Erlandsson A, Lin CHA, Yu FG, Morshead CM. Immunosuppression promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury. Experimen Neurol 230: 48-57

Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Experimental Neurology (Impact Factor: 4.7). 07/2011; 230(1):48-57. DOI: 10.1016/j.expneurol.2010.05.018
Source: PubMed

ABSTRACT Recent work has demonstrated that self-repair in the adult brain can be augmented by the infusion of growth factors to activate endogenous neural precursor cells that contribute to new tissue formation and functional recovery in a model of stroke. Using both a genetic model and drug treatment, we demonstrate that immunosuppression mimics the effects of growth factor activation, including tissue regeneration, neural precursor cell migration and functional recovery following ischemic injury. In the absence of growth factor treatment, mice with a functional immune system develop a prominent cavity in the cortex underlying the ischemic injury. In untreated immunodeficient NOD/SCID mice, however, the cortical cavity forms but is then filled with regenerated cortical tissue containing glial cells and subependyma derived neural stem and progenitor cells that migrate from their niche lining the lateral ventricles. The daily administration of Cyclosporine A also results in endogenous neural precursor cell migration and regenerated cortical tissue at the site of the cortical injury. Different from growth factor-treated animals is the finding that the regenerated cortical tissue in immunosuppressed animals is devoid of new neurons. Interestingly, both the growth factor and immunosuppressed (NOD/SCID and Cyclosporine A) treated animals displayed functional behavioural recovery despite the lack of neurogenesis within the regenerated cortical tissue. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."

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    • "Immunological reactions, such as graft vs. host, along with complications secondary to adjunctive immunosuppression, impart another barrier of stem cell treatment for stroke. The immunosuppressant cyclosporine A promotes endogenous neural stem cell activity and migration, thus aiding in the recovery of cortical injury following a stroke [4]. Stroke research in immunocompromised animals has documented elevated endogenous neurogenesis via a CD4+ T cell, but not a CD25+ T cell-dependent mechanism [5]. "
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    ABSTRACT: Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still being determined. Along this line of the need for optimization studies, we discuss studies that demonstrate effective dose, timing, and route of stem cells. We recognize that stem cell derivations also provide uniquely individual difficulties and limitations in their therapeutic applications. This review will outline the current knowledge, including benefits and challenges, of the many current sources of stem cells for stroke therapy.
    07/2013; 3(1):239-261. DOI:10.3390/brainsci3010239
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    • "Les CSN sont en effet peu immunogè nes (Modo et al., 2002) contrairement aux CSM susceptibles de dé clencher une forte ré action inflammatoire conduisant a ` leur rejet aigu (Coyne et al., 2006). Les immunosuppresseurs, en particulier la ciclosporine, peuvent avoir un effet bé né fique propre dans la neurorestauration post-isché mique en favorisant la migration et la croissance des CSN endogè nes et la ré gé né ration du tissu cortical lé sé (Erlandsson et al., 2011). Cependant, aucune amé lioration de fonctions neurocognitives lié e a ` l'immunosuppression du receveur n'a e ´ té dé montré e. Une mé ta-analyse a d'ailleurs suggé ré que la ré cupé ration des animaux lé sé s ayant reçu des CS d'origine humaine e ´ tait meilleure en l'absence d'immunosuppression (Janowski et al., 2010). "
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    ABSTRACT: IntroductionStroke is one of the leading causes of death and disability worldwide. Intravenous recombinant tissue plasminogen activator is the only available therapy for acute ischemic stroke, but its use is limited by a narrow therapeutic window and cannot stimulate endogenous repair and regeneration of damaged brain tissue. Stem cell-based approaches hold much promise as potential novel treatments to restore neurological function after stroke.State of the artIn this review, we summarize data from preclinical and clinical studies to investigate the potential application of stem cell therapies for treatment of stroke. Stem cells have been proposed as a potential source of new cells to replace those lost due to central nervous system injury, as well as a source of trophic molecules to minimize damage and promote recovery. Various stem cells from multiple sources can generate neural cells that survive and form synaptic connections after transplantation in the stroke-injured brain. Stem cells also exhibit neurorevitalizing properties that may ameliorate neurological deficits through stimulation of neurogenesis, angiogenesis and inhibition of inflammation.Perspectives/Conclusion Performed in stroke, cell therapy would decrease brain damage and reduce functional deficits. After the damage has been done, it would still improve neurological functions by activating endogenous repair. Nevertheless, many questions raised by experimental studies particularly related to long-term safety and technical details of cell preparation and administration must be resolved before wider clinical use.
    Revue Neurologique 04/2013; 169(4):291–306. DOI:10.1016/j.neurol.2012.08.009 · 0.66 Impact Factor
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    • "Summation of the CsA content at the depth of the SVZ or below (Fig. 4E) revealed a constant drug concentration over the 24-day time period [slope of linear regression line in Fig. 4E was not statistically different from zero, determined via an F-test (p=0.7243)]. This is critical for the therapeutic benefit of the system, as a constant concentration of CsA over a prolonged period of time is required to stimulate NSPCs [8] [9]. Additionally, the HAMC implant was extracted at each time point and analyzed for CsA content. "
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    ABSTRACT: Stimulation of endogenous neural stem/progenitor cells (NSPCs) with therapeutic factors holds potential for the treatment of stroke. Cyclosporin A (CsA) is a particularly promising candidate molecule because it has been shown to act as a survival factor for these cells over a period of weeks both in vitro and in vivo; however, systemically-delivered CsA compromises the entire immune system, necessitating sustained localized delivery. Herein we describe a local delivery strategy for CsA using an epi-cortical hydrogel of hyaluronan-methylcellulose (HAMC) as the drug reservoir. Three methods of incorporating the drug into the hydrogel (solubilized, particulate, and poly(lactic-co-glycolic) acid (PLGA) microsphere-encapsulated) resulted in tunable release, spanning a period of hours to weeks. Importantly, PLGA-encapsulated CsA released from the hydrogel had equivalent bioactivity to fresh drug as measured by the neurosphere assay. Moreover, when CsA was released from the PLGA/HAMC composite that was injected on the cortex of adult mice, CsA was detected in the NSPC niche at a constant concentration for at least 24 days post-implant. Thus this hydrogel composite system may be promising for the treatment of stroke.
    Journal of Controlled Release 01/2013; 166(3). DOI:10.1016/j.jconrel.2013.01.002 · 7.71 Impact Factor
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