Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes. Brain Res Rev

Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Brain Research Reviews (Impact Factor: 5.93). 05/2009; 61(1):1-13. DOI: 10.1016/j.brainresrev.2009.03.003
Source: PubMed


After ischemic brain injury various cell types including neurons, glia and endothelial cells are damaged and lose their function. Effective regeneration of brain tissue requires that all these cell types have to be replenished and combined to form a new functional network. Recent advances in regenerative medicine show the ability of stem cells to differentiate into various cell lineages. Several types of stem cells have been used to treat ischemic brain injury in rodent models including neuronal stem cells, mesenchymal stem cells and hematopoietic stem cells. Although these studies show promising results, it remains to be determined whether the beneficial effect of cell-based therapies in ischemic brain injury results from direct replacement of damaged cells by the transplanted cells. On the basis of the current literature we propose that neuroprotection by activation of anti-apoptotic mechanisms as well as improvement of the trophic milieu necessary for endogenous repair processes may be more important mechanisms underlying the improved functional outcome after stem cell treatment. Transplantation of native unmodified stem cells as such may not be sufficient to boost repair mechanisms provided by the endogenous stem cell population. An important aim of this review is to discuss the literature on the possible enhancement of regenerative function by combining stem cell transplantation with gene transduction into stem cells to enhance their regenerative and neuroprotective therapeutic potential. Finally, we briefly discuss the possibility of translation of this therapy to the clinic.

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Available from: Cindy Van Velthoven, Aug 18, 2014
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    • "Although exogenous administration of stem cells seems beneficial for the preterm ischemic brain, the alternative of pharmacologically potentiating the endogenous regenerative capacity after injury remains appealing as biological risks, logistics and costs remain as potential obstacles for exogenous stem cell therapy (Gortner et al., 2012). In preterm infants especially, the brain and other tissues possess high numbers of regenerative stem cells (Bennet et al., 2012; Titomanlio et al., 2011; van Velthoven et al., 2009). Pharmacological interventions aimed at mobilizing these stem cells after injury form a promising prospect in the preterm environment (Gortner et al., 2012). "
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    ABSTRACT: Hypoxic-ischemic encephalopathy (HIE) is common in preterm infants, but currently no curative therapy is available. Cell-based therapy has a great potential in the treatment of hypoxic-ischemic preterm brain injury. Granulocyte-colony stimulating factor (G-CSF) is known to mobilize endogenous hematopoietic stem cells (HSC) and promotes proliferation of endogenous neural stem cells. On these grounds, we hypothesized that systemic G-CSF would be neuroprotective in a large translational animal model of hypoxic-ischemic injury in the preterm brain.
    Full-text · Article · Oct 2013 · Experimental Neurology
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    • "Efforts to improve the efficacy of MSCs include ischemic preconditioning [41,42], blood–brain barrier (BBB) manipulation [43], and use of genetically modified MSCs (although this is not feasible in clinical practice) [44,45]. Ischemic preconditioning enhances ischemic tolerance in various tissues including heart and brain [46,47]. "
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    ABSTRACT: Recovery after a major stroke is usually limited, but cell therapy for patients with fixed neurologic deficits is emerging. Several recent clinical trials have investigated mesenchymal stem cell (MSC) therapy for patients with ischemic stroke. We previously reported the results of a controlled trial on the application of autologous MSCs in patients with ischemic stroke with a long-term follow-up of up to 5 years (the 'STem cell Application Researches and Trials In NeuroloGy' (STARTING) study). The results from this pilot trial are challenging, but also raise important issues. In addition, there have been recent efforts to improve the safety and efficacy of MSC therapy for stroke.Methods and design: The clinical and preclinical background and the STARTING-2 study protocol are provided. The trial is a prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial. Both acute and chronic stroke patients will be selected based on clinical and radiological features and followed for 3 months after MSC treatment. The subjects will be randomized into one of two groups: (A) a MSC group (n = 40) or (B) a control group (n = 20). Autologous MSCs will be intravenously administered after ex vivo culture expansion with autologous ischemic serum obtained as early as possible, to enhance the therapeutic efficacy (ischemic preconditioning). Objective outcome measurements will be performed using multimodal MRI and detailed functional assessments by blinded observers. This trial is the first to evaluate the efficacy of MSCs in patients with ischemic stroke. The results may provide better evidence for the effectiveness of MSC therapy in patients with ischemic stroke.Trial registration: NCT01716481.
    Full-text · Article · Oct 2013 · Trials
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    • "In recent years, cell based therapy came into the focus of the different approaches to increase myelin regeneration [2]. Mesenchymal stem cells (MSC) are of particular interest since they secrete factors which are known to influence regeneration [3]–[5] and suppress immune cells [6], [7]. MSC are multipotent cells that can differentiate into different cell types such as osteocytes, adipocytes, and chondrocytes [8], [9]. "
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    ABSTRACT: For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC) have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS). In order to investigate remyelination and regeneration in the CNS we analysed the effects of intravenously and intranasally applied murine and human bone marrow-derived MSC on cuprizone induced demyelination, a toxic animal model which allows analysis of remyelination without the influence of the peripheral immune system. In contrast to EAE no effects of MSC on de- and remyelination and glial cell reactions were found. In addition, neither murine nor human MSC entered the lesions in the CNS in this toxic model. In conclusion, MSC are not directed into CNS lesions in the cuprizone model where the blood-brain-barrier is intact and thus cannot provide support for regenerative processes.
    Full-text · Article · Jul 2013 · PLoS ONE
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