| 1. |
- Carén, Helena, 1979, et al.
(författare)
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Glioblastoma stem cells respond to differentiation cues but fail to undergo differentiation commitment and terminal cell cycle arrest
- 2015
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Ingår i: STEM CELL REPORTS. - : Elsevier BV. - 2213-6711. ; 5:5, s. 829-842
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stem cell-like cells. BMP signaling triggers cell-cycle exit and differentiation of GBM stem cells (GSCs) and, therefore, might have therapeutic value. However, the epigenetic mechanisms that accompany differentiation remain poorly defined. It is also unclear whether cell-cycle arrest is terminal. Here we find only a subset of GSC cultures exhibit astrocyte differentiation in response to BMP. Although overtly differentiated non-cycling astrocytes are generated, they remain vulnerable to cell-cycle re-entry and fail to appropriately reconfigure DNA methylation patterns. Chromatin accessibility mapping identified loci that failed to alter in response to BMP and these were enriched in SOX transcription factor-binding motifs. SOX transcription factors, therefore, may limit differentiation commitment. A similar propensity for cell-cycle re-entry and de-differentiation was observed in GSC-derived oligodendrocyte-like cells. These findings highlight significant obstacles to BMP-induced differentiation as therapy for GBM.
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| 4. |
- Djelloul, Mehdi, et al.
(författare)
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Alpha-Synuclein Expression in the Oligodendrocyte Lineage: an In Vitro and In Vivo Study Using Rodent and Human Models.
- 2015
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 5:2, s. 174-184
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we sought evidence for alpha-synuclein (ASYN) expression in oligodendrocytes, as a possible endogenous source of ASYN to explain its presence in glial inclusions found in multiple system atrophy (MSA) and Parkinson's disease (PD). We identified ASYN in oligodendrocyte lineage progenitors isolated from the rodent brain, in oligodendrocytes generated from embryonic stem cells, and in induced pluripotent stem cells produced from fibroblasts of a healthy individual and patients diagnosed with MSA or PD, in cultures in vitro. Notably, we observed a significant decrease in ΑSYN during oligodendrocyte maturation. Additionally, we show the presence of transcripts in PDGFRΑ/CD140a(+) cells and SOX10(+) oligodendrocyte lineage nuclei isolated by FACS from rodent and human healthy and diseased brains, respectively. Our work identifies ASYN in oligodendrocyte lineage cells, and it offers additional in vitro cellular models that should provide significant insights of the functional implication of ASYN during oligodendrocyte development and disease.
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| 6. |
- Grealish, Shane, et al.
(författare)
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Monosynaptic Tracing using Modified Rabies Virus Reveals Early and Extensive Circuit Integration of Human Embryonic Stem Cell-Derived Neurons.
- 2015
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 4:6, s. 975-983
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Tidskriftsartikel (refereegranskat)abstract
- Human embryonic stem cell (hESC)-derived dopamine neurons are currently moving toward clinical use for Parkinson's disease (PD). However, the timing and extent at which stem cell-derived neurons functionally integrate into existing host neural circuitry after transplantation remain largely unknown. In this study, we use modified rabies virus to trace afferent and efferent connectivity of transplanted hESC-derived neurons in a rat model of PD and report that grafted human neurons integrate into the host neural circuitry in an unexpectedly rapid and extensive manner. The pattern of connectivity resembled that of local endogenous neurons, while ectopic connections were not detected. Revealing circuit integration of human dopamine neurons substantiates their potential use in clinical trials. Additionally, our data present rabies-based tracing as a valuable and widely applicable tool for analyzing graft connectivity that can easily be adapted to analyze connectivity of a variety of different neuronal sources and subtypes in different disease models.
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| 7. |
- Rönn, Roger, et al.
(författare)
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Retinoic Acid regulates hematopoietic development from human pluripotent stem cells.
- 2015
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 4:2, s. 269-281
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Tidskriftsartikel (refereegranskat)abstract
- The functions of retinoic acid (RA), a potent morphogen with crucial roles in embryogenesis including developmental hematopoiesis, have not been thoroughly investigated in the human setting. Using an in vitro model of human hematopoietic development, we evaluated the effects of RA signaling on the development of blood and on generated hematopoietic progenitors. Decreased RA signaling increases the generation of cells with a hematopoietic stem cell (HSC)-like phenotype, capable of differentiation into myeloid and lymphoid lineages, through two separate mechanisms: by increasing the commitment of pluripotent stem cells toward the hematopoietic lineage during the developmental process and by decreasing the differentiation of generated blood progenitors. Our results demonstrate that controlled low-level RA signaling is a requirement in human blood development, and we propose a new interpretation of RA as a regulatory factor, where appropriate control of RA signaling enables increased generation of hematopoietic progenitor cells from pluripotent stem cells in vitro.
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| 8. |
- Zhang, Jing, et al.
(författare)
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The Phosphatases STS1 and STS2 Regulate Hematopoietic Stem and Progenitor Cell Fitness.
- 2015
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 5:4, s. 633-646
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Tidskriftsartikel (refereegranskat)abstract
- FLT3 and c-KIT are crucial regulators of hematopoietic stem and progenitor cells. We investigated the role of STS1 and STS2 on FLT3 and c-KIT phosphorylation, activity, and function in normal and stress-induced hematopoiesis. STS1/STS2-deficient mice show a profound expansion of multipotent progenitor and lymphoid primed multipotent progenitor cells with elevated colony-forming capacity. Although long-term hematopoietic stem cells are not increased in numbers, lack of STS1 and STS2 significantly promotes long-term repopulation activity, demonstrating a pivotal role of STS1/STS2 in regulating hematopoietic stem and progenitor cell fitness. Biochemical analysis identified STS1/STS2 as direct phosphatases of FLT3 and c-KIT. Loss of STS1/STS2 induces hyperphosphorylation of FLT3, enhances AKT signaling, and confers a strong proliferative advantage. Therefore, our study reveals that STS1 and STS2 may serve as novel pharmaceutical targets to improve hematopoietic recovery after bone marrow transplantation.
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