| 1. |
- Johansson, M. K., et al.
(författare)
-
Hematopoietic stem cell-targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice
- 2007
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 109:12, s. 5178-85
-
Tidskriftsartikel (refereegranskat)abstract
- Infantile malignant osteopetrosis (IMO) is a fatal disease caused by lack of functional osteoclasts, and the only available treatment is hematopoietic stem cell (HSC) transplantation. In the majority of patients, the TCIRG1 gene, coding for a subunit of a proton pump essential for bone resorption, is mutated. Oc/oc mice have a deletion in the homologue gene (tcirg1) and die at 3 to 4 weeks, but can be rescued by neonatal transplantation of HSCs. Here, HSC-targeted gene therapy of osteopetrosis in the oc/oc mouse model was developed. Oc/oc fetal liver cells depleted of Ter119-expressing erythroid cells were transduced with a retroviral vector expressing tcirg1 and GFP, and subsequently transplanted intraperitoneally to irradiated neonatal oc/oc mice. Eight of 15 mice survived past the normal life span of oc/oc mice. In vitro osteoclastogenesis revealed formation of GFP-positive osteoclasts and bone resorption, albeit at a lower level than from wild-type cells. The skeletal phenotype was analyzed by X-ray and histopathology and showed partial correction at 8 weeks and almost normalization after 18 weeks. In summary, osteopetrosis in oc/oc mice can be reversed by neonatal transplantation of gene-modified HSCs leading to long-term survival. This represents a significant step toward the development of gene therapy for osteopetrosis.
|
|
| 2. |
- Järås, Marcus, et al.
(författare)
-
Adenoviral vectors for transient gene expression in human primitive hematopoietic cells: Applications and prospects.
- 2007
-
Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 35:3, s. 343-349
-
Forskningsöversikt (refereegranskat)abstract
- The proliferation and differentiation of primitive hematopoietic cells is tightly controlled by a number of signaling pathways. Transient blockage or enhancement of these signaling pathways may provide a new approach to manipulate the proliferation and differentiation of primitive hematopoietic cells. Adenoviral vectors have in recent years emerged as powerful tools for transient gene expression in human primitive hematopoietic cells. Important advantageous properties of adenoviral vectors include: feasible production of high-titer vector preparations, high efficiency in transducing both quiescent and actively dividing cells, high levels of transient gene expression, and a lack of mutagenic properties associated with integrating vectors. Progress in adenoviral fiber retargeting was recently demonstrated to enable high gene transfer efficiency into nondividing human CD34(+) cells and nonobese diabetic/severe combined immunodeficient mouse bone marrow repopulating cells (SRCs), via the ubiquitously expressed CD46 as a cellular receptor. Importantly, fiber-retargeted adenoviral vectors can be engineered to report gene expression in single living CD34(+) cells, thereby facilitating the isolation and characterization of SRCs and its downstream progenitors based on intrinsic signaling pathways. This review focuses on the current progress and the potential future applications of adenoviral gene transfer into human primitive hematopoietic cells and leukemic cells. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.
|
|
| 3. |
- Magnusson, Mattias, et al.
(författare)
-
HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development
- 2007
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 109:9, s. 3687-3696
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 4. |
- Magnusson, Mattias, et al.
(författare)
-
Hoxa9/hoxb3/hoxb4 compound null mice display severe hematopoietic defects
- 2007
-
Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 35:9, s. 1421-1428
-
Tidskriftsartikel (refereegranskat)abstract
- Obyective. Members of the box family of homeodomain-containing transcription factors, including hoxa9, hoxb3, and hoxb4 play an important role in the regulation of differentiation, proliferation and self-renewal of hematopoietic stem and progenitor cells. Lack-of-function studies using hoxa9, hoxb4, or hoxb3/hoxb4 null mice demonstrate that all these mutations compromise the repopulating ability of hematopoietic stem cells (HSC), implying similar functions of each of these genes in hematopoiesis. Because cross regulation and cooperativity are known features of box proteins, we investigated mice with a compound deficiency in hoxa9, hoxb3 and hoxb4 (hoxa9/b3/b4) for evidence of synergy between these genes in hematopoiesis. Materials and Methods. Hoxa9/b3/b4 were generated by mating the hoxb3/boxb4 null mice with the hoxa9 null strain and HSC function was measured by competitive repopulating assay and by immunophenotype using fluorescence-activated cell sorting. Results. Our findings demonstrate that the hoxa9/b3/b4 null mice are smaller in body weight, and display a marked reduction in spleen size and cellularity compared to control mice. The numbers of colony-forming unit (CFU)-granulocyte macrophage and CFU-spleen progenitor colonies were normal but hoxa9/b3/b4 null bone marrow contained increased numbers of immunophenotypic HSC (Lin(-), c-kit(+), Sca-1(+), CD150(+)). However the reconstitution defect in hoxa9 null HSC was not enhanced further in the hoxa9/b3/b4 null HSC. Conclusion. These findings demonstrate overlapping functions of hoxa9, hoxb3, and hoxb4 in hernatopoietic cells, and emphasize an important role for these transcription factors for regulation of HSC proliferation. However, none of these box proteins is absolutely essential for generation or maintenance of all major blood lineages. (c) 2007 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
|
|
| 5. |
- Nordmark, Gunnel, et al.
(författare)
-
Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome
- 2009
-
Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 10:1, s. 68-76
-
Tidskriftsartikel (refereegranskat)abstract
- Primary Sjögren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) >1.4 and P-values <0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P=2.5 × 10−9. The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.
|
|
| 6. |
|
|
| 7. |
|
|
