| 1. |
- Canals, Isaac, et al.
(författare)
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Rapid and efficient induction of functional astrocytes from human pluripotent stem cells
- 2018
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Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 15:9, s. 693-696
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Tidskriftsartikel (refereegranskat)abstract
- The derivation of astrocytes from human pluripotent stem cells is currently slow and inefficient. We demonstrate that overexpression of the transcription factors SOX9 and NFIB in human pluripotent stem cells rapidly and efficiently yields homogeneous populations of induced astrocytes. In our study these cells exhibited molecular and functional properties resembling those of adult human astrocytes and were deemed suitable for disease modeling. Our method provides new possibilities for the study of human astrocytes in health and disease.
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| 2. |
- Hidalgo, Isabel, et al.
(författare)
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Bmi1 induction protects hematopoietic stem cells against pronounced long-term hematopoietic stress
- 2022
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Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 109, s. 35-44
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Tidskriftsartikel (refereegranskat)abstract
- The Polycomb complex protein Bmi1 is regarded as a master regulator of hematopoietic stem cells (HSCs). In the blood system, HSCs express Bmi1 most abundantly and Bmi1 expression vanes as cells differentiate. Furthermore, Bmi1 has been found overexpressed in several hematologic cancers. Most studies exploring the normal role of Bmi1 in HSC biology have utilized loss-of-function models, which have established Bmi1 as an important regulator for HSC maintenance. Additionally, gain-of-function studies using retroviral and lentiviral approaches have observed increased self-renewal of Bmi-1 transduced HSCs. However, the clinical and biological relevance of such studies are typically hampered by uncontrolled transgenic integration and supraphysiological expression levels. Here, we developed a novel Tetracycline-inducible gain-of-function Bmi1 (iBmi1) transgenic mouse model. We find that Bmi1 induction had minor, if any, effects on steady-state hematopoiesis or following 5-fluorouracil-induced cytostatic stress. On the contrary, secondary transplantation of iBmi1 HSCs into wild type recipients resulted in remarkable increases of HSC numbers and chimerism levels. These data, in concert with previous loss-of-function studies, suggest that while endogenous Bmi1 levels are required and sufficient for normal HSC maintenance, the stabilization of these levels over time protects HSC from transplantation-associated stress.
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| 3. |
- Rundberg Nilsson, Alexandra, et al.
(författare)
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Temporal dynamics of TNF-mediated changes in hematopoietic stem cell function and recovery
- 2023
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 26:4
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Tidskriftsartikel (refereegranskat)abstract
- While tumor necrosis factor (TNF) is a critical mediator of appropriate immune response and tissue repair, its misregulation is linked to cancer, autoimmunity, bone marrow failure, and aging. Understanding the context-dependent roles of TNF is essential for elucidating normal and pathogenic conditions and to guide clinical therapy advancements. Prior studies suggested that TNF restricts the self-renewal capacity of hematopoietic stem cells (HSCs), but its long-term effect on HSCs remains unclear. Here, we demonstrate that in vivo TNF administration results in a transient exit of HSCs from quiescence, which coincides with a compromised repopulation capacity. These functional changes are; however, fully reversible even following prolonged/chronic transient exposure to TNF. Notably, antagonizing TNF signaling in transplantation recipients enhances donor HSC reconstitution. Our findings provide molecular and functional insight into HSC regulation, with implications for both acute and chronic inflammatory conditions.
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| 4. |
- Velasco-Hernandez, Talia, et al.
(författare)
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Hif-1 alpha Deletion May Lead to Adverse Treatment Effect in a Mouse Model of MLL-AF9-Driven AML
- 2019
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 12:1, s. 112-121
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Tidskriftsartikel (refereegranskat)abstract
- Relapse of acute myeloid leukemia (AML) remains a significant clinical challenge due to limited therapeutic options and poor prognosis. Leukemic stem cells (LSCs) are the cellular units responsible for relapse in AML, and strategies that target LSCs are thus critical. One proposed potential strategy to this end is to break the quiescent state of LSCs, thereby sensitizing LSCs to conventional cytostatics. The hypoxia-inducible factor (HIF) pathway is a main driver of cellular quiescence and a potential therapeutic target, with precedence from both solid cancers and leukemias. Here, we used a conditional knockout Hif-1 alpha mouse model together with a standard chemotherapy regimen to evaluate LSC targeting in AML. Contrary to expectation, our studies revealed that Hif-1 alpha-deleted-leukemias displayed a faster disease progression after chemotherapy. Our studies thereby challenge the general notion of cancer stem cell sensitization by inhibition of the HIF pathway, and warrant caution when applying HIF inhibition in combination with chemotherapy in AML.
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| 5. |
- Wahlestedt, Martin, et al.
(författare)
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Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 21:8, s. 2251-2263
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Tidskriftsartikel (refereegranskat)abstract
- A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor hepatic leukemia factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid, and ablation of lymphoid gene programs, with Hlf induction of nuclear factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis. Regulators of early blood cell formation are important in both health and disease. Wahlestedt et al. identify abrupt downregulation of the transcription factor Hlf during hematopoietic differentiation. Failure to downregulate Hlf leads to a drastically skewed output of mature blood cells, positioning Hlf as a critical regulator of hematopoiesis.
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| 6. |
- Yuan, Ouyang, et al.
(författare)
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A somatic mutation in moesin drives progression into acute myeloid leukemia
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:16
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg(295)Cys) in the ERM protein moesin that markedly accelerated leukemogenesis. Human cancer-associated moesin mutations at the conserved arginine-295 residue similarly enhanced MLL-ENL-driven leukemogenesis. Mechanistically, the mutation interrupted the stability of moesin and conferred a neomorphic activity to the protein, which converged on enhanced extracellular signal-regulated kinase activity. Thereby, our studies demonstrate a critical role of ERM proteins in AML, with implications also for human cancer.
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