| 1. |
- Beerman, Isabel, et al.
(författare)
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Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion
- 2010
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Ingår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:12, s. 5465-5470
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Tidskriftsartikel (refereegranskat)abstract
- Aging of the hematopoietic stem cell compartment is believed to contribute to the onset of a variety of age-dependent blood cell pathophysiologies. Mechanistic drivers of hematopoietic stem cell (HSC) aging include DNA damage accumulation and induction of tumor suppressor pathways that combine to reduce the regenerative capacity of aged HSCs. Such mechanisms do not however account for the change in lymphoid and myeloid lineage potential characteristic of HSC aging, which is believed to be central to the decline of immune competence and predisposition to myelogenous diseases in the elderly. Here we have prospectively isolated functionally distinct HSC clonal subtypes, based on cell surface phenotype, bearing intrinsically different capacities to differentiate toward lymphoid and myeloid effector cells mediated by quantitative differences in lineage priming. Finally, we present data supporting a model in which clonal expansion of a class of intrinsically myeloid-biased HSCs with robust self-renewal potential is a central component of hematopoietic aging.
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| 2. |
- Bryder, David, et al.
(författare)
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Shaping up a lineage-lessons from B lymphopoesis
- 2010
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Ingår i: CURRENT OPINION IN IMMUNOLOGY. - : Elsevier Science B.V., Amsterdam.. - 0952-7915 .- 1879-0372. ; 22:2, s. 148-153
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Forskningsöversikt (refereegranskat)abstract
- Even though the development of B lymphoid cells from hematopoietic stem cells is one of the most carefully investigated models of cell differentiation in adult mammalians, a set of recent findings has to a large extent increased our understanding for how B lymphoid commitment is achieved. These include the identification of IKAROS, PU.1 and E2A as transcription factors responsible for lymphoid lineage priming in multipotent cells, as well as the identification of EBF1 dependent B lineage restricted progenitors among cells lacking expression of the classical B lineage markers CD19 or 8220. The insight that the B cell identity may be defined at an earlier stage then previously thought, allows for an increased understanding of B lymphoid development likely to unravel molecular mechanisms of high relevance also for other differentiation processes within as well as outside of the hematopoietic system.
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| 3. |
- Hansen, Nils, et al.
(författare)
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SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function.
- 2013
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 27, s. 130-135
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Tidskriftsartikel (refereegranskat)abstract
- Suppressor of cytokine signaling 2 (SOCS2) is known as a feedback inhibitor of cytokine signaling and is highly expressed in primary bone marrow (BM) cells from patients with chronic myeloid leukemia (CML). However, it has not been established whether SOCS2 is involved in CML, caused by the BCR/ABL1 fusion gene, or important for normal hematopoietic stem cell (HSC) function. In this study, we demonstrate that although Socs2 was found to be preferentially expressed in long-term HSCs, Socs2-deficient HSCs were indistinguishable from wild-type HSCs when challenged in competitive BM transplantation experiments. Furthermore, by using a retroviral BCR/ABL1-induced mouse model of CML, we demonstrate that SOCS2 is dispensable for the induction and propagation of the disease, suggesting that the SOCS2-mediated feedback regulation of the JAK/STAT pathway is deficient in BCR/ABL1-induced CML.Leukemia advance online publication, 24 July 2012; doi:10.1038/leu.2012.169.
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| 4. |
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| 5. |
- Jaako, Pekka, et al.
(författare)
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Dietary L-leucine improves the anemia in a mouse model for Diamond-Blackfan anemia.
- 2012
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 120:11, s. 2225-2228
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Recently, a case study reported a patient who became transfusion-independent in response to treatment with the amino acid L-leucine. Therefore, we have validated the therapeutic effect of L-leucine using our recently generated mouse model for RPS19-deficient DBA. Administration of L-leucine significantly improved the anemia in Rps19-deficient mice (19 % improvement in hemoglobin concentration; 18% increase in the number of erythrocytes), increased the bone marrow cellularity and alleviated stress hematopoiesis. Furthermore, the therapeutic response to L-leucine appeared specific for Rps19-deficient hematopoiesis and was associated with downregulation of p53 activity. Our study supports the rationale for clinical trials of L-leucine as a therapeutic agent for DBA.
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| 6. |
- Jaako, Pekka, et al.
(författare)
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Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118, s. 6087-6096
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging since the phenotype is highly dependent on the level of RPS19 downregulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded downregulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.
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| 7. |
- Mandal, Pankaj K, et al.
(författare)
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Efficient Ablation of Genes in Human Hematopoietic Stem and Effector Cells using CRISPR/Cas9.
- 2014
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 15:5, s. 643-652
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Tidskriftsartikel (refereegranskat)abstract
- Genome editing via CRISPR/Cas9 has rapidly become the tool of choice by virtue of its efficacy and ease of use. However, CRISPR/Cas9-mediated genome editing in clinically relevant human somatic cells remains untested. Here, we report CRISPR/Cas9 targeting of two clinically relevant genes, B2M and CCR5, in primary human CD4(+) T cells and CD34(+) hematopoietic stem and progenitor cells (HSPCs). Use of single RNA guides led to highly efficient mutagenesis in HSPCs but not in T cells. A dual guide approach improved gene deletion efficacy in both cell types. HSPCs that had undergone genome editing with CRISPR/Cas9 retained multilineage potential. We examined predicted on- and off-target mutations via target capture sequencing in HSPCs and observed low levels of off-target mutagenesis at only one site. These results demonstrate that CRISPR/Cas9 can efficiently ablate genes in HSPCs with minimal off-target mutagenesis, which could have broad applicability for hematopoietic cell-based therapy.
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| 8. |
- Manesso, Erica, et al.
(författare)
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Dynamical modelling of haematopoiesis: an integrated view over the system in homeostasis and under perturbation.
- 2013
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Ingår i: Journal of the Royal Society Interface. - : The Royal Society. - 1742-5662 .- 1742-5689. ; 10:80
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Tidskriftsartikel (refereegranskat)abstract
- A very high number of different types of blood cells must be generated daily through a process called haematopoiesis in order to meet the physiological requirements of the organism. All blood cells originate from a population of relatively few haematopoietic stem cells residing in the bone marrow, which give rise to specific progenitors through different lineages. Steady-state dynamics are governed by cell division and commitment rates as well as by population sizes, while feedback components guarantee the restoration of steady-state conditions. In this study, all parameters governing these processes were estimated in a computational model to describe the haematopoietic hierarchy in adult mice. The model consisted of ordinary differential equations and included negative feedback regulation. A combination of literature data, a novel divide et impera approach for steady-state calculations and stochastic optimization allowed one to reduce possible configurations of the system. The model was able to recapitulate the fundamental steady-state features of haematopoiesis and simulate the re-establishment of steady-state conditions after haemorrhage and bone marrow transplantation. This computational approach to the haematopoietic system is novel and provides insight into the dynamics and the nature of possible solutions, with potential applications in both fundamental and clinical research.
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| 9. |
- Månsson, Robert, et al.
(författare)
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Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 115:13, s. 2601-2609
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Tidskriftsartikel (refereegranskat)abstract
- To investigate molecular events involved in the regulation of lymphoid lineage commitment, we crossed lambda 5 reporter transgenic mice to Rag1-GFP knockin mice. This allowed us to subfractionate common lymphoid progenitors and pre-pro-B (fraction A) cells into lambda 5(-)Rag1(low), lambda 5(-)Rag1(high), and lambda 5(+)Rag1(high) cells. Clonal in vitro differentiation analysis demonstrated that Rag1(low) cells gave rise to B/T and NK cells. Rag1(high) cells displayed reduced NK-cell potential with preserved capacity to generate B- and T-lineage cells, whereas the lambda 5(+) cells were B-lineage restricted. Ebf1 and Pax5 expression was largely confined to the Rag1high populations. These cells also expressed a higher level of the surface protein LY6D, providing an additional tool for the analysis of early lymphoid development. These data suggest that the classic common lymphoid progenitor compartment composes a mixture of cells with relatively restricted lineage potentials, thus opening new possibilities to investigate early hematopoiesis.
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| 10. |
- Norddahl, Gudmundur, et al.
(författare)
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Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging
- 2011
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Ingår i: Cell Stem Cell. - Cambridge Mass. : Cell Press. - 1934-5909 .- 1875-9777. ; 8:5, s. 499-510
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Tidskriftsartikel (refereegranskat)abstract
- Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging.
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