| 1. |
- Heuer, Andreas, et al.
(författare)
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HESC-derived neural progenitors prevent xenograft rejection through neonatal desensitisation
- 2016
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 282, s. 78-85
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Tidskriftsartikel (refereegranskat)abstract
- Stem cell therapies for neurological disorders are rapidly moving towards use in clinical trials. Before initiation of clinical trials, extensive pre-clinical validation in appropriate animal models is essential. However, grafts of human cells into the rodent brain are rejected within weeks after transplantation and the standard methods of immune-suppression for the purpose of studying human xenografts are not always sufficient for the long-term studies needed for transplanted human neurons to maturate, integrate and provide functional benefits in the host brain. Neonatal injections in rat pups using human fetal brain cells have been shown to desensitise the host to accept human tissue grafts as adults, whilst not compromising their immune system. Here, we show that differentiated human embryonic stem cells (hESCs) can be used for desensitisation to achieve long-term graft survival of human stem cell-derived neurons in a xenograft setting, surpassing the time of conventional pharmacological immune-suppressive treatments. The use of hESCs for desensitisation opens up for a widespread use of the technique, which will be of great value when performing pre-clinical evaluation of stem cell-derived neurons in animal models.
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| 2. |
- Rogelius, Nina, et al.
(författare)
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Retrovirally delivered Islet-1 increases recruitment of Ng2 expressing cells from the postnatal SVZ into the striatum.
- 2006
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 201:Jun 23, s. 388-398
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Tidskriftsartikel (refereegranskat)abstract
- Neural stem and progenitor cells hold the promise to be used in cell-based therapies to treat both acute and degenerative neurological diseases. To date, most research has been focused on the use of in vitro propagated stem cells used as a source of cells in cell replacement therapies. However, mobilization of endogenous neural stem cells to generate a specific differentiated cell type offers an attractive alternative. In this study, we investigate the possibility to direct the formation of specific cells from the endogenous stem and progenitor cells residing in the subventricular region of the postnatal brain. With the aim to induce postnatal generation of striatal neurons, we ectopically expressed Islet-1, a LIM homeodomain transcription factor expressed by striatal progenitors during development, in cells of the subventricular zone (SVZ) of neonatal and adult rats. Ectopic expression of Islet-1 in the neonatal, but not adult, SVZ resulted in the appearance of a population of cells in the striatum. These cells were primarily located in the ventrolateral area of the striatum where they differentiate into Ng2 expressing cells. However, no neurogenesis was observed in the striatum, nor was ectopic striatal differentiation observed in any other area of the brain after retroviral expression of Islet-1 in the SVZ. Thus, although ectopic expression of Islet-1 is sufficient to direct the migration of cells into the striatum in neonatal animals, it does not specify a striatal projection neuron phenotype in cells generated from the SVZ after birth. (c) 2006 Elsevier Inc. All rights reserved.
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| 3. |
- Thompson, Lachlan, et al.
(författare)
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Neurogenin2 identifies a transplantable dopamine neuron precursor in the developing ventral mesencephalon.
- 2006
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 198:1, s. 183-198
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Tidskriftsartikel (refereegranskat)abstract
- In neural transplantation studies, there is an interest in identifying and isolating mesencephalic dopamine (mesDA) neuron precursors that have the capacity to differentiate into fully mature mesDA neurons after transplantation. We report here that in the developing ventral mesencephalon (VM) the proneural gene Neurogenin2 (Ngn2) is expressed exclusively in the part of the ventricular zone that gives rise to the migrating mesDA neuroblasts, but not in the differentiated mesDA neurons. From other studies, we know that Ngn2 is involved in the generation of mesDA neurons and that the development of mesDA neurons is severely compromised in Ngn2-null mutant mice. We show here that cells isolated by FACS from the developing VM of Ngn2-GFP knock-in mice are capable of generating mesDA neurons, both in vitro and after transplantation to the striatum of neonatal rats. All mesDA neuron precursors, but not the serotonergic or GABAergie neuron precursors, are contained in the Ngn2-GFP-expressing population. Moreover, all glial cells were generated from cells contained in the GFP-negative cell fraction. The results show that surviving mesDA neurons in VM grafts are derived from early postmitotic, probably Nurr1-expressing precursors before they have acquired their fully differentiated neuronal phenotype. The Ngn2-GFP reporter construct used here thus provides a tool for the identification of inesDA neuron precursors in the VM and selective isolation of transplantable mesDA neuron precursors for transplantation. (c) 2005 Elsevier Inc. All rights reserved.
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