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
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."
Available from: Cindi M Morshead
- "The pro-survival effects were shown to be mediated by a calcineurinindependent pathway which promotes survival by inhibiting mitochondrial permeability transition (MPT) pore formation (Sachewsky et al., 2014). Most interesting, administration of CsA was shown to promote tissue repair in a mouse model of stroke (Erlandsson et al., 2011; Sachewsky et al., 2014). Based on these findings, we asked whether CsA had similar effects on the NPC population within the neurogenic DG of the hippocampus. "
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ABSTRACT: Neural precursor cells (NPCs) in the adult mammalian brain demonstrate potential in applications of neural repair in the CNS. Recent work has shown that cyclosporin A (CsA), a commonly used immunosuppressive drug, expands the size of the NPC pool in the subventricular region by promoting cell survival. We asked if CsA had similar effects on NPCs in the dentate gyrus (DG) of the hippocampus, leading to increased neurogenesis. We used the in vitro and in vivo assays to examine CsA's effect on the size of the NPC pool and the proliferation and differentiation profile of cells within the DG. We found that CsA increases the numbers of NPCs and enriches for neurogenic NPCs in vitro. Similarly, in vivo systemic administration of CsA for 7days increases the size of the NPC pool in the DG observed through increases in numbers of proliferating cells and newborn neurons. Consistent with CsA's pro-survival effects, we have shown that CsA enhances the survival of newborn cells that normally undergo cell death over the time of infusion. Together these findings support the hypothesis that CsA administration promotes neurogenesis and may have implications for neural repair.
Available from: Hiroto Ishikawa
- "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 . Stroke research in immunocompromised animals has documented elevated endogenous neurogenesis via a CD4+ T cell, but not a CD25+ T cell-dependent mechanism . "
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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.
Available from: Lionel J VELLY
- "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.
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