Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes.
ABSTRACT 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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ABSTRACT: Occlusive cerebrovascular disease leads to brain ischemia that causes neurological deficits. Here we introduce a new strategy combining mesenchymal stromal cells (MSCs) and ex vivo hepatocyte growth factor (HGF) gene transferring with a multimutated herpes simplex virus type-1 vector in a rat transient middle cerebral artery occlusion (MCAO) model. Gene-transferred MSCs were intracerebrally transplanted into the rats' ischemic brains at 2 h (superacute) or 24 h (acute) after MCAO. Behavioral tests showed significant improvement of neurological deficits in the HGF-transferred MSCs (MSC-HGF)-treated group compared with the phosphate-buffered saline (PBS)-treated and MSCs-only-treated group. The significant difference of infarction areas on day 3 was detected only between the MSC-HGF group and the PBS group with the superacute treatment, but was detected among each group on day 14 with both transplantations. After the superacute transplantation, we detected abundant expression of HGF protein in the ischemic brain of the MSC-HGF group compared with others on day 1 after treatment, and it was maintained for at least 2 weeks. Furthermore, we determined that the increased expression of HGF was derived from the transferred HGF gene in gene-modified MSCs. The percentage of apoptosis-positive cells in the ischemic boundary zone (IBZ) was significantly decreased, while that of remaining neurons in the cortex of the IBZ was significantly increased in the MSC-HGF group compared with others. The present study shows that combined therapy is more therapeutically efficient than MSC cell therapy alone, and it may extend the therapeutic time window from superacute to acute phase.Journal of Cerebral Blood Flow & Metabolism 10/2006; 26(9):1176-88. · 5.40 Impact Factor
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ABSTRACT: Human mesenchymal stem cells (hMSCs) are considered a source of cells for regenerative medicine, and cell and gene therapy. Efficient gene transfer into hMSCs is essential for basic investigations into cellular differentiation and developmental biology, and for therapeutic applications in gene-modified regenerative medicine. In the present study, we optimized the transduction of hMSCs by means of fiber-modified adenovirus (Ad) vectors. Among the various types of Ad vectors tested, the polylysine modification of the C-terminal of the fiber knob most markedly improved the efficiency of hMSC transduction. At 300 vector particles per cell of polylysine-modified Ad vectors, more than 95% of the hMSCs expressed transgene. In this condition, polylysine-modified Ad vectors mediated 460-fold more transgene activity than the conventional Ad vectors. Ad vectors containing the Ad type 35 fiber or an Arg-Gly-Asp (RGD) peptide in the fiber knob mediated 130 or 16 times, respectively, the transgene activity mediated by the conventional Ad vectors. We also examined the efficiency of transduction into adipogenic-differentiated hMSCs. In this latter case, only Ad vectors containing the Ad type 35 fiber showed efficient gene expression. These results showed that fiber-modified Ad vectors could become a potent tool for basic research into, and the therapeutic application of, hMSCs and adipogenic-differentiated hMSCs.Biochemical and Biophysical Research Communications 08/2005; 332(4):1101-6. · 2.41 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) have demonstrated efficacy as cellular vectors for treating a variety of nervous system disorders. Nevertheless, few studies have quantified MSC engraftment levels or explored the mechanisms that promote their survival and migration in nervous tissue. In this study, we compared the engraftment kinetics and anatomical distribution of murine, male MSCs injected intracranially into neonatal versus adult female mice using a real-time PCR assay that targets the mouse SRY gene. These analyses revealed that MSCs exhibited low but equivalent engraftment levels in the central nervous system (CNS) of neonatal and adult transplant recipients at 12 days post-injection. However, MSC engraftment levels were significantly greater at 60 and 150 days post-transplantation in neonates as compared to adults. Despite these differences, engrafted MSCs were widely distributed along the neuraxis of the CNS in both transplant groups. Collectively, these data indicate that proliferation, but not engraftment and migration, of MSCs in brain are regulated by the host microenvironment. Using a genomics approach, we also identified MSC subpopulations that express neural adhesion proteins and receptors that regulate neuronal cell migration in brain, including cadherin 2, neurexin 1, ninjurin 1, neogenin 1, neuropilin 2, and roundabout homolog 1 and 4. Functional studies indicate these proteins confer cell adhesion and migration of MSCs in response to the appropriate chemoattractant. On the basis of these findings, we conclude that the unique molecular composition of MSC subpopulations imparts to them an inherent capacity to engraft and migrate in brain. These subpopulations may represent more potent cellular vectors for treating CNS disorders.Stem Cells and Development 07/2006; 15(3):437-47. · 4.67 Impact Factor