| 1. |
- Deierborg, Tomas, et al.
(author)
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Absence of striatal newborn neurons with mature phenotype following defined striatal and cortical excitotoxic brain injuries.
- 2009
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In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 219, s. 363-367
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Journal article (peer-reviewed)abstract
- Experimental stroke and excitotoxic brain lesion to the striatum or cortex increase the proliferation of cells residing within the ventricular wall and cause subsequent migration of newborn neuroblasts into the lesioned brain parenchyma. In this study, we clarify the different events of neurogenesis following striatal or cortical excitotoxic brain lesions in adult rats. Newborn cells were labeled by intraperitoneal injection of bromo-deoxy-uridine (BrdU), or by green fluorescent protein (GFP)-expressing lentiviral vectors injected into the subventricular zone (SVZ). We show that only neural progenitors born the first 5 days in the SVZ reside and expand within this neurogenic niche over time, and that these early labeled cells are more prone to migrate towards the striatum as neuroblasts. However, these neuroblasts could not mature into NeuN(+) neurons in the striatum. Furthermore, we found that cortical lesions, close or distant from the SVZ, could not upregulate SVZ cell proliferation nor promote neurogenesis. Our study demonstrates that both the time window for labeling proliferating cells and the site of lesion are crucial when assessing neurogenesis following brain injury.
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| 2. |
- Honeth, Gabriella, et al.
(author)
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Chemokine-directed migration of tumor-inhibitory neural progenitor cells towards an intracranially growing glioma.
- 2006
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In: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 312:8, s. 1265-1276
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Journal article (peer-reviewed)abstract
- We have earlier shown that the rat neural progenitor cell line HiB5 is capable of suppressing intracranial growth of glioma cells in Fisher rats. Unlike some neural progenitor cells, HiB5 cells have not shown homing capacity towards glioma cells growing intracranially. In this study, we have genetically modified HiB5 progenitor cells to over-express the chemokine receptor CXCR3. We show that the introduced receptor is functionally responding to ligand stimulation with increased phosphorylation levels of ERK and SAPK/JNK and a transcriptional response of an AP-1 reporter system introduced into HIB5 cells. These transfected progenitor cells migrate in vitro in response to IP-10 and I-TAC. Further, we show an enhanced in vivo migration of the CXCR3 transfected HiB5 cells over the corpus callosum towards an IP-10 and I-TAC expressing glioma, as compared to wild type HiB5 cells. Our data indicate that it is possible to take advantage of chemokines natural capacity to initiate migratory responses, and to use this ability to enhance tumor-inhibitory neural progenitor cells to target an intracranially growing glioma.
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| 3. |
- Jakobsson, Johan, et al.
(author)
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Efficient transduction of neurons using Ross River glycoprotein-pseudotyped lentiviral vectors.
- 2006
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In: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 13:12, s. 966-973
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Journal article (peer-reviewed)abstract
- Lentiviral vectors are promising tools for CNS gene transfer since they efficiently transduce the cells of the nervous system in vivo. In this study, we have investigated the transduction efficiency of lentiviral vectors pseudotyped with Ross River virus glycoprotein (RRV-G) (RRV-G-pseudotyped lentiviral vectors (RRV-LV)). The RRV is an alphavirus with an extremely broad host range, including the cells of the central nervous system. Previous studies have shown that lentiviral vectors can be efficiently pseudotyped with this envelope protein and have demonstrated promising features of such vectors, including the possibility to establish stable producer cell lines. After injection of RRV-LV expressing green fluorescent protein into different structures in the rat brain we found efficient transduction of both neurons and glial cells. By using two cell-type-specific promoters, neuron-specific enolase and human glial fibrillary acidic protein, we demonstrated cell-specific transgene expression in the desired cell type. Ross River virus glycoprotein-pseudotyped lentiviral vectors also transduced human neural progenitor cells in vitro, showing that receptors for the RRV-G are present on human neural cells.
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| 4. |
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| 5. |
- Staflin, Karin, et al.
(author)
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Identification of proteins involved in neural progenitor cell targeting of gliomas
- 2009
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 9
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Journal article (peer-reviewed)abstract
- Background: Glioblastoma are highly aggressive tumors with an average survival time of 12 months with currently available treatment. We have previously shown that specific embryonic neural progenitor cells (NPC) have the potential to target glioma growth in the CNS of rats. The neural progenitor cell treatment can cure approximately 40% of the animals with malignant gliomas with no trace of a tumor burden 6 months after finishing the experiment. Furthermore, the NPCs have been shown to respond to signals from the tumor environment resulting in specific migration towards the tumor. Based on these results we wanted to investigate what factors could influence the growth and progression of gliomas in our rodent model. Methods: Using microarrays we screened for candidate genes involved in the functional mechanism of tumor inhibition by comparing glioma cell lines to neural progenitor cells with or without anti-tumor activity. The expression of candidate genes was confirmed at RNA level by quantitative RT-PCR and at the protein level by Western blots and immunocytochemistry. Moreover, we have developed in vitro assays to mimic the antitumor effect seen in vivo. Results: We identified several targets involved in glioma growth and migration, specifically CXCL1, CD81, TPT1, Gas6 and AXL proteins. We further showed that follistatin secretion from the NPC has the potential to decrease tumor proliferation. In vitro co-cultures of NPC and tumor cells resulted in the inhibition of tumor growth. The addition of antibodies against proteins selected by gene and protein expression analysis either increased or decreased the proliferation rate of the glioma cell lines in vitro. Conclusion: These results suggest that these identified factors might be useful starting points for performing future experiments directed towards a potential therapy against malignant gliomas.
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| 6. |
- Staflin, Karin, et al.
(author)
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Instructive cross-talk between neural progenitor cells and gliomas.
- 2007
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In: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 85:10, s. 2147-2159
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Journal article (peer-reviewed)abstract
- Gliomas are the most common primary brain tumors and offer a poor prognosis in patients because of their infiltrative and treatment-resistant nature. The median survival time after diagnosis is approximately 11-12 months. There is a strong need for novel treatment modalities in targeting gliomas, and recent advances use neural progenitor cells as delivery systems for different therapeutic strategies. In this study, we show that rat embryonic neural progenitor cell (NPC) lines, transplanted at a distant site from a 3-day-preestablished glioma in the striatum, were able to migrate toward and colocalize with tumor isles without general spread into the brain parenchyma. Upon encounter with tumor, neural progenitor cells changed phenotype and became vimentin positive. These results demonstrate that transplanted neural progenitor cells respond to queues from a tumor and home to and exert an antitumor effect on the preestablished glioma, significantly decreasing the tumor volume with approximately 67% compared with control tumors after 1-2 weeks. Moreover, these early effects could be translated into increased survival times of animals treated with neural progenitor cell grafts 3 days after intrastriatal tumor inoculation. In contrast, there was no activation or migration of endogenous subventricular zone (SVZ) neuroblasts in response to an intrastriatal syngeneic tumor. In conclusion, NPC possess the ability to influence tumor growth as well as respond to queues from the tumor or tumor microenvironment, demonstrating a cross-talk between the cells. (c) 2007 Wiley-Liss, Inc.
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| 7. |
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| 8. |
- Staflin, Karin
(author)
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Neural Progenitor Cells in malignancy and injury of the brain. A Trojan Horse fro gliomas?
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Gliomas are neoplasms arising in the central nervous system (CNS), and constitute the most common primary brain tumor. They are classified depending on the grade and morphology, from grade I, pilocytic astrocytoma, to grade IV, glioblastoma multiforme (GBM). Glioblastomas constitute a great challenge in treatment due to their disseminating nature. Classical treatments such as surgery, radiation therapy and chemotherapy still offer a poor prognosis for the patient, depending on the location and grade of the tumor. Patients with high grade gliomas have rapid deterioration and a predicted survival time of approximately 12 months with current treatment modalities. Pre-clinical research for treating gliomas has, during the last years, tried to develop neural progenitor cells as delivery vehicles for therapeutic genes. This is based on the fact that neural progenitor cells (NPC) have a great migratory potential and have been shown to specifically migrate to tumor cells. In this thesis we have tried to address the novel approach of using NPC to target malignant gliomas in rodents. This was done to increase the understanding of tumor progression and to investigate the impact of tumor growth on surrounding cells and their interaction with NPC. When the work on this thesis was started, novel findings of NPC with the ability to specifically home to gliomas in the brain were revolutionizing the notion of targeting disseminating single tumor cells. We wanted to investigate the potential of using NPC as specific delivery vehicles or a ?Trojan horse? for delivering harmful substances or molecules to tumor cells. We made the spectacular finding that certain NPC could prolong the lifespan of animals with gliomas and even cure 25% of the animals. This showed that some NPC themselves displayed antitumor properties. We focused our work towards understanding the underlying mechanism of this and the interaction of NPC and glioma cells in the brain. It appeared that the NPC acted as a true ?Trojan horse? bearing within them the ability to reduce tumor burden as well as tumor invasion in the animals. We have so far investigated and shown that there is a mutual responsiveness between tumor cells and embryonic NPC, which seem to be lacking in the adult brain, at least in response to the syngeneic glioma N29. The NPC can specifically migrate to tumor cells if transplanted at a distance. Upon tumor encounter they change phenotype to express the marker vimentin and can reduce the tumor volume with 67% during the first two weeks. However, no endogenous neuroblast activation, from the subventricular zone, towards a glioma was seen. This was in contrast to the extensive neuroblast activation observed to an excitotoxic lesion, as reported previously. Characterization of the tumor cells and NPC show that there is a genetical difference between NPC which display antitumor effects compared to NPC which do not. Genetical and protein screenings revealed candidate proteins, expressed by the NPC, which could be able to target glioma outgrowth in the brain either through direct toxicity or more likely secondary effects on the tumor microenvironment.
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