SwePub
Tyck till om SwePub Sök här!
Sök i SwePub databas

  Extended search

Träfflista för sökning "AMNE:(MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Hematologi) ;pers:(Karlsson Stefan)"

Search: AMNE:(MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Hematologi) > Karlsson Stefan

  • Result 1-10 of 94
Sort/group result
   
EnumerationReferenceCoverFind
1.
  • Björnsson, Jon Mar, et al. (author)
  • Reduced proliferative capacity of hematopoietic stem cells deficient in hoxb3 and hoxb4
  • 2003
  • In: Blood. - 0006-4971 .- 1528-0020. ; 23:11, s. 3872-3883
  • Journal article (peer-reviewed)abstract
    • Several homeobox transcription factors, such as HOXB3 and HOXB4, have been implicated in regulation of hematopoiesis. In support of this, studies show that overexpression of HOXB4 strongly enhances hematopoietic stem cell regeneration. Here we find that mice deficient in both Hoxb3 and Hoxb4 have defects in endogenous hematopoiesis with reduced cellularity in hematopoietic organs and diminished number of hematopoietic progenitors without perturbing lineage commitment. Analysis of embryonic day 14.5 fetal livers revealed a significant reduction in the hematopoietic stem cell pool, suggesting that the reduction in cellularity observed postnatally is due to insufficient expansion during fetal development. Primitive Lin(-) Scal(+) c-kit(+) hematopoietic progenitors lacking Hoxb3 and Hoxb4 displayed impaired proliferative capacity in vitro. Similarly, in vivo repopulating studies of Hoxb3/Hoxb4-deficient hematopoietic cells resulted in lower repopulating capability compared to normal littermates. Since no defects in homing were observed, these results suggest a slower regeneration of mutant HSC. Furthermore, treatment with cytostatic drugs demonstrated slower cell cycle kinetics of hematopoietic stem cells deficient in Hoxb3 and Hoxb4, resulting in increased tolerance to antimitotic drugs. Collectively, these data suggest a direct physiological role of Hoxb4 and Hoxb3 in regulating stem cell regeneration and that these genes are required for maximal proliferative response.
  •  
2.
  • Matsson, H, et al. (author)
  • Erythropoiesis in the Rps19 disrupted mouse: Analysis of erythropoietin response and biochemical markers for Diamond-Blackfan anemia.
  • 2006
  • In: Blood Cells Mol Dis. - : Elsevier BV. ; 36:2, s. 259-264
  • Journal article (peer-reviewed)abstract
    • The human ribosomal protein S19 gene (RPS19) is mutated in approximately 20% of patients with Diamond-Blackfan anemia (DBA), a congenital disease with a specific defect in erythropoiesis. The clinical expression of DBA is highly variable, and subclinical phenotypes may be revealed by elevated erythrocyte deaminase (eADA) activity only. In mice, complete loss of Rps19 results in early embryonic lethality whereas Rps19+/− mice are viable and without major abnormalities including the hematopoietic system. We have performed a detailed analysis of the Rps19+/− mice. We estimated the Rps19 levels in hematopoietic tissues and we analyzed erythrocyte deaminase activity and globin isoforms which are used as markers for DBA. The effect of a disrupted Rps19 allele on a different genetic background was investigated as well as the response to erythropoietin (EPO). From our results, we argue that the loss of one Rps19 allele in mice is fully compensated for at the transcriptional level with preservation of erythropoiesis.
  •  
3.
  • Ittner, Lars M, et al. (author)
  • Compound developmental eye disorders following inactivation of TGFbeta signaling in neural-crest stem cells
  • 2005
  • In: Journal of Biology. - : Springer Science and Business Media LLC. - 1475-4924. ; 4:11
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Development of the eye depends partly on the periocular mesenchyme derived from the neural crest (NC), but the fate of NC cells in mammalian eye development and the signals coordinating the formation of ocular structures are poorly understood. RESULTS: Here we reveal distinct NC contributions to both anterior and posterior mesenchymal eye structures and show that TGFbeta signaling in these cells is crucial for normal eye development. In the anterior eye, TGFbeta2 released from the lens is required for the expression of transcription factors Pitx2 and Foxc1 in the NC-derived cornea and in the chamber-angle structures of the eye that control intraocular pressure. TGFbeta enhances Foxc1 and induces Pitx2 expression in cell cultures. As in patients carrying mutations in PITX2 and FOXC1, TGFbeta signal inactivation in NC cells leads to ocular defects characteristic of the human disorder Axenfeld-Rieger's anomaly. In the posterior eye, NC cell-specific inactivation of TGFbeta signaling results in a condition reminiscent of the human disorder persistent hyperplastic primary vitreous. As a secondary effect, retinal patterning is also disturbed in mutant mice. CONCLUSION: In the developing eye the lens acts as a TGFbeta signaling center that controls the development of eye structures derived from the NC. Defective TGFbeta signal transduction interferes with NC-cell differentiation and survival anterior to the lens and with normal tissue morphogenesis and patterning posterior to the lens. The similarity to developmental eye disorders in humans suggests that defective TGFbeta signal modulation in ocular NC derivatives contributes to the pathophysiology of these diseases.
  •  
4.
  • Flygare, Johan, et al. (author)
  • Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia
  • 2005
  • In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 105:12, s. 4627-4634
  • Journal article (peer-reviewed)abstract
    • Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. To study effects of RPS19 deficiency in hematopoiesis we transduced CD34+ umbilical cord blood (CB) and bone marrow (BM) cells with 3 lentiviral vectors expressing small interfering RNA (siRNA) against RPS19 and 1 scrambled control vector. All vectors also express green fluorescent protein (GFP). Transduction with the siRNA vectors reduced RPS19 mRNA levels to various degrees, which resulted in erythroid defects, correlating to the degree of RPS19 down-regulation, and was rescued by expression of an siRNA-resistant RPS19 transcript. Erythroid colony formation capacity conjointly decreased with RPS19 levels in CD34+ CB and BM cells. In liquid culture supporting erythroid differentiation, RPS19-silenced as well as DBA patient CD34+ cells exhibited reduced proliferative capacity and impaired erythroid differentiation resulting in fewer erythroid colony-forming units (CFU-Es). When assaying myeloid development, a less pronounced influence on proliferation was seen. This study shows for the first time that RPS19 silencing decreases the proliferative capacity of hematopoietic progenitors and leads to a defect in erythroid development.
  •  
5.
  • Flygare, Johan, et al. (author)
  • Diamond-Blackfan Anemia: Erythropoiesis Lost in Translation
  • 2007
  • In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 109:8, s. 3152-3160
  • Doctoral thesis (other academic/artistic)abstract
    • Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents as macrocytic anemia during infancy. Linkage analysis suggests that at least four genes are associated with DBA of which two have been identified so far. The known DBA genes encode the ribosomal proteins S19 and S24 accounting for 25% and 2% of the patients respectively. This study shows that RPS19 gene transfer improves the proliferation defect and erythroid development in RPS19 deficient DBA patient CD34+ cells in vitro. These results indicate that RPS19-deficient DBA patients are potential candidates for gene therapy. We next created two disease models for RPS19-deficient DBA. We were able to induce a DBA phenotype in normal cells by reducing RPS19 expression using RNA interference (RNAi) to silence RPS19 expression in human CD34+ BM cells. Analogous in vitro DBA models were created using erythroid leukemia TF-1 and UT7 cell lines that harbor Doxycycline-dependent RNAi-mediated RPS19 silencing. When induced to silence RPS19 expression, TF-1 cell proliferation decreased together with a marked reduction in the number of erythroid cells. The DBA disease model cell lines were next used in a study showing that RPS19-deficient TF-1 cells and DBA patient cells share a defect in 18S rRNA processing which ultimately hampers ribosomal 40S subunit maturation. We predict that these RPS19-deficient cell lines can be used for further mechanistic studies on RPS19 deficiency in erythropoiesis. The study is concluded by a discussion where links between ribosomal proteins and erythropoiesis are reviewed together with considerations regarding future directions of DBA research.
  •  
6.
  • Magnusson, Mattias, et al. (author)
  • HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development
  • 2007
  • In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 109:9, s. 3687-3696
  • Journal article (peer-reviewed)abstract
    • The Homeobox (Hox) transcription factors are important regulators of normal and malignant hematopoiesis because they control proliferation, differentiation, and self-renewal of hematopoietic cells at different levels of the hematopoietic hierarchy. In transgenic mice we show that the expression of HOXA10 is tightly regulated by doxycycline. Intermediate concentrations of HOXA10 induced a 15-fold increase in the repopulating capacity of hematopoietic stem cells (HSCs) after 13 days of in vitro culture. Notably, the proliferation induction of HSC by HOXA10 was dependent on the HOXA10 concentration, because high levels of HOXA10 had no effect on HSC proliferation. Furthermore, high levels of HOXA10 blocked erythroid and megakaryocyte development, demonstrating that tight regulation of HOXA10 is critical for normal development of the erythroid and megakaryocytic lineages. The HOXA10-mediated effects on hematopoietic cells were associated with altered expression of genes that govern stem-cell self-renewal and lineage commitment (eg, hepatic leukemia factor [HlF], Dickkopf-1 [Dkk-1], growth factor independent-1 [Gfi-1], and Gata-1). Interestingly, binding sites for HOXA10 were found in HLF, Dkk-1, and Gata-1, and Dkk-1 and Gfi-1 were transcriptionally activated by HOXA10. These findings reveal novel molecular pathways that act downstream of HOXA10 and identify HOXA10 as a master regulator of postnatal hematopoietic development.
  •  
7.
  • Vlachos, Adrianna, et al. (author)
  • Diagnosing and treating Diamond Blackfan anaemia : results of an international clinical consensus conference
  • 2008
  • In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 142:6, s. 859-876
  • Research review (peer-reviewed)abstract
    • Diamond Blackfan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA affects about seven per million live births and presents during the first year of life. However, as mutated genes have been discovered in DBA, non-classical cases with less distinct phenotypes are being described in adults as well as children. In caring for these patients it is often difficult to have a clear understanding of the treatment options and their outcomes because of the lack of complete information on the natural history of the disease. The purpose of this document is to review the criteria for diagnosis, evaluate the available treatment options, including corticosteroid and transfusion therapies and stem cell transplantation, and propose a plan for optimizing patient care. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are also reviewed. Evidence-based conclusions will be made when possible; however, as in many rare diseases, the data are often anecdotal and the recommendations are based upon the best judgment of experienced clinicians. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference.
  •  
8.
  • Woods, Niels-Bjarne, et al. (author)
  • Development of Gene Therapy for Hematopoietic Stem Cells using Lentiviral Vectors
  • 2002
  • In: Leukemia. - 1476-5551. ; 16:4, s. 563-569
  • Doctoral thesis (other academic/artistic)abstract
    • Hematopoietic stem cells are an ideal target for genetic manipulation for the purpose of curing hematological disorders as they have the ability to develop into all blood lineages and to self-renew. In this study we demonstrate that lentiviral vectors, based on HIV-1, can efficiently transfer genes into human hematopoietic progenitor and stem cells as assessed following stem cell transplantation in immune compromised mice. High efficiency transduction of repopulating cells was achieved in both primary (48±23%, n=6) and secondary transplant recipients (64±13%). These results demonstrate the ability of lentiviral vectors to efficiently transduce human pluripotent candidate stem cells. Modifications to the vector design were performed to optimize the vector for high-level transgene expression in the progeny of the repopulating cells. Eight-fold higher expression levels were achieved in mice in both the lymphoid and myeloid progeny cells compared to the original lentiviral vectors. We also analyzed the vector copy number in the bone marrow cells by semi-quantitative PCR. To our surprise we found that on average there were multiple vector copies integrated per transduced cell (5.6±3.3 n=12). While the multiple vector copy integration into stem cells is efficient in terms of transduction and expression, it may increase the risk for insertional mutagenesis. Transduction of murine embryonic stem cells was performed to study transgene expression throughout in vitro differentiation to hematopoietic cells. In addition, we optimized the conditions for gene transfer into murine hematopoietic progenitors in order to be able to test hematopoietic stem cell gene therapy in animal models of human disease. These studies demonstrate the ability of lentiviral vectors to efficiently transduce human hematopoietic stem cells, and advance lentiviral vectors as a tool for the treatment of hematological disorders.
  •  
9.
  • Karlsson, Göran, et al. (author)
  • Gene expression profiling demonstrates that TGF-{beta}1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-{beta} signaling.
  • 2005
  • In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 21:3, s. 396-403
  • Journal article (peer-reviewed)abstract
    • Transforming growth factor-β 1 (TGF-β) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-β binds to receptor complexes consisting of TGF-β receptor type II (Tβ RII) and activin-like kinase receptor-5 (Alk5), and the downstream signaling is transduced by Smad and MAPK proteins. Recent data have shown that alternative receptor combinations aside from the classical pairing of Tβ RII/Alk5 can be relevant for TGF-β signaling. We have screened for alternative receptors for TGF-β and also for gene targets of TGF-β signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-β-stimulated Alk5(-/-) cells show them to be completely unaffected by TGF-β. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5(-/-) or TGF-β-stimulated Alk5(+/+) MEFs with unstimulated Alk5(+/+) cells. Our results demonstrate that, in MEFs, TGF-β signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.
  •  
10.
  • Relander, Thomas, et al. (author)
  • Retroviral transduction of human CD34+ cells on fibronectin fragment CH-296 is inhibited by high concentrations of vector containing medium
  • 2001
  • In: Journal of Gene Medicine. - 1521-2254. ; 3:3, s. 207-218
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The objective of the present study was to optimize conditions for retroviral transduction of human cord blood (CB) CD34+ cells and to reveal mechanisms which interfere with efficient gene transfer. METHODS: An MSCV based retroviral vector with the gene for enhanced green fluorescent protein (MGIN) produced by GP+envAM12 (amphotropic envelope), PG13 (gibbon ape leukemia virus envelope) or 293GPG (vesicular stomatitis virus envelope) cell lines was used to transduce cord blood CD34+ cells on Retronectin (fibronectin fragment CH-296) in three different ways: either in vector containing medium (VCM), in fresh medium on Retronectin pre-loaded with vector or in VCM on Retronectin pre-loaded with vector. RESULTS: Paradoxically, the transduction efficiency obtained with pre-load of vector onto Retronectin alone was higher than pre-load plus VCM for PG13-MGIN (67.9 +/- 6.0% vs 24.9 +/- 8.0%) and AM12-MGIN (47.5 +/- 5.8% vs 38.7 +/- 2.2%). Further experiments showed that transduction on Retronectin pre-loaded with PG13-MGIN or AM12-MGIN was inhibited by the presence of the same VCM at high concentrations, but not by the presence of a VCM with a different receptor specificity. If no pre-load of vector was performed, the highest transduction efficiencies were seen when VCMs were diluted 1:10 (MOIs of 3). The inhibitory effect of high titer PG13-MGIN VCM was confirmed in more primitive CD34+CD38low cells and in NOD/SCID repopulating cells, and was also seen in experiments with bone marrow CD34+ cells. CONCLUSIONS: Retroviral transduction of CB CD34+ cells on Retronectin is inhibited by high titer PG13 and GP+envAM12 vector containing medium. Efficient gene transfer to human hematopoietic cells can be obtained by preload alone of the vector onto Retronectin. These findings are of importance for the design of transduction protocols for repopulating hematopoietic cells.
  •  
Skapa referenser, mejla, bekava och länka
  • Result 1-10 of 94

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Close

Copy and save the link in order to return to this view