Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke (original) (raw)
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Brain Research, 2008
The potential for using stem cells to treat stroke has garnered much interest, but stem cell therapies must be rigorously tested in animal models before transplantation studies progress to clinical trials. An enriched environment enhances transplanted subventricular zone (SVZ) cell migration and functional benefit following stroke in rats. However, the ability of SVZ cells to survive, migrate, differentiate and promote functional recovery at protracted survival times (e.g., 3 months) has not been investigated. The vasoconstrictive peptide endothelin-1 was injected adjacent to the middle cerebral artery to produce focal ischemia. Seven days later, cells derived from the SVZ of adult mice (800,000 cells/rat or vehicle injection) were transplanted into the sensory-motor cortex and striatum, and rats were then housed in enriched or standard conditions. Rats in enriched housing had access to running wheels once per week. Recovery was assessed in the forelimb-use asymmetry task (cylinder) at 1, 2, or 3 months after transplantation immediately prior to euthanasia. Transplanted cell survival and migration were quantified using stereology. Cell phenotype was determined with immunohistochemistry and confocal microscopy. Enriched housing did not enhance survival or migration of transplanted SVZ cells at protracted survival times, and the majority (~ 99%) of cells died within 2 months of transplantation. Cell survival was significantly, and negatively, correlated with microglial activation. Many surviving cells expressed an astrocytic phenotype. Functional recovery was not improved at any time. Therapies involving transplantation of SVZ cells following stroke must be further optimized in order to enhance long-term cell survival and thereby maximize functional benefit.
Cell-Based Therapies and Functional Outcome in Experimental Stroke
Cell stem cell, 2009
The potential for using stem cells to treat stroke has garnered much interest, but stem cell therapies must be rigorously tested in animal models before transplantation studies progress to clinical trials. An enriched environment enhances transplanted subventricular zone (SVZ) cell migration and functional benefit following stroke in rats. However, the ability of SVZ cells to survive, migrate, differentiate and promote functional recovery at protracted survival times (e.g., 3 months) has not been investigated. The vasoconstrictive peptide endothelin-1 was injected adjacent to the middle cerebral artery to produce focal ischemia.
Stem Cell Mediation of Functional Recovery after Stroke in the Rat
PLoS ONE, 2010
Background: Regenerative strategies of stem cell grafting have been demonstrated to be effective in animal models of stroke. In those studies, the effectiveness of stem cells promoting functional recovery was assessed by behavioral testing. These behavioral studies do, however, not provide access to the understanding of the mechanisms underlying the observed functional outcome improvement.
Recovery and rehabilitation in stroke Stem cells
The recent demostration that neurons for transplantation can be generated from stem cells and that the adult brain produces new neurons in response to stroke has raised hope for the development of a stem cell therapy for patients affected with this disorder. In this review we propose a road map to the clinic and describe the different scientific tasks that need to be accomplished to move stem cell-based approaches toward application in stroke patients. (Stroke. 2004; 35[suppl I]:2691-2694.)
Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke
Progress in neurobiology, 2017
One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differe...
Research Square (Research Square), 2023
The major aim of stroke therapy is to stimulate brain repair and improve behavioral recuperation after cerebral ischemia. One option is to stimulate endogenous neurogenesis in the sub-ventricular zone (SVZ) and direct the newly formed neurons to the damaged area. However, only a small percentage of these neurons survive and, of those that do, many will not reach the damaged area possibly because the corpus callosum impedes the migration of SVZ-derived stem cells into the lesioned cortex. A second major obstacle to stem cell therapy is the strong in ammatory reaction induced by cerebral ischemia whereby the associated phagocytic activity of brain macrophages removes both therapeutic cells and/or cellbased drug carriers. In order to address these issues, neurogenesis was electrically stimulated in the SVZ followed by isolation of proliferating cells including the newly formed neurons which were subsequently mixed with a nutritional hydrogel. This mixture was then transferred to the stroke cavity of day 14 poststroke mice. We found that the treated animals showed improved performance with behavioral tests including novel object, open eld, hole board, grooming, and "time-to-feel' the adhesive tape. Furthermore, immunostaining showed that the stem cell markers nestin and Mash1, found in stimulated SVZ, survived for 2 weeks following transplantation. These results clearly indicate that transplantation of committed SVZ stem cells combined with a protective nutritional gel, directly into the infarct cavity after the peak of stroke-induced neuroin ammation, represents a feasible approach to improve neurorestoration after cerebral ischemia.
Stem cells for brain repair and recovery after stroke
Expert Opinion on Biological Therapy, 2013
Introduction: Stroke is a major worldwide cause of death and disability. Currently, intravenous thrombolysis and reperfusion therapies, but not the socalled neuroprotectant drugs, have been shown to be effective for acute ischemic stroke. Thus, new strategies to promote brain plasticity are necessary. Stem cell administration is an attractive future therapeutic approach. Areas covered: Brain protection and repair mechanisms are activated after stroke. This article is focused on the capacity of stem cell-based therapy to enhance this postinfarct brain plasticity and recovery. Future therapeutic considerations and prospects for stroke are discussed. Expert opinion: Although cell therapy is promising in stroke treatment, mechanisms of action need to be characterized in detail. Further, the different mechanisms of axonal plasticity and remodeling involucrated in brain repair, not only in the gray but also in white matter, must be investigated through noninvasive techniques, and a multidisciplinary approach is fundamental in this.
Recent Advances in Mono- and Combined Stem Cell Therapies of Stroke in Animal Models and Humans
International Journal of Molecular Sciences, 2019
Following the failure of acute neuroprotection therapies, major efforts are currently made worldwide to promote neurological recovery and brain plasticity in the subacute and post-acute phases of stroke. Currently, there is hope that stroke recovery might be promoted by cell-based therapies. The field of stem cell therapy for cerebral ischemia has made significant progress in the last five years. A variety of stem cells have been tested in animal models and humans including adipose stem cells, human umbilical cord blood-derived mesenchymal stem cells, human amnion epithelial cells, human placenta amniotic membrane-derived mesenchymal stem cells, adult human pluripotent-like olfactory stem cells, human bone marrow endothelial progenitor cells, electrically-stimulated human neuronal progenitor cells, or induced pluripotent stem cells (iPSCs) of human origin. Combination therapies in animal models include a mix of two or more therapeutic factors consisting of bone marrow stromal cells, exercise and thyroid hormones, endothelial progenitor cells overexpressing the chemokine CXCL12. Mechanisms underlying the beneficial effects of transplanted cells include the “bystander” effects, paracrine mechanisms, or extracellular vesicles-mediated restorative effects. Mitochondria transfer also appears to be a powerful strategy for regenerative processes. Studies in humans are currently limited to a small number of studies using autologous stem cells mainly aimed to assess tolerability and side-effects of human stem cells in the clinic.
Brain Research, 2011
Mesenchymal stem cells (MSCs) have been successfully used for the treatment of experimental stroke. However, the neurorestorative mechanisms by which MSCs improve neurological functional recovery are not fully understood. Endogenous cell proliferation in the subventricular zone (SVZ) after stroke is well known, but most of newly formed cells underwent apoptosis. In the present study, we tested the hypothesis that neurotrophic factors secreted by human bone marrow-derived MSCs (hBMSCs) promote endogenous neurogenesis, reduce apoptosis, and improve functional recovery. Adult rats subjected to 2-h middle cerebral artery occlusion (MCAO) were transplanted with hBMSCs or saline into the ipsilateral brain parenchyma at 3 days after ischemia. There was a significant recovery of behavior in the hBMSCs-treated rats beginning at 14 days after MCAO compared with the control animals.