs or CM, but not in those receiving vehicle media. In conclusion, we demonstrate for the first time that the administration of EPC-secreted factors could become a safe and effective cell-free option to be considered in future therapeutic strategies for stroke.
    PLoS ONE 09/2013; 8(9):e73244. DOI:10.1371/journal.pone.0073244 · 3.23 Impact Factor
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