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. This study found that the implantation of CTX0E03 human neural stem cells in rats after MCAO stroke promoted significant behavioral recovery depending on cell dose. The authors propose a paracrine trophic mechanism, which is triggered early after CTX0E03 cell implantation, and which in turn targets restoration of neurogenesis in the SVZ of MCAO rats.

BackgroundHuman neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute—chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study.MethodsWe undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2–13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation.FindingsTwenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures.InterpretationAdministration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials.FundingReNeuron, Innovate UK (application no 32074-222145).Trial registration numberEudraCT Number: 2012-003482-18

Penumbra tissue becomes highly angiogenic after ischaemic stroke in man, and the re-establishment of a functional vasculature might be beneficial to patients. Unilateral ischaemia was induced in male Sprague-Dawley rats by permanent occlusion of the distal left middle cerebral artery (MCAO). Animals with stroke were kept alive for 1, 7, 14, 21 or 28 days after which time they were terminally anaesthetized. Vascular casts of infarcted areas, analyzed by scanning electron microscopy demonstrated that radially arranged neocortical arterioles and venules lost their regular patterns within one day of occlusion, and soon afterwards started to form a very dense network of anastomosing microvessels. At 1 week, vascular budding was visible at many sites. The smallest microvessels (4-10 microm) formed connections with the surrounding proliferating vessels similar to those in the normal brain. Survival of microvascular endothelial cells (ECs) was studied by double labeling of tissue sections using immunohistochemistry and antibodies to caspase-3, and TUNEL staining for apoptotic cells. ECs demonstrated intensive staining for caspase-3 and also staining by TUNEL, particularly near the infarct border, 14 days post-MCAO. These data support the hypothesis that growing blood vessels in ischaemic tissue form new connections, the pattern of which is similar to that in normal rat brain, but different to those formed in growing tumours. This normal growth pattern might be essential in future therapies involving induction of vascularization and neuroprotection to enhance long-term survival of the penumbra.

 Strong patent portfolio  Proven clinical efficacy  Multiple cell types included Effective therapy for stroke Rats were subjected to middle cerebral artery occlusion. Top-Cell therapy treated rat. Bottom-Saline treated rat