107 research outputs found
Exploring extramedullary hematopoiesis: unraveling the hematopoietic microenvironments
Hematopoiesis is a process by which all blood cells are formed. The mechanisms controlling it have been studied for decades. Surprisingly, while hematopoietic stem cells are among the most extensively studied stem cell types, the complete understanding of how they are regulated during development, adulthood, or in non-homeostatic conditions remains elusive. In this review, our primary focus is on research findings that explore where hematopoietic precursors are found in adults outside their primary niches in the bone marrow. This phenomenon is termed extramedullary hematopoiesis (EMH). Early in development hematopoietic stem cells migrate through different regions within and outside the embryo and later the fetus. Although, the primary home for hematopoietic progenitors is the adult bone marrow, it is now recognized that other adult organs may act as hematopoietic progenitor reservoirs both in mice and humans. The first reports about this topic were principally originated from clinical observations, in cases where the bone marrow was malfunctioning, leading to an aberrant hematopoiesis outside the bone marrow. It is worth highlighting that those extramedullary organs, like the small intestine or fat tissue, contain subsets of fully functioning hematopoietic progenitors demonstrated by both in vitro and in vivo studies. Nonetheless, there are still some unanswered questions regarding the source of these cells, how they differ in function compared to their counterparts in the bone marrow, and the specific roles they play within the tissues where they are located
Maternal microchimerism in the livers of patients with Biliary atresia
BACKGROUND: Biliary atresia (BA) is a neonatal cholestatic disease of unknown etiology. It is the leading cause of liver transplantation in children. Many similarities exist between BA and graft versus host disease suggesting engraftment of maternal cells during gestation could result in immune responses that lead to BA. The aim of this study was to determine the presence and extent of maternal microchimerism (MM) in the livers of infants with BA. METHODS: Using fluorescent in situ hybridization (FISH), 11 male BA & 4 male neonatal hepatitis (NH) livers, which served as controls, were analyzed for X and Y-chromosomes. To further investigate MM in BA, 3 patients with BA, and their mothers, were HLA typed. Using immunohistochemical stains, the BA livers were examined for MM. Four additional BA livers underwent analysis by polymerase chain reaction (PCR) for evidence of MM. RESULTS: By FISH, 8 BA and 2 NH livers were interpretable. Seven of eight BA specimens showed evidence of MM. The number of maternal cells ranged from 2–4 maternal cells per biopsy slide. Neither NH specimen showed evidence of MM. In addition, immunohistochemical stains confirmed evidence of MM. Using PCR, a range of 1–142 copies of maternal DNA per 25,000 copies of patients DNA was found. CONCLUSIONS: Maternal microchimerism is present in the livers of patients with BA and may contribute to the pathogenesis of BA
A Neutralizing Monoclonal Antibody Targeting the Acid-Sensitive Region in Chikungunya Virus E2 Protects from Disease.
The mosquito-borne alphavirus, chikungunya virus (CHIKV), has recently reemerged, producing the largest epidemic ever recorded for this virus, with up to 6.5 million cases of acute and chronic rheumatic disease. There are currently no licensed vaccines for CHIKV and current anti-inflammatory drug treatment is often inadequate. Here we describe the isolation and characterization of two human monoclonal antibodies, C9 and E8, from CHIKV infected and recovered individuals. C9 was determined to be a potent virus neutralizing antibody and a biosensor antibody binding study demonstrated it recognized residues on intact CHIKV VLPs. Shotgun mutagenesis alanine scanning of 98 percent of the residues in the E1 and E2 glycoproteins of CHIKV envelope showed that the epitope bound by C9 included amino-acid 162 in the acid-sensitive region (ASR) of the CHIKV E2 glycoprotein. The ASR is critical for the rearrangement of CHIKV E2 during fusion and viral entry into host cells, and we predict that C9 prevents these events from occurring. When used prophylactically in a CHIKV mouse model, C9 completely protected against CHIKV viremia and arthritis. We also observed that when administered therapeutically at 8 or 18 hours post-CHIKV challenge, C9 gave 100% protection in a pathogenic mouse model. Given that targeting this novel neutralizing epitope in E2 can potently protect both in vitro and in vivo, it is likely to be an important region both for future antibody and vaccine-based interventions against CHIKV
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Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures
We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large intercompartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Oxford University Press on behalf of Nucleic Acids Research. The published article can be found at: http://nar.oxfordjournals.org/
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Searching for common stem cells of the hepatic and hematopoietic systems in the human fetal liver: CD34(+) cytokeratin 7/8(+) cells express markers for stellate cells
Background/Aims: The hematopoietic and hepatic systems are intertwined in the liver during fetal life. Cells expressing the hematopoietic stem cell marker CD34 and cytokeratin 7/8 (CK7/8) are hypothesized to be common stem cells for the hematopoietic and hepatic systems. Our aim was to determine if human fetal liver cells expressing CD34 and CK7/8 represent a common stem cell for both the hernatopoietic and hepatic systems. Methods: CD34(+)CK7/8(+) cells from midgestation livers were analyzed for the expression of various markers by flow cytometry and isolated based on their expression of CD34, nerve growth factor receptor (NGFR) and lack of CD45 expression. CD34(+)CD38(-) hematopoietic stem cells were also isolated and cultured in the presence of various hepatopoietins. Results: CD34(+)CK7/8(+) cells comprised 3.4-8.5% of the erythrocyte-depleted liver. CD34(+)CK7/8(+) cells had unique light-scatter properties compared to hematopoietic precursors and did not express most markers associated with hernatopoietic cells. They did stain with CD13, CD59, NGFR, desmin and alpha-smooth muscle actin. In culture, these cells had a stellate appearance. Cultured hernatopoietic stem cells failed to generate hepatocytes. Conclusions: CD34(+)CK7/8(+) cells are not common stem cells but rather appear to be hepatic stellate cells. A link between the hematopoietic and hepatic systems during fetal life requires further investigation. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved
Isolation, growth and identification of colony-forming cells with erythroid, myeloid, dendritic cell and NK-cell potential from human fetal liver
Megakaryocyte growth and development factor (MGDF), or thrombopoietin, has received considerable attention as a therapeutic agent for treating thrombocytopenia or for its use in the ex vivo culture of hematopoietic stein cells. MGDF is known to support the growth of a broad spectrum of hematopoietic precursors obtained from adult or neonatal tissues, but its effects on the growth of fetal progenitors and stem cells has not been studied. Human CD38(+)CD34(2+) progenitors and CD38(-)CD34(2+) cells, a population that contains stem cells, were isolated from midgestation liver and grown under defined conditions with MGDF and various cytokines known to support the growth of primitive hematopoietic precursors. In clonal assays of colony-forming cells (CFCs), MGDF supported the growth of 15-25% of candidate stem cells when combined with granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), flk-2/flt3 ligand, or stem cell factor. MGDF was observed to strongly support the early stages of hematopoiesis and expansion of high proliferative potential CFCs. More mature progenitors were expanded nearly 78-fold in 1 wk of culture with MGDF+SCF+GM-CSF. MGDF alone was also found to support the short-term (2 d) survival of CD38(-)CD34(2+) high proliferative potential CFCs. The effects of MGDF were more modest on CD38(+)CD34(2+) progenitors with only additive increases in colony formation being observed. These findings suggest that MGDF administration in fetuses and neonates may strongly affect the growth and mobilization of primitive hematopoietic progenitors and that MGDF may find use in the ex vivo growth and expansion of fetal stem cells
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A kinetic study of the murine mixed lymphocyte reaction by 5,6-carboxyfluorescein diacetate succinimidyl ester labeling
Alternatives to the use of radioisotopes to measure cell proliferation in mixed lymphocyte reactions (MLR) are desirable to avoid the hazards and costs associated with radioisotope use. The versatile fluorochrome 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) has been used to measure MLR and provides the opportunity to measure several different growth parameters. This study was aimed at determining which growth parameter is most practical and suitable for measuring murine MLR. The parameters measured were: the relative number of daughter T-cells, the relative number and frequency of reactive T-cell precursors and the relative number of mitotic events. Responder cells were CFSE-labeled unfractionated splenocytes from C57BL/6 mice. Stimulator cells included irradiated splenocytes from C57BL/6 (control), B6D2F(1) (haplo-allogeneic) or FVB/N (allogeneic) mice. Cultures were harvested daily for 1 week. Stimulator T-cells rapidly declined to less than 0.2-0.3% of the mixed population by day 2 of culture. Experimental groups had a significantly higher number of daughter T-cells and mitotic events after 2 days of culture with the number of daughter T-cells climbing exponentially after 5 days of culture. The number and frequency of reactive T-cell precursors were significantly higher in experimental groups on days 2-3, but this difference became insignificant by day 4. Among all the parameters, the relative number of daughter T-cells was the most practical for measuring MLR, after 5 days of culture, based upon the growth kinetics of responder T-cells and the survival of the stimulator cells. (C) 2003 Elsevier B.V. All rights reserved
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