Targets for neural repair therapies after stroke.
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ABSTRACT:
SUBMITTER: Carmichael ST
PROVIDER: S-EPMC2955885 | biostudies-other | 2010 Oct
REPOSITORIES: biostudies-other
Publications
Studies of neural repair after stroke have developed from a relatively small number of laboratories doing highly creative discovery science to a field in which reproducible evidence supports distinct pathways, processes, and molecules that promote recovery. This review focuses on some emerging targets for neural repair or recovery in stroke and on their limitations. ...[more]
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Project description:This article reviews the progress that has been made in the development of cell therapies for the repair of nervous system damage caused by strokes, since the first report on the use of cell transplants in animal models of ischemic brain injury in 1988. At that time neural progenitor cells derived from fetal brain tissue were used as sources of cells to replace specific subsets of neuronal cells that were lost in various regions of the brain following experimentally induced strokes. Since 1988, cells from other sources, such as embryonic stem cells and inducible pluripotent stem cells, have been investigated for their ability to replace neuronal cells and repair the damaged brain. Most recently, mesenchymal stem cells and cord blood stem cells have been studied for the ability to modulate the immune system and ameliorate the neuropathology and neurological deficits associated with experimental stroke. The preclinical investigation of different cell therapy approaches for treating stroke during the past three decades has now led to many ongoing clinical trials, with the clinical evaluation of stem cell therapies for stroke now involving global participants.
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Project description:Stroke remains a major cause of human disability worldwide. In parallel with advances in acute stroke interventions, new therapies are under development that target restorative processes. Such therapies have a treatment time window measured in days, weeks, or longer and so have the advantage that they may be accessible by a majority of patients. Several categories of restorative therapy have been studied and are reviewed herein, including drugs, growth factors, monoclonal antibodies, activity-related therapies including telerehabilitation, and a host of devices such as those related to brain stimulation or robotics. Many patients with stroke do not receive acute stroke therapies or receive them and do not derive benefit, often surviving for years thereafter. Therapies based on neural repair hold the promise of providing additional treatment options to a majority of patients with stroke.
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Project description:Stem cell-based therapies for the treatment of stroke have received considerable attention. Two broad approaches to stem cell-based therapies have been taken: the transplantation of exogenous stem cells, and the activation of endogenous neural stem and progenitor cells (together termed neural precursors). Studies examining the transplantation of exogenous cells have demonstrated that neural stem and progenitor cells lead to the most clinically promising results. Endogenous activation of neural precursors has also been explored based on the fact that resident precursor cells have the inherent capacity to proliferate, migrate and differentiate into mature neurons in the uninjured adult brain. Studies have revealed that these neural precursor cell behaviours can be activated following stroke, whereby neural precursors will expand in number, migrate to the infarct site and differentiate into neurons. However, this innate response is insufficient to lead to functional recovery, making it necessary to enhance the activation of endogenous precursors to promote tissue repair and functional recovery. Herein we will discuss the current state of the stem cell-based approaches with a focus on endogenous repair to treat the stroke injured brain.
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Project description:Stem cells have been touted as a potential source of cells for repair in regenerative medicine. When transplanted into the central nervous system, stem cells have been shown to differentiate into neurons and glia. Recent studies, however, have also revealed neuroprotective properties of stem cells. These studies suggest that various types of stem cells are able to protect against the loss of neurons in conditions of ischemic brain injury. In this article, we discuss the use of stem cells for ischemic stroke and the parameters under which neuroprotection can occur in the translation of stem cell therapy to the clinical setting.
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Project description:Stem cell therapy ameliorates motor deficits in experimental stroke model. Multimodal molecular imaging enables real-time longitudinal monitoring of infarct location, size, and transplant survival. In the present study, we used magnetic resonance imaging (MRI) and positron emission tomography (PET) to track the infarct evolution,tissue repair, and the fate of grafted cells. We genetically engineered embryonic stem cell-derived neural stem cells (NSCs) with a triple fusion reporter gene to express monomeric red fluorescence protein and herpes simplex virus-truncated thymidine kinase for multimodal molecular imaging and SPIO labeled for MRI. The infarct size as well as fate and function of grafted cells were tracked in real time for 3 months using MRI and PET. We report that grafted NSCs reduced the infarct size in animals with less than 0.1 cm(3) initial infarct in a dose-dependent manner, while larger stroke was not amenable to such beneficial effects. PET imaging revealed increased metabolic activity in grafted animals and visualized functioning grafted cells in vivo. Immunohistopathological analysis demonstrated that, after a 3-month survival period, grafted NSCs dispersed in the stroke-lesioned parenchyma and differentiated into neurons, astrocytes, and oligodendrocytes. Longitudinal multimodal imaging provides insights into time course dose-dependent interactions between NSC grafts and structural changes in infarcted tissue.
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Project description:Current experimental stroke research has evolved to focus on detailed understanding of the brain's self-protective and restorative mechanisms, and harness this knowledge for development of new therapies. In this context, the role of peptidases and neuropeptides is of growing interest. In this focused review, peptidase neurolysin (Nln) and its extracellular peptide substrates are briefly discussed in relation to pathophysiology of ischemic stroke. Upregulation of Nln following stroke is viewed as a compensatory cerebroprotective mechanism in the acute phase of stroke, because the main neuropeptides inactivated by Nln are neuro/cerebrotoxic (bradykinin, substance P, neurotensin, angiotensin II, hemopressin), whereas the peptides generated by Nln are neuro/cerebroprotective (angiotensin-(1-7), Leu-/Met-enkephalins). This notion is confirmed by experimental studies documenting aggravation of stroke outcomes in mice after inhibition of Nln following stroke, and dramatic improvement of stroke outcomes in mice overexpressing Nln in the brain. The role of Nln in the (sub)chronic phase of stroke is less clear and it is likely, that this peptidase does not have a major role in neural repair mechanisms. This is because, the substrates of Nln are less uniform in modulating neurorestorative mechanisms in one direction, some appearing to have neural repair enhancing/stimulating potential, whereas others doing the opposite. Future studies focusing on the role of Nln in pathophysiology of stroke should determine its potential as a cerebroprotective target for stroke therapy, because its unique ability to modulate multiple neuropeptide systems critically involved in brain injury mechanisms is likely advantageous over modulation of one pathogenic pathway for stroke pharmacotherapy.
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Project description:Hemorrhagic stroke is a life-threatening disease characterized by a sudden rupture of cerebral blood vessels, and it is widely believed that neural cell death occurs after exposure to blood metabolites or subsequently damaged cells. Neural stem cells (NSCs), which maintain neurogenesis and are found in subgranular zone and subventricular zone, are thought to be an endogenous neuroprotective mechanism for these brain injuries. However, due to the complexity of NSCs and their microenvironment, current strategies cannot satisfactorily enhance functional recovery after hemorrhagic stroke. It is well known that transcriptional and genomic pathways play important roles in ensuring the normal functions of NSCs, including proliferation, migration, differentiation, and neural reconnection. Recently, emerging evidence from the use of new technologies such as next-generation sequencing and transcriptome profiling has provided insight into our understanding of genomic function and regulation of NSCs. In the present article, we summarize and present the current data on the control of NSCs at both the transcriptional and genomic levels. Using bioinformatics methods, we sought to predict novel therapeutic targets of endogenous neurogenesis and exogenous NSC transplantation for functional recovery after hemorrhagic stroke, which could also advance our understanding of its pathophysiology.
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Project description:Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce neural repair and recovery. We also provide evidence that CXCL12 from peri-infarct vasculature signals to CXCR4-expressing cells arising from the SVZ to direct their ectopic migration. These results support a model in which vasculature surrounding the site of injury attracts cells from the SVZ, and these cells subsequently provide trophic support that drives neural repair and recovery.
| S-EPMC10564905 | biostudies-literature
Project description:The repair of white matter damage is of paramount importance for functional recovery after brain injuries.We report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 days after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific PPARγ knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the CNS, which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.
2019-08-31 | GSE131774 | GEO
Project description:BackgroundAbout one in five strokes occur during sleep (wake-up stroke). People with wake-up strokes have traditionally been considered ineligible for thrombolytic treatment because the time of stroke onset is unknown. However, some studies suggest that these people may benefit from recanalisation therapies.ObjectivesTo assess the effects of intravenous thrombolysis and other recanalisation therapies versus control in people with acute ischaemic stroke presenting on awakening.Search methodsWe searched the Cochrane Stroke Group Trials Register (last search: 9 January 2018). In addition, we searched the following electronic databases in December 2017: Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 11) in the Cochrane Library, MEDLINE, Embase, US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the ISRCTN registry, and Stroke Trials Registry. We also screened references lists of relevant trials, contacted trialists, undertook forward tracking of relevant references, and contacted manufacturers of relevant devices and equipment.Selection criteriaRandomised controlled trials of intravenous thrombolytic drugs or intra-arterial therapies in people with acute ischaemic stroke presenting upon awakening.Data collection and analysisTwo review authors applied the inclusion criteria, extracted data, and assessed trial quality and risk of bias using the GRADE approach. We obtained both published and unpublished data.Main resultsWe included one pilot trial with nine participants. The trial was a feasibility trial that included participants with an unknown onset of stroke and signs on perfusion computed tomography of ischaemic tissue at risk of infarction, who were randomised to alteplase (0.9 mg/kg) or placebo. One trial was prematurely terminated due to signs of efficacy of the intervention arm; we did not include this trial because we were not able to obtain data for the portion of the participants with wake-up stroke after requesting this information from the trial authors. We identified six ongoing trials.Authors' conclusionsThere is insufficient evidence from randomised controlled trials for recommendations concerning recanalisation therapies for wake-up stroke. Results from ongoing trials will hopefully establish the efficacy and safety of such therapies.
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