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[PMID]: 26275430
[Au] Autor:Redelinghuys P; Whitehead L; Augello A; Drummond RA; Levesque JM; Vautier S; Reid DM; Kerscher B; Taylor JA; Nigrovic PA; Wright J; Murray GI; Willment JA; Hocking LJ; Fernandes MJ; De Bari C; Mcinnes IB; Brown GD
[Ad] Address:Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK....
[Ti] Title:MICL controls inflammation in rheumatoid arthritis.
[So] Source:Ann Rheum Dis;75(7):1386-91, 2016 Jul.
[Is] ISSN:1468-2060
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: Myeloid inhibitory C-type lectin-like receptor (MICL, Clec12A) is a C-type lectin receptor (CLR) expressed predominantly by myeloid cells. Previous studies have suggested that MICL is involved in controlling inflammation. OBJECTIVE: To determine the role of this CLR in inflammatory pathology using Clec12A(-/-) mice. METHODS: Clec12A(-/-) mice were generated commercially and primarily characterised using the collagen antibody-induced arthritis (CAIA) model. Mechanisms and progress of disease were characterised by clinical scoring, histology, flow cytometry, irradiation bone-marrow chimera generation, administration of blocking antibodies and in vivo imaging. Characterisation of MICL in patients with rheumatoid arthritis (RA) was determined by immunohistochemistry and single nucleotide polymorphism analysis. Anti-MICL antibodies were detected in patient serum by ELISA and dot-blot analysis. RESULTS: MICL-deficient animals did not present with pan-immune dysfunction, but exhibited markedly exacerbated inflammation during CAIA, owing to the inappropriate activation of myeloid cells. Polymorphisms of MICL were not associated with disease in patients with RA, but this CLR was the target of autoantibodies in a subset of patients with RA. In wild-type mice the administration of such antibodies recapitulated the Clec12A(-/-) phenotype. CONCLUSIONS: MICL plays an essential role in regulating inflammation during arthritis and is an autoantigen in a subset of patients with RA. These data suggest an entirely new mechanism underlying RA pathogenesis, whereby the threshold of myeloid cell activation can be modulated by autoantibodies that bind to cell membrane-expressed inhibitory receptors.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1606
[Cu] Class update date: 160611
[Lr] Last revision date:160611
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1136/annrheumdis-2014-206644

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[PMID]: 27090590
[Au] Autor:Beck EC; Barragan M; Tadros MH; Gehrke SH; Detamore MS
[Ad] Address:Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, United States....
[Ti] Title:Approaching the compressive modulus of articular cartilage with a decellularized cartilage-based hydrogel.
[So] Source:Acta Biomater;38:94-105, 2016 Jul 1.
[Is] ISSN:1878-7568
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:UNLABELLED: ECM-based materials are appealing for tissue engineering strategies because they may promote stem cell recruitment, cell infiltration, and cell differentiation without the need to supplement with additional biological factors. Cartilage ECM has recently shown potential to be chondroinductive, particularly in a hydrogel-based system, which may be revolutionary in orthopedic medicine. However, hydrogels composed of natural materials are often mechanically inferior to synthetic materials, which is a major limitation for load-bearing tissue applications. The objective was therefore to create an unprecedented hydrogel derived entirely from native cartilage ECM that was both mechanically more similar to native cartilage tissue and capable of inducing chondrogenesis. Porcine cartilage was decellularized, solubilized, and then methacrylated and UV photocrosslinked to create methacrylated solubilized decellularized cartilage (MeSDCC) gels. Methacrylated gelatin (GelMA) was employed as a control for both biomechanics and bioactivity. Rat bone marrow-derived mesenchymal stem cells were encapsulated in these networks, which were cultured in vitro for 6weeks, where chondrogenic gene expression, the compressive modulus, swelling, and histology were analyzed. One day after crosslinking, the elastic compressive modulus of the 20% MeSDCC gels was 1070±150kPa. Most notably, the stress strain profile of the 20% MeSDCC gels fell within the 95% confidence interval range of native porcine cartilage. Additionally, MeSDCC gels significantly upregulated chondrogenic genes compared to GelMA as early as day 1 and supported extensive matrix synthesis as observed histologically. Given that these gels approached the mechanics of native cartilage tissue, supported matrix synthesis, and induced chondrogenic gene expression, MeSDCC hydrogels may be promising materials for cartilage tissue engineering applications. Future efforts will focus on improving fracture mechanics as well to benefit overall biomechanical performance. STATEMENT OF SIGNIFICANCE: Extracellular matrix (ECM)-based materials are appealing for tissue engineering strategies because they may promote stem cell recruitment, cell infiltration, and cell differentiation without the need to supplement with additional biological factors. One such ECM-based material, cartilage ECM, has recently shown potential to be chondroinductive; however, hydrogels composed of natural materials are often mechanically inferior to synthetic materials, which is a major limitation for load-bearing tissue applications. Therefore, this work is significant because we were the first to create hydrogels derived entirely from cartilage ECM that had mechanical properties similar to that of native cartilage until hydrogel failure. Furthermore, these hydrogels had a compressive modulus of 1070±150kPa, they were chondroinductive, and they supported extensive matrix synthesis. In the current study, we have shown that these new hydrogels may prove to be a promising biomaterial for cartilage tissue engineering applications.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1606
[Cu] Class update date: 160611
[Lr] Last revision date:160611
[Js] Journal subset:IM
[St] Status:In-Data-Review

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[PMID]: 26871861
[Au] Autor:Yoon DS; Lee KM; Kim SH; Kim SH; Jung Y; Kim SH; Park KH; Choi Y; Ryu HA; Choi WJ; Lee JW
[Ad] Address:1 Department of Orthopedic Surgery, Yonsei University College of Medicine , Seoul, South Korea ....
[Ti] Title:Synergistic Action of IL-8 and Bone Marrow Concentrate on Cartilage Regeneration Through Upregulation of Chondrogenic Transcription Factors.
[So] Source:Tissue Eng Part A;22(3-4):363-74, 2016 Feb.
[Is] ISSN:1937-335X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The objective of this study was to determine whether a biphasic scaffold loaded with a combination of a chemokine and bone marrow concentrate (BMC) could improve tissue regeneration in knee articular cartilage of beagles with cylindrical osteochondral defects. For this investigation, an osteochondral defect (6 mm in diameter and 8 mm deep) was created in the weight-bearing articular surface of the femoral medial condyle in beagles. Bone marrow was aspirated from the posterior iliac crests of beagles to obtain mesenchymal stem cells (MSCs) for in vitro assay. Hematoxylin and eosin (HE), Masson's trichrome (MT), safranin O/fast green staining, and immunohistochemistry were performed for histological analysis. Quantitative real-time polymerase chain reaction was performed to understand the roles of BMC in chondrogenic differentiation of MSCs. At 12 weeks after transplantation of biphasic scaffolds, we observed that interleukin-8 (IL-8) or the combination of IL-8 and BMC induced massive bone regeneration compared to saline, BMC only, and MSCs. In gross appearance, the osteochondral defect site was nearly completely filled with repair tissue in the group that received the combination of IL-8 and BMC but not in the other groups. Moreover, histological analysis showed obvious differences in cartilage regeneration among groups. HE and MT staining showed that the cartilage defect sites of the group receiving the combination of IL-8 and BMC were regenerated with cartilage-like tissues showing chondrocyte morphology. Safranin O staining showed hyaline cartilage regeneration in the group receiving IL-8 and BMC, whereas fibrous-like tissues were formed in the other groups. Furthermore, immunostaining revealed the presence of type II collagen and aggrecan in regenerated cartilage tissue of the group receiving IL-8 and BMC, whereas regenerated cartilage tissues of the other groups weakly expressed type II collagen and aggrecan. These results indicate that the combination of a chemokine IL-8 and BMC has significant positive effects on osteochondral regeneration in a beagle model through enhancing expression of the chondrogenic transcription factors and markers such as Sox9 and type II collagen.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1602
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1089/ten.tea.2015.0425

  4 / 337498 MEDLINE  
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[PMID]: 26871860
[Au] Autor:Kosaraju R; Rennert RC; Maan ZN; Duscher D; Barrera J; Whittam AJ; Januszyk M; Rajadas J; Rodrigues M; Gurtner GC
[Ad] Address:1 Department of Surgery, Stanford University School of Medicine , Stanford, California....
[Ti] Title:Adipose-Derived Stem Cell-Seeded Hydrogels Increase Endogenous Progenitor Cell Recruitment and Neovascularization in Wounds.
[So] Source:Tissue Eng Part A;22(3-4):295-305, 2016 Feb.
[Is] ISSN:1937-335X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Adipose-derived mesenchymal stem cells (ASCs) are appealing for cell-based wound therapies because of their accessibility and ease of harvest, but their utility is limited by poor cell survival within the harsh wound microenvironment. In prior work, our laboratory has demonstrated that seeding ASCs within a soft pullulan-collagen hydrogel enhances ASC survival and improves wound healing. To more fully understand the mechanism of this therapy, we examined whether ASC-seeded hydrogels were able to modulate the recruitment and/or functionality of endogenous progenitor cells. Employing a parabiosis model and fluorescence-activated cell sorting analysis, we demonstrate that application of ASC-seeded hydrogels to wounds, when compared with injected ASCs or a noncell control, increased the recruitment of provascular circulating bone marrow-derived mesenchymal progenitor cells (BM-MPCs). BM-MPCs comprised 23.0% of recruited circulating progenitor cells in wounds treated with ASC-seeded hydrogels versus 8.4% and 2.1% in those treated with controls, p < 0.05. Exploring the potential for functional modulation of BM-MPCs, we demonstrate a statistically significant increase in BM-MPC migration, proliferation, and tubulization when exposed to hydrogel-seeded ASC-conditioned medium versus control ASC-conditioned medium (73.8% vs. 51.4% scratch assay closure; 9.1% vs. 1.4% proliferation rate; 10.2 vs. 5.5 tubules/HPF; p < 0.05 for all assays). BM-MPC expression of genes related to cell stemness and angiogenesis was also significantly increased following exposure to hydrogel-seeded ASC-conditioned medium (p < 0.05). These data suggest that ASC-seeded hydrogels improve both progenitor cell recruitment and functionality to effect greater neovascularization.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Em] Entry month:1602
[Cu] Class update date: 160318
[Lr] Last revision date:160318
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1089/ten.tea.2015.0277

  5 / 337498 MEDLINE  
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[PMID]: 26603220
[Au] Autor:Tang C; Jin C; Xu Y; Wei B; Wang L
[Ad] Address:1 Department of Orthopaedic Surgery, Nanjing First Hospital, Nanjing Medical University , Nanjing, China ....
[Ti] Title:Chondrogenic Differentiation Could Be Induced by Autologous Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Matrix Scaffolds Without Exogenous Growth Factor.
[So] Source:Tissue Eng Part A;22(3-4):222-32, 2016 Feb.
[Is] ISSN:1937-335X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:We previously found that the combination of an autologous bone mesenchymal stem cell-derived extracellular matrix (aBMSC-dECM) scaffold with bone marrow stimulation could enhance hyaline cartilage regeneration. We suspected that chondrogenic differentiation could be induced by the aBMSC-dECM scaffold. This study aimed to investigate whether aBMSC-dECM scaffolds could promote chondrogenic differentiation without exogenous growth factors. BMSCs were seeded on aBMSC-dECM scaffolds and cultured in vitro with or without transforming growth factor-ß3 (E(+) or E(-) group). Atelocollagen scaffolds were used as controls (C(+) or C(-) group). The chondrogenic differentiation was evaluated by histological, biochemical, and real-time polymerase chain reaction assays. After 3 weeks, cartilage-like tissue with a homogeneous structure, a high cartilaginous matrix content (proteoglycan and type II collagen), and high expression levels of cartilage-associated genes (COL2A1, ACAN, and SOX9) were observed in the E(+), E(-), and C(+) groups. In addition, BMSCs in each scaffold (E group or C group) were preconditioned with chondrogenic media in vitro for 1 week, and then implanted in the backs of nude mice for 3 weeks. Three weeks later, cartilage matrix formation (proteoglycan and type II collagen) was achieved only in the E group, confirmed by safranin O staining and immunohistochemical staining for type II collagen. Taken together, these results indicate that aBMSC-dECM scaffolds could induce chondrogenic differentiation. Thus, they could be successful candidate scaffolds for cartilage tissue engineering.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1602
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1089/ten.TEA.2014.0491

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[PMID]: 26870936
[Au] Autor:Schneier A; Stueck AE; Petersen B; Thung SN; Perumalswami P
[Ad] Address:Hospital Medicine, Kaiser Permanente Panorama City Medical Center, Panorama City, California....
[Ti] Title:An Unusual Cause of Acute Liver Failure: Three Cases of Hemophagocytic Lymphohistiocytosis Presenting at a Transplant Center.
[So] Source:Semin Liver Dis;36(1):99-105, 2016 Feb.
[Is] ISSN:1098-8971
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Acquired hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disorder of the immune system. Hemophagocytic lymphohistiocytosis has been associated with infections, autoimmune disorders, and malignancy. This case series describes three patients admitted to an academic liver transplant center from February 2014 to February 2015 with acute liver failure (ALF) who were ultimately diagnosed with HLH. All cases were female patients (44 to 53 years of age) transferred for workup of ALF. All developed fevers and cytopenias and underwent rapid evaluation for liver transplant by a multidisciplinary team. A complete workup for ALF was negative for intrinsic liver disease and none had significant alcohol or toxin exposure. The patients had liver biopsies showing diffuse lobular necroinflammation, of which two had evidence of hemophagocytosis on histopathology. The diagnosis of HLH was made by bone marrow biopsy featuring histiocytes with hemophagocytosis. All cases were treated with chemotherapy, but died during their hospitalization. Hemophagocytic lymphohistiocytosis can present as ALF in adult patients. Given the low success rate of treatment, early diagnosis is critical. Therefore, a high degree of suspicion should be exercised in patients with unexplained ALF.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1602
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1055/s-0036-1571299

  7 / 337498 MEDLINE  
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[PMID]: 26588861
[Au] Autor:Wang Y; Wang H; Qian C; Tang J; Zhou W; Liu X; You Q; Hu R
[Ad] Address:State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, China....
[Ti] Title:3-(2-Oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one (compound 1), a novel potent Nrf2/ARE inducer, protects against DSS-induced colitis via inhibiting NLRP3 inflammasome.
[So] Source:Biochem Pharmacol;101:71-86, 2016 Feb 1.
[Is] ISSN:1873-2968
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:NLRP3 inflammasome is a key component of the inflammatory process and its dysregulation contributes to IBD for its ability to induce IL-1ß release. Previously, we reported that a novel small molecular activator of Nrf2, 3-(2-oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino-[2,1-a]isoquinolin-4(11bH)-one (compound 1) can prevent the development of colorectal adenomas in AOM-DSS models. Here we further investigated the anti-inflammatory effect of compound 1 in DSS-induced colitis in C57BL/6 and NLRP3(-/-) mice, and revealed the possible modulation by compound 1 of NLRP3 inflammasome-mediated IL-1ß release from macrophages. In C57BL/6 mice, oral administration of compound 1 significantly attenuated DSS-induced colonic pathological damage, remarkably inhibited inflammatory cells infiltration and decreased myeloperoxidase (MPO) and IL-1ß secretion in colons. In contrast, mice deficient for NLRP3 were less sensitive to DSS-induced acute colitis, and compound 1 treatment exerted no protective effect on DSS-induced intestinal inflammation in NLRP3(-/-) mice. The protective effect of compound 1 may be attributed to its inhibition of NLRP3 inflammasome and Nrf2 activation in colons. Furthermore, compound 1, as a small molecular activator of Nrf2, significantly inhibited NLRP3 inflammasome activation in both THP-1 derived macrophages and bone-marrow derived macrophages, as indicated by reduced expression of NLRP3 and cleaved caspase-1, and lowered IL-1ß secretion. Finally, compound 1-induced NLRP3 inflammasome inhibition is through blocking NLRP3 priming step and dependent on Nrf2 activation. Taken together, our findings demonstrate that compound 1 might be a potential agent for the treatment of IBD by targeting Nrf2 and NLRP3 inflammasome.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1602
[Js] Journal subset:IM
[St] Status:In-Process

  8 / 337498 MEDLINE  
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[PMID]: 27155399
[Au] Autor:Stiehler M; Rauh J; Bünger C; Jacobi A; Vater C; Schildberg T; Liebers C; Günther KP; Bretschneider H
[Ad] Address:University Centre for Orthopaedics & Trauma Surgery and Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus at Technische Universität Dresden, Germany....
[Ti] Title:In vitro characterization of bone marrow stromal cells from osteoarthritic donors.
[So] Source:Stem Cell Res;16(3):782-9, 2016 May.
[Is] ISSN:1876-7753
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BMSCs, also known as bone marrow-derived mesenchymal stem cells, provide an excellent source of progenitor cells for regenerative therapy. To assess whether osteoarthritis (OA) affects the regenerative potential of BMSCs we compared the proliferation and differentiation potential as well as the surface marker expression profile of OA- versus control BMSCs. BMSCs were isolated from bone marrow aspirates of n=14 patients with advanced-stage idiopathic hip OA (67±6years) and n=15 healthy individuals (61±4years). Proliferation was quantified by total DNA content and colony-forming-units of fibroblastsmax (CFU-F) assay. Differentiation assays included immunohistology, cell-specific alkaline phosphatase (ALP) activity, and osteogenic, chondrogenic as well as adipogenic marker gene qRT-PCR. Expression of BMSC-associated surface markers was analyzed using flow cytometry. No significant intergroup differences were observed concerning the proliferation potential, cell-specific ALP activity as well as adipogenic and osteogenic differentiation marker gene expressions. Interestingly, SOX9 gene expression levels were significantly increased in OA-BMSCs after 14days of chondrogenic stimulation (p<0.01). The surface markers CD73, CD90 and STRO-1 were elevated in relation to CD14, CD34 and CD45 in both groups (p<0.0001). Notably, OA-BMSCs showed significantly increased CD90 (p<0.01) and decreased CD166 (p<0.001) levels. Overall, the in vitro characteristics of BMSCs are not markedly influenced by OA. However, increased SOX9 and CD90 as well as reduced CD166 expression levels in OA-BMSCs warrant further investigation. These data will help to further understand the role of BMSC in OA and facilitate the application of autologous cell-based strategies for musculoskeletal tissue regeneration in OA patients.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1606
[Js] Journal subset:IM
[St] Status:In-Data-Review

  9 / 337498 MEDLINE  
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[PMID]: 27107345
[Au] Autor:Beeravolu N; Khan I; McKee C; Dinda S; Thibodeau B; Wilson G; Perez-Cruet M; Bahado-Singh R; Chaudhry GR
[Ad] Address:Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA; OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI 48309, USA....
[Ti] Title:Isolation and comparative analysis of potential stem/progenitor cells from different regions of human umbilical cord.
[So] Source:Stem Cell Res;16(3):696-711, 2016 May.
[Is] ISSN:1876-7753
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Human umbilical cord (hUC) blood and tissue are non-invasive sources of potential stem/progenitor cells with similar cell surface properties as bone marrow stromal cells (BMSCs). While they are limited in cord blood, they may be more abundant in hUC. However, the hUC is an anatomically complex organ and the potential of cells in various sites of the hUC has not been fully explored. We dissected the hUC into its discrete sites and isolated hUC cells from the cord placenta junction (CPJ), cord tissue (CT), and Wharton's jelly (WJ). Isolated cells displayed fibroblastoid morphology, and expressed CD29, CD44, CD73, CD90, and CD105, and showed evidence of differentiation into multiple lineages in vitro. They also expressed low levels of pluripotency genes, OCT4, NANOG, SOX2 and KLF4. Passaging markedly affected cell proliferation with concomitant decreases in the expression of pluripotency and other markers, and an increase in chondrogenic markers. Microarray analysis further revealed the differences in the gene expression of CPJ-, CT- and WJ-hUC cells. Five coding and five lncRNA genes were differentially expressed in low vs. high passage hUC cells. Only MAEL was expressed at high levels in both low and high passage CPJ-hUC cells. They displayed a greater proliferation limit and a higher degree of multi-lineage differentiation in vitro and warrant further investigation to determine their full differentiation capacity, and therapeutic and regenerative medicine potential.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1606
[Js] Journal subset:IM
[St] Status:In-Data-Review

  10 / 337498 MEDLINE  
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[PMID]: 27100840
[Au] Autor:Manukjan G; Ripperger T; Venturini L; Stadler M; Göhring G; Schambach A; Schlegelberger B; Steinemann D
[Ad] Address:Institute of Human Genetics, Hannover Medical School, Hannover, Germany. Electronic address: manukjan.georgi@mh-hannover.de....
[Ti] Title:GABP is necessary for stem/progenitor cell maintenance and myeloid differentiation in human hematopoiesis and chronic myeloid leukemia.
[So] Source:Stem Cell Res;16(3):677-81, 2016 May.
[Is] ISSN:1876-7753
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Maintenance of hematopoietic stem cells and their potential to give rise to progenitors of differentiated lymphoid and myeloid cells are accomplished by a network of regulatory processes. As a part of this network, the heteromeric transcription factor GA-binding protein (GABP) plays a crucial role in self-renewal of murine hematopoietic and leukemic stem cells. Here, we report the consequences of functional impairment of GABP in human hematopoietic and in leukemic stem/progenitor cells. Ectopic overexpression of a dominant-negative acting GABP mutant led to impaired myeloid differentiation of CD34(+) hematopoietic stem/progenitor cells obtained from healthy donors. Moreover, drastically reduced clonogenic capacity of leukemic stem/progenitor cells isolated from bone marrow aspirates of chronic myeloid leukemia (CML) patients underlines the importance of GABP on stem/progenitor cell maintenance and confirms the relevance of GABP for human myelopoiesis in healthy and diseased states.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1606
[Js] Journal subset:IM
[St] Status:In-Data-Review


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