Clinical-Grade Human Neural Stem Cells Promote Reparative Neovascularization in Mouse Models of Hindlimb Ischemia (original) (raw)
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Stem Cells and Development, 2017
Chronic disability after stroke represents a major unmet neurologic need. ReNeuron's development of a human neural stem cell (hNSC) therapy for chronic disability after stroke is progressing through early clinical studies. A Phase I trial has recently been published, showing no safety concerns and some promising signs of efficacy. A single-arm Phase II multicenter trial in patients with stable upper-limb paresis has recently completed recruitment. The hNSCs administrated are from a manufactured, conditionally immortalized hNSC line (ReNeuron's CTX0E03 or CTX), generated with c-mycER TAM technology. This technology has enabled CTX to be manufactured at large scale under cGMP conditions, ensuring sufficient supply to meets the demands of research, clinical development, and, eventually, the market. CTX has key pro-angiogenic, pro-neurogenic, and immunomodulatory characteristics that are mechanistically important in functional recovery poststroke. This review covers the progress of CTX cell therapy from its laboratory origins to the clinic, concluding with a look into the late stage clinical future.
Opportunities and Challenges: Stem Cell-Based Therapy for the Treatment of Ischemic Stroke
CNS Neuroscience & Therapeutics, 2015
Stem cell-based therapy for ischemic stroke has been widely explored in animal models and provides strong evidence of benefits. In this review, we summarize the types of stem cells, various delivery routes, and tracking tools for stem cell therapy of ischemic stroke. MSCs, EPCs, and NSCs are the most explored cell types for ischemic stroke treatment. Although the mechanisms of stem cell-based therapies are not fully understood, the most possible functions of the transplanted cells are releasing growth factors and regulating microenvironment through paracrine mechanism. Clinical application of stem cell-based therapy is still in its infancy. The next decade of stem cell research in stroke field needs to focus on combining different stem cells and different imaging modalities to fully explore the potential of this therapeutic avenue: from bench to bedside and vice versa.
Stem cell-based therapies for ischemic stroke
BioMed research international, 2014
In recent years, stem cell-based approaches have attracted more attention from scientists and clinicians due to their possible therapeutical effect on stroke. Animal studies have demonstrated that the beneficial effects of stem cells including embryonic stem cells (ESCs), inducible pluripotent stem cells (iPSCs), neural stem cells (NSCs), and mesenchymal stem cell (MSCs) might be due to cell replacement, neuroprotection, endogenous neurogenesis, angiogenesis, and modulation on inflammation and immune response. Although several clinical studies have shown the high efficiency and safety of stem cell in stroke management, mainly MSCs, some issues regarding to cell homing, survival, tracking, safety, and optimal cell transplantation protocol, such as cell dose and time window, should be addressed. Undoubtably, stem cell-based gene therapy represents a novel potential therapeutic strategy for stroke in future.
Neural Stem Cell-Based Therapy for Ischemic Stroke
Translational Stroke Research, 2011
Stem cell-based approaches for the treatment of stroke have been the subject of intensive research over the past decade. Based on accumulated experimental evidence, stem cell-based therapy is a very promising prospect for the development of a novel treatment to restore stroke-damaged brain and impaired neurological function. Studies performed on experimental animal models of stroke employed a variety of stem cell types from diverse sources and have demonstrated their ability to replace lost neurons and functionally integrate into the brain, modulate inflammation, and stimulate angiogenesis and neurogenesis from an endogenous stem cell pool, most likely through trophic actions. A few clinical trials in stroke patients using stem cell transplantation have been completed or are ongoing but the results have not yet proven the effectiveness of the stem cell-based approaches. A joint effort of stroke researchers and clinicians is needed to further optimize treatment protocols using safe and reproducible stem cell sources tested in relevant animal models of stroke and showing substantial neurological recovery of strokeimpaired function.
In vivo and in vitro characterization of the angiogenic effect of CTX0E03 human neural stem cells
Cell Transplantation, 2012
CTX0E03 is a human neural stem cell line previously reported to reduce sensory motor deficits in a middle cerebral artery occlusion (MCAo) model of stroke. The objective of this study was to investigate if CTX0E03 treatment promotes angiogenesis. As stroke leads to damage of the vasculature in the brain, angiogenesis may contribute to the functional recovery. To test this hypothesis, the angiogenic activity of CTX0E03 was assessed both in vitro and in vivo. In vitro, CTX0E03 expression of trophic and proangiogenic factors was determined by real-time RT-PCR, Western blot, and ELISA, and its angiogenic activity was investigated in well-established angiogenesis assays. In vivo, angiogenesis was investigated in naive mice and MCAo rat brain and was evaluated by immunohistochemistry (IHC) using Von Willebrand factor (VWF), a marker of blood vessel formation, and BrdU/CD31 double labeling in naive mice only. In vitro results showed that CTX0E03-conditioned medium and coculture significant...
Cell based therapies for ischemic stroke: From basic science to bedside
Progress in Neurobiology, 2014
Cell therapy is emerging as a viable therapy to restore neurological function after stroke. Many types of stem/progenitor cells from different sources have been explored for their feasibility and efficacy for the treatment of stroke. Transplanted cells not only have the potential to replace the lost circuitry, but also produce growth and trophic factors, or stimulate the release of such factors from host brain cells, thereby enhancing endogenous brain repair processes. Although stem/ progenitor cells have shown a promising role in ischemic stroke in experimental studies as well as initial clinical pilot studies, cellular therapy is still at an early stage in humans. Many critical issues need to be addressed including the therapeutic time window, cell type selection, delivery route, and in vivo monitoring of their migration pattern. This review attempts to provide a comprehensive synopsis of preclinical evidence and clinical experience of various donor cell types, their restorative mechanisms, delivery routes, imaging strategies, future prospects and challenges for translating cell therapies as a neurorestorative regimen in clinical applications.
Stem Cells: Implications in Experimental Ischaemic Stroke Therapy
Stem Cell Reviews, 2008
Ischaemic stroke is a syndrome characterized by rapid onset of neurological injury due to interruption of blood flow to the brain. Widespread neuronal damage throughout the CNS has been shown to cause marked and multifarious functional impairments in the ischaemic brain. Recent advances as enumerated above have propelled acute ischaemic stroke management into a therapeutic era. However, once the damage from a stroke event has maximized, little can be done to recover premorbid function. Experimental animal data suggests that stem cell therapy may be an effective alternate to the conventional disease management strategies of ischaemic stroke. Therefore, the present review focuses on detailing the scope of stem cell therapy in the treatment of ischaemic stroke.
2018
Worldwide, stroke is the second single most common cause of death and is a major cause of permanent disability. Moreover, the highest incidence of these pathologies is observed in the elderly, increasing the socioeconomic burden in an aging population. Current available therapies lead to insufficient functional improvement or are not applicable to all patients. This stresses the urgent need for alternative strategies in treating stroke patients, for example cell-based therapies. These cells showed great preclinical potential although the underlying therapeutic mechanisms, preferential route of administration and most suitable stem cell-subtype are unknown. Mechanisms of action include neuroprotection, cell replacement, neurogenesis, immunomodulation and the promotion of both neuroplasticity and angiogenesis in damaged central nervous system regions. Moreover, stem cells have been genetically engineered to enhance their beneficial effects after transplantation. Additionally, noninvas...
Frontiers in cellular neuroscience, 2014
Ischemic stroke remains a heavy burden for industrialized countries. The only causal therapy is the recanalization of occluded vessels via thrombolysis, which due to a narrow time window still can be offered only to a minority of patients. Since the majority of patients continues to exhibit neurological deficits even following successful thrombolysis, restorative therapies are urgently needed that promote brain remodeling and repair once stroke injury has occurred. Due to their unique properties of action, stem cell-based strategies gained increasing interest during recent years. Using various stroke models in both rodents and primates, the transplantation of stem cells, namely of bone marrow derived mesenchymal stem cells (MSCs) or neural progenitor cells (NPCs), has been shown to promote neurological recovery most likely via indirect bystander actions. In view of promising observations, clinical proof-of-concept studies are currently under way, in which effects of stem and precurs...