| 1. |
- Aldskogius, Håkan, 1943-, et al.
(författare)
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Regulation of boundary cap neural crest stem cell differentiation after transplantation
- 2009
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 27:7, s. 1592-1603
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Tidskriftsartikel (refereegranskat)abstract
- Success of cell replacement therapies for neurological disorders will dependlargely on the optimization of strategies to enhance viability and control thedevelopmental fate of stem cells after transplantation. Once transplanted,stem/progenitor cells display a tendency to maintain an undifferentiatedphenotype or differentiate into inappropriate cell types. Gain and loss offunction experiments have revealed key transcription factors which drivedifferentiation of immature stem/progenitor cells toward more mature stages andeventually to full differentiation. An attractive course of action to promotesurvival and direct the differentiation of transplanted stem cells to a specific cell type would therefore be to force expression of regulatory differentiationmolecules in already transplanted stem cells, using inducible gene expressionsystems which can be controlled from the outside. Here, we explore thishypothesis by employing a tetracycline gene regulating system (Tet-On) to drivethe differentiation of boundary cap neural crest stem cells (bNCSCs) toward asensory neuron fate after transplantation. We induced the expression of the keytranscription factor Runx1 in Sox10-expressing bNCSCs. Forced expression of Runx1strongly increased transplant survival in the enriched neurotrophic environmentof the dorsal root ganglion cavity, and was sufficient to guide differentiationof bNCSCs toward a nonpeptidergic nociceptive sensory neuron phenotype both invitro and in vivo after transplantation. These findings suggest that exogenousactivation of transcription factors expression after transplantation instem/progenitor cell grafts can be a constructive approach to control theirsurvival as well as their differentiation to the desired type of cell and thatthe Tet-system is a useful tool to achieve this.
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| 2. |
- Kozlova, Elena, 1956-, et al.
(författare)
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Guiding differentiation of stem cells in vivo by tetracycline-controlled expression of key transcription factors
- 2012
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Ingår i: Cell Transplantation. - 0963-6897 .- 1555-3892. ; 21, s. 2537-2554
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Forskningsöversikt (refereegranskat)abstract
- Transplantation of stem or progenitor cells is an attractive strategy for cell replacement therapy. However, poor long-term survival and insufficiently reproducible differentiation to functionally appropriate cells in vivo still present major obstacles for translation of this methodology to clinical applications. Numerous experimental studies have revealed that the expression of just a few transcription factors can be sufficient to drive stem cell differentiation towards a specific cell type, to transdifferentiate cells from one fate to another, or to dedifferentiate mature cells to pluripotent stem/progenitor cells (iPSCs). We thus propose here to apply the strategy of expressing the relevant key transcription factors to guide the differentiation of transplanted cells to the desired cell fate in vivo. To achieve this requires tools allowing us to control the expression of these genes in the transplant. Here, we describe drug-inducible systems that allow us to sequentially and timely activate gene expression from the outside, with a particular emphasis on the Tet system which has been widely and successfully used in stem cells. These regulatory systems offer a tool for strictly limiting gene expression to the respective optimal stage after transplantation. This approach will direct the differentiation of the immature stem/progenitor cells in vivo to the desired cell type.
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| 3. |
- Kozlova, Elena N., 1956-, et al.
(författare)
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Differentiation and migration of neural crest stem cells are stimulated by pancreatic islets
- 2009
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Ingår i: NeuroReport. - 0959-4965 .- 1473-558X. ; 20:9, s. 833-838
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Tidskriftsartikel (refereegranskat)abstract
- Neural crest stem cells (NCSCs) migrate during embryonic development towards the endoderm-derived pancreas and the interaction between NCSCs and beta-cellprogenitors is crucial for their mutual differentiation. In diabetes, loss ofbeta-cells or impaired beta-cell function is accompanied by nerve degeneration,which contributes to the progression of the disease. Here we show that adultpancreatic islets markedly promote differentiation of NCSCs towards neuronalphenotype in vitro and in vivo after transplantation and increase their migrationtowards islets. These findings indicate that pancreatic islets can be used topromote differentiation of NCSCs towards neuronal phenotype and that thisin-vitro system may help elucidate interactions between NCSCs and healthy ordiseased beta-cells.
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| 4. |
- Olerud, Johan, et al.
(författare)
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Neural crest stem cells increase beta cell proliferation and improve islet function in co-transplanted murine pancreatic islets
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 52:12, s. 2594-2601
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Long-term graft survival after islet transplantation to patientswith type 1 diabetes is insufficient, necessitating the development of newstrategies to enhance transplant viability. Here we investigated whetherco-transplantation of neural crest stem cells (NCSCs) with islets improves islet survival and function in normoglycaemic and diabetic mice. METHODS: Islets alone or together with NCSCs were transplanted under the kidney capsule tonormoglycaemic or alloxan-induced diabetic mice. Grafts were analysed for size,proliferation, apoptosis and insulin release. In diabetic recipients bloodglucose levels were examined before and after graft removal. RESULTS: In mixedtransplants NCSCs actively migrated and extensively associated withco-transplanted pancreatic islets. Proliferation of beta cells was markedlyincreased and transplants displayed improved insulin release in normoglycaemicmice compared with those receiving islet-alone transplants. Mixed grafts survivedsuccessfully and partially restored normoglycaemia in alloxan-induced diabeticmice. CONCLUSIONS/INTERPRETATION: Co-grafting of NCSCs with pancreatic isletsimproved insulin release in mixed transplants and enhanced beta cellproliferation, resulting in increased beta cell mass. This co-transplantationmodel offers an opportunity to restore neural-islet interactions and improveislet functions after transplantation.
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