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ABSTRACT: Despite a well-defined role for the Fanconi anemia (FA) pathway in mediating DNA repair, the mechanisms underlying the bone marrow failure in FA patients are poorly defined. Recently in Nature, Garaycoechea et al. (2012), identify aldehyde-mediated genotoxicity of hematopoietic stem cells as a cause for bone marrow failure.
Cell stem cell 11/2012; 11(5):583-4. · 23.56 Impact Factor
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Eva C Guinan,
Christine M Barbon,
Leslie A Kalish, Kalindi Parmar,
Jeff Kutok,
Christy J Mancuso,
Liat Stoler-Barak,
Eugénie E Suter,
Janice D Russell,
Christine D Palmer,
Leighanne C Gallington,
Annie Voskertchian,
Jo-Anne Vergilio,
Geoffrey Cole,
Kaya Zhu,
Alan D'Andrea,
Robert Soiffer,
Jerrold P Weiss,
Ofer Levy
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ABSTRACT: Identification of safe, effective treatments to mitigate toxicity after extensive radiation exposure has proven challenging. Only a limited number of candidate approaches have emerged, and the U.S. Food and Drug Administration has yet to approve any agent for a mass-casualty radiation disaster. Because patients undergoing hematopoietic stem cell transplantation undergo radiation treatment that produces toxicities similar to radiation-disaster exposure, we studied patients early after such treatment to identify new approaches to this problem. Patients rapidly developed endotoxemia and reduced plasma bactericidal/permeability-increasing protein (BPI), a potent endotoxin-neutralizing protein, in association with neutropenia. We hypothesized that a treatment supplying similar endotoxin-neutralizing activity might replace the BPI deficit and mitigate radiation toxicity and tested this idea in mice. A single 7-Gy radiation dose, which killed 95% of the mice by 30 days, was followed 24 hours later by twice-daily, subcutaneous injections of the recombinant BPI fragment rBPI21 or vehicle alone for 14 or 30 days, with or without an oral fluoroquinolone antibiotic with broad-spectrum antibacterial activity, including that against endotoxin-bearing Gram-negative bacteria. Compared to either fluoroquinolone alone or vehicle plus fluoroquinolone, the combined rBPI21 plus fluoroquinolone treatment improved survival, accelerated hematopoietic recovery, and promoted expansion of stem and progenitor cells. The observed efficacy of rBPI21 plus fluoroquinolone initiated 24 hours after lethal irradiation, combined with their established favorable bioactivity and safety profiles in critically ill humans, suggests the potential clinical use of this radiation mitigation strategy and supports its further evaluation.
Science translational medicine 11/2011; 3(110):110ra118. · 7.80 Impact Factor
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ABSTRACT: The aminothiol WR1065 is a highly effective free radical scavenger which can protect cells from the cytotoxic effects of ionizing radiation. Currently, WR1065 is used clinically to protect patients from radiation injury occurring during radiation therapy protocols. However, it is becoming increasingly clear that WR1065 can alter radiosensitivity through a mechanism which is independent of its ability to function as a free radical scavenger. Here, we examined the ability of WR1065 to directly regulate signaling pathways involved in the DNA damage response.
The ability of WR1065 to enhance the survival of irradiated bone marrow cells and primary cultures was established. DNA damage signaling was monitored by measuring activation of the ATM kinase by western blot analysis and activation of Tip60 using an in vitro acetylation assay. Tip60 function was abrogated by expression of a catalytically inactive Tip60, and the effect on radiosensitivity evaluated. Principal findings: Treatment of cells with WR1065 led to a small but significant increase in the kinase activity of ATM. Further, WR1065 robustly activated the Tip60 acetyltransferase, which is a key upstream regulator of the ATM kinase. In addition, WR1065 directly activated the acetyltransferase activity of purified Tip60 in vitro, indicating a direct interaction between WR1065 and Tip60. Finally, cells with reduced levels of Tip60 activity exhibited a significant reduction in radioprotection by WR1065.
Direct regulation of Tip60's acetyltransferase activity by WR1065 makes a significant contribution to the radioprotective effects of WR1065. Activators of Tip60 may therefore make effective clinical radioprotectors.
International journal of biochemistry and molecular biology. 01/2011; 2(4):295-302.
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ABSTRACT: Hypoxia inducible factor 1α (Hif1α) is a stress responsive transcription factor, which regulates the expression of genes required for adaption to hypoxia. Hif1α is normally hydroxylated by an oxygen-dependent prolylhydroxylase, leading to degradation and clearance of Hif1α from the cell. Under hypoxic conditions, the activity of the prolylhydroxylase is reduced and Hif1α accumulates. Hif1α is also constitutively expressed in tumor cells, where it is associated with resistance to ionizing radiation. Activation of the Hif1α transcriptional regulatory pathway may therefore function to protect normal cells from DNA damage caused by ionizing radiation. Here, we utilized the prolylhydroxylase inhibitor dimethyloxalylglycine (DMOG) to elevate Hif1α levels in mouse embryonic fibroblasts (MEFs) to determine if DMOG could function as a radioprotector. The results demonstrate that DMOG increased Hif1α protein levels and decreased the sensitivity of MEFs to ionizing radiation. Further, the ability of DMOG to function as a radioprotector required Hif1α, indicating a key role for Hif1α's transcriptional activity. DMOG also induced the Hif1α -dependent accumulation of several DNA damage response proteins, including CHD4 and MTA3 (sub-units of the NuRD deacetylase complex) and the Suv39h1 histone H3 methyltransferase. Depletion of Suv39h1, but not CHD4 or MTA3, reduced the ability of DMOG to protect cells from radiation damage, implicating increased histone H3 methylation in the radioprotection of cells. Finally, treatment of mice with DMOG prior to total body irradiation resulted in significant radioprotection of the mice, demonstrating the utility of DMOG and related prolylhydroxylase inhibitors to protect whole organisms from ionizing radiation. Activation of Hif1α through prolylhydroxylase inhibition therefore identifies a new pathway for the development of novel radiation protectors.
PLoS ONE 01/2011; 6(10):e26064. · 4.09 Impact Factor
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Shuxian Jiang,
Radoslaw Zagozdzon,
Meritxell Alberich Jorda, Kalindi Parmar,
Yigong Fu,
John S Williams,
Jodi Anne T Wood,
Alexandros Makriyannis,
Naheed Banu,
Shalom Avraham,
Jerome E Groopman,
Hava Karsenty Avraham
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ABSTRACT: Endocannabinoids are lipid signaling molecules that act via G-coupled receptors, CB(1) and CB(2). The endocannabinoid system is capable of activation of distinct signaling pathways on demand in response to pathogenic events or stimuli, hereby enhancing cell survival and promoting tissue repair. However, the role of endocannabinoids in hematopoietic stem and progenitor cells (HSPCs) and their interaction with hematopoietic stem cells (HSC) niches is not known. HSPCs are maintained in the quiescent state in bone marrow (BM) niches by intrinsic and extrinsic signaling. We report that HSPCs express the CB(1) receptors and that BM stromal cells secrete endocannabinoids, anandamide (AEA) (35 pg/10(7) cells), and 2-AG (75.2 ng/10(7) cells). In response to the endotoxin lipopolysaccharide (LPS), elevated levels of AEA (75.6 pg/10(7) cells) and 2-AG (98.8 ng/10(7) cells) were secreted from BM stromal cells, resulting in migration and trafficking of HSPCs from the BM niches to the peripheral blood. Furthermore, administration of exogenous cannabinoid CB(1) agonists in vivo induced chemotaxis, migration, and mobilization of human and murine HSPCs. Cannabinoid receptor knock-out mice Cnr1(-/-) showed a decrease in side population (SP) cells, whereas fatty acid amide hydrolase (FAAH)(-/-) mice, which have elevated levels of AEA, yielded increased colony formation as compared with WT mice. In addition, G-CSF-induced mobilization in vivo was modulated by endocannabinoids and was inhibited by specific cannabinoid antagonists as well as impaired in cannabinoid receptor knock-out mice Cnr1(-/-), as compared with WT mice. Thus, we propose a novel function of the endocannabinoid system, as a regulator of HSPC interactions with their BM niches, where endocannabinoids are expressed in HSC niches and under stress conditions, endocannabinoid expression levels are enhanced to induce HSPC migration for proper hematopoiesis.
Journal of Biological Chemistry 11/2010; 285(46):35471-8. · 4.77 Impact Factor
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Shuxian Jiang,
Radoslaw Zagozdzon,
Meritxell Alberich Jorda, Kalindi Parmar,
Yigong Fu,
John S. Williams,
Jodi Anne T. Wood,
Alexandros Makriyannis,
Naheed Banu,
Shalom Avraham,
Jerome E. Groopman,
Hava Karsenty Avraham
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ABSTRACT: Endocannabinoids are lipid signaling molecules that act via G-coupled receptors, CB1 and CB2. The endocannabinoid system is capable of activation of distinct signaling pathways on demand in response to pathogenic events
or stimuli, hereby enhancing cell survival and promoting tissue repair. However, the role of endocannabinoids in hematopoietic
stem and progenitor cells (HSPCs) and their interaction with hematopoietic stem cells (HSC) niches is not known. HSPCs are
maintained in the quiescent state in bone marrow (BM) niches by intrinsic and extrinsic signaling. We report that HSPCs express
the CB1 receptors and that BM stromal cells secrete endocannabinoids, anandamide (AEA) (35 pg/107 cells), and 2-AG (75.2 ng/107 cells). In response to the endotoxin lipopolysaccharide (LPS), elevated levels of AEA (75.6 pg/107 cells) and 2-AG (98.8 ng/107 cells) were secreted from BM stromal cells, resulting in migration and trafficking of HSPCs from the BM niches to the peripheral
blood. Furthermore, administration of exogenous cannabinoid CB1 agonists in vivo induced chemotaxis, migration, and mobilization of human and murine HSPCs. Cannabinoid receptor knock-out mice Cnr1−/− showed a decrease in side population (SP) cells, whereas fatty acid amide hydrolase (FAAH)−/− mice, which have elevated levels of AEA, yielded increased colony formation as compared with WT mice. In addition, G-CSF-induced
mobilization in vivo was modulated by endocannabinoids and was inhibited by specific cannabinoid antagonists as well as impaired in cannabinoid
receptor knock-out mice Cnr1−/−, as compared with WT mice. Thus, we propose a novel function of the endocannabinoid system, as a regulator of HSPC interactions
with their BM niches, where endocannabinoids are expressed in HSC niches and under stress conditions, endocannabinoid expression
levels are enhanced to induce HSPC migration for proper hematopoiesis.
Journal of Biological Chemistry 11/2010; 285(46):35471-35478. · 4.77 Impact Factor
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Shuxian Jiang,
Meritxell Alberich-Jorda,
Radoslaw Zagozdzon, Kalindi Parmar,
Yigong Fu,
Peter Mauch,
Naheed Banu,
Alexandros Makriyannis,
Daniel G Tenen,
Shalom Avraham,
Jerome E Groopman,
Hava Karsenty Avraham
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ABSTRACT: Endocannabinoids are arachidonic acid derivatives and part of a novel bioactive lipid signaling system, along with their G-coupled cannabinoid receptors (CB₁ and CB₂) and the enzymes involved in their biosynthesis and degradation. However, their roles in hematopoiesis and hematopoietic stem and progenitor cell (HSPC) functions are not well characterized. Here, we show that bone marrow stromal cells express endocannabinoids (anandamide and 2-arachidonylglycerol), whereas CB₂ receptors are expressed in human and murine HSPCs. On ligand stimulation with CB₂ agonists, CB₂ receptors induced chemotaxis, migration, and enhanced colony formation of bone marrow cells, which were mediated via ERK, PI3-kinase, and Gαi-Rac1 pathways. In vivo, the CB₂ agonist AM1241 induced mobilization of murine HSPCs with short- and long-term repopulating abilities. In addition, granulocyte colony-stimulating factor -induced mobilization of HSPCs was significantly decreased by specific CB₂ antagonists and was impaired in Cnr2(-/-) cannabinoid type 2 receptor knockout mice. Taken together, these results demonstrate that the endocannabinoid system is involved in hematopoiesis and that CB₂/CB₂ agonist axis mediates repopulation of hematopoiesis and mobilization of HSPCs. Thus, CB₂ agonists may be therapeutically applied in clinical conditions, such as bone marrow transplantation.
Blood 11/2010; 117(3):827-38. · 9.90 Impact Factor
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ABSTRACT: Fanconi anemia (FA) is a genomic instability disorder characterized by bone marrow failure and cancer predisposition. FA is caused by mutations in any one of several genes that encode proteins cooperating in a repair pathway and is required for cellular resistance to DNA crosslinking agents. Recent studies suggest that the FA pathway may also play a role in mitosis, since FANCD2 and FANCI, the 2 key FA proteins, are localized to the extremities of ultrafine DNA bridges (UFBs), which link sister chromatids during cell division. However, whether FA proteins regulate cell division remains unclear. Here we have shown that FA pathway-deficient cells display an increased number of UFBs compared with FA pathway-proficient cells. The UFBs were coated by BLM (the RecQ helicase mutated in Bloom syndrome) in early mitosis. In contrast, the FA protein FANCM was recruited to the UFBs at a later stage. The increased number of bridges in FA pathway-deficient cells correlated with a higher rate of cytokinesis failure resulting in binucleated cells. Binucleated cells were also detectable in primary murine FA pathway-deficient hematopoietic stem cells (HSCs) and bone marrow stromal cells from human patients with FA. Based on these observations, we suggest that cytokinesis failure followed by apoptosis may contribute to bone marrow failure in patients with FA.
The Journal of clinical investigation 10/2010; 120(11):3834-42. · 15.39 Impact Factor
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Kalindi Parmar,
Jungmin Kim,
Stephen M Sykes,
Akiko Shimamura,
Patricia Stuckert,
Kaya Zhu,
Abigail Hamilton,
Mary Kathryn Deloach,
Jeffery L Kutok,
Koichi Akashi,
D Gary Gilliland,
Alan D'andrea
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ABSTRACT: Fanconi anemia (FA) is a human genetic disease characterized by a DNA repair defect and progressive bone marrow failure. Central events in the FA pathway are the monoubiquitination of the Fancd2 protein and the removal of ubiquitin by the deubiquitinating enzyme, Usp1. Here, we have investigated the role of Fancd2 and Usp1 in the maintenance and function of murine hematopoietic stem cells (HSCs). Bone marrow from Fancd2-/- mice and Usp1-/- mice exhibited marked hematopoietic defects. A decreased frequency of the HSC populations including Lin-Sca-1+Kit+ cells and cells enriched for dormant HSCs expressing signaling lymphocyte activation molecule (SLAM) markers, was observed in the bone marrow of Fancd2-deficient mice. In addition, bone marrow from Fancd2-/- mice contained significantly reduced frequencies of late-developing cobblestone area-forming cell activity in vitro compared to the bone marrow from wild-type mice. Furthermore, Fancd2-deficient and Usp1-deficient bone marrow had defective long-term in vivo repopulating ability. Collectively, our data reveal novel functions of Fancd2 and Usp1 in maintaining the bone marrow HSC compartment and suggest that FA pathway disruption may account for bone marrow failure in FA patients.
Stem Cells 07/2010; 28(7):1186-95. · 7.78 Impact Factor
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ABSTRACT: Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 05/2009; 668(1-2):133-40. · 2.85 Impact Factor
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ABSTRACT: Fanconi anemia (FA) is a human genetic disease characterized by chromosome instability, cancer predisposition, and cellular hypersensitivity to DNA crosslinking agents. The FA pathway regulates the repair of DNA crosslinks. A critical step in this pathway is the monoubiquitination and deubiquitination of FANCD2. Deubiquitination of FANCD2 is mediated by the ubiquitin protease, USP1. Here, we demonstrate that targeted deletion of mouse Usp1 results in elevated perinatal lethality, male infertility, crosslinker hypersensitivity, and an FA phenotype. Usp1(-/-) mouse embryonic fibroblasts had heightened levels of monoubiquitinated Fancd2 in chromatin. Usp1(-/-) cells exhibited impaired Fancd2 foci assembly and a defect in homologous recombination repair. Double knockout of Usp1 and Fancd2 resulted in a more severe phenotype than either single knockout. Our results indicate that mouse Usp1 functions downstream in the FA pathway. Deubiquitination is a critical event required for Fancd2 nuclear foci assembly, release from chromatin, and function in DNA repair.
Developmental cell 03/2009; 16(2):314-20. · 13.36 Impact Factor
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ABSTRACT: The interaction of stem cells with their bone marrow microenvironment is a critical process in maintaining normal hematopoiesis. We applied an approach to resolve the spatial organization that underlies these interactions by evaluating the distribution of hematopoietic cell subsets along an in vivo Hoechst 33342 (Ho) dye perfusion gradient. Cells isolated from different bone marrow regions according to Ho fluorescence intensity contained the highest concentration of hematopoietic stem cell (HSC) activity in the lowest end of the Ho gradient (i.e., in the regions reflecting diminished perfusion). Consistent with the ability of Ho perfusion to simulate the level of oxygenation, bone marrow fractions separately enriched for HSCs were found to be the most positive for the binding of the hypoxic marker pimonidazole. Moreover, the in vivo administration of the hypoxic cytotoxic agent tirapazamine exhibited selective toxicity to the primitive stem cell subset. These data collectively indicate that HSCs and the supporting cells of the stem cell niche are predominantly located at the lowest end of an oxygen gradient in the bone marrow with the implication that regionally defined hypoxia plays a fundamental role in regulating stem cell function.
Proceedings of the National Academy of Sciences 04/2007; 104(13):5431-6. · 9.68 Impact Factor
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ABSTRACT: We previously observed high levels (>40%) of multilineage hematopoietic cell chimerism following spleen transplantation across full MHC barriers in immunosuppressed miniature swine. We therefore investigated the spleen as a source of hematopoietic progenitor cells (HPCs).
Specific cell-surface markers were used to identify HPCs in the spleen and bone marrow (BM) of young adult (n = 15) and fetal (n = 9) miniature swine by flow cytometry. Hoechst dye-effluxing side population (SP) cells were analyzed in adult spleen, BM, and blood for their expression of c-kit. Functional HPC activity of varying repopulation potential in vitro was investigated by the ability of spleens and BM to give rise to colony-forming units (CFUs) and cobblestone area-forming cells (CAFCs) in long-term stromal cultures. Studies were also carried out on baboon and human spleens and BM.
Spleen c-kit+ cells co-expressed more lymphoid markers, but equal myeloid markers, when compared with BM c-kit+ cells. BM and spleen both contained significant percentages of c-kit+ SP cells. Although the frequency of early-forming CFUs in the spleen was only 0.1 to 1.3% of that in the BM, the frequency of CAFCs developing after 8 weeks in culture was comparable to that of BM. Secondary CFUs in long-term culture-initiating cell assays confirmed the presence of long-term repopulating cells at comparable frequencies in spleen and BM. Similar findings were found with regard to baboon and human spleen cells.
The adult spleen is a relatively rich source of very primitive HPCs, possibly hematopoietic stem cells (HSCs), and may be of therapeutic value.
Experimental Hematology 12/2006; 34(11):1573-82. · 2.90 Impact Factor
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ABSTRACT: Primitive hematopoietic stem cells (HSCs) can be purified from murine bone marrow by sorting Hoechst 33342-effluxing side population (SP) cells. The aim of this study was to establish whether SP cells from peripheral blood contain primitive HSCs and whether this is altered in mice following mobilization. SP cells were analyzed and isolated from bone marrow and blood of mice after mobilization; the HSC content of isolated SP cells was determined through surrogate cobblestone area-forming cell (CAFC) assays. SP cells in normal blood were not found in the high Hoechst dye effluxing portion of the SP tail, did not express the stem cell markers c-Kit and CD34, and did not have measurable CAFC activity. In contrast, SP cells in mobilized blood expressed both stem cell markers, contained cells in the high dye efflux portion of the SP tail, and displayed significant day- 28 to day-35 CAFC activity with 165- to 334-fold enrichment. In comparison to mobilized blood SP cells, normal marrow SP cells contained a higher proportion of cells expressing c-Kit and CD34 and had a greater percentage of cells in the high Hoechst dye-effluxing portion of the SP tail. Analysis of SP cells in the bone marrow after mobilization revealed a decrease in the frequency of SP cells, in expression of c-Kit and Sca+ CD34(+)/CD34(-), and in day-7 to day-35 CAFC activity, consistent with mobilization into blood. We conclude that murine SP cells mobilized into blood contain primitive hematopoietic stem cell activity (day-28 to day-35 CAFC activity). This model offers a means to study the mechanisms of mobilization of primitive stem cells directly in a murine model.
Stem Cells and Development 09/2005; 14(4):452-61. · 4.46 Impact Factor
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ABSTRACT: Suppression of apoptosis is an important feature of the Abelson murine leukemia virus (Ab-MLV) transformation process. During multistep transformation, Ab-MLV-infected pre-B cells undergo p53-dependent apoptosis during the crisis phase of transformation. Even once cells are fully transformed, an active v-Abl protein tyrosine kinase is required to suppress apoptosis because cells transformed by temperature-sensitive (ts) kinase mutants undergo rapid apoptosis after a shift to the nonpermissive temperature. However, inactivation of the v-Abl protein by a temperature shift interrupts signals transmitted via multiple pathways, making it difficult to identify those that are critically important for the suppression of apoptosis. To begin to dissect these pathways, we tested the ability of an SH2 domain Ab-MLV mutant, P120/R273K, to rescue aspects of the ts phenotype of pre-B cells transformed by the conditional kinase domain mutant. The P120/R273K mutant suppressed apoptosis at the nonpermissive temperature, a phenotype correlated with its ability to activate Akt. Apoptosis also was suppressed at the nonpermissive temperature by constitutively active Akt and in p53-null pre-B cells transformed with the ts kinase domain mutant. These data indicate that an intact Src homology 2 (SH2) domain is not critical for apoptosis suppression and suggest that signals transmitted through Akt and p53 play an important role in the response.
Journal of Virology 03/2004; 78(4):1636-44. · 5.40 Impact Factor
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ABSTRACT: The aim of this study was to characterize murine side population (SP) stem cells and SP cell subpopulations for primitive stem cell capacity.
SP cells, characterized by a specific Hoechst dye efflux pattern, were isolated by flow cytometric analysis and sorting from murine adult whole bone marrow (WBM). Different subpopulations of SP cells were isolated by staining with anti-Sca and anti-CD34 antibodies. Primitive stem cell content of SP cells and SP subsets were determined by cobblestone area-forming cell (CAFC) frequencies.
Measurement of CAFC frequencies revealed that SP cells are greatly enriched for both primitive stem cells (day-28-35 CAFC) and somewhat more mature hematopoietic cells (day-14-21 CAFC) compared to WBM. The day-28 and day-35 CAFC enrichments in SP cells vs WBM cells were 1065 and 471, respectively. Analysis of the subpopulations of SP cells revealed that SP(+)Sca(-)CD34(+) cells contained almost exclusively day-7 CAFC and had little day-28-35 CAFC activity. SP(+)Sca(+)CD34(+) cells had high day-7-14 CAFC frequencies, but lower day-35 CAFC frequencies compared to SP(+)Sca(+)CD34(-) cells. SP(+)Sca(+)CD34(-) cells contained very low day-7 CAFC activity, but nearly 2200 times the day-28-35 CAFC activity as normal bone marrow. To evaluate the influence of Hoechst dye efflux capacity, we divided the SP tail into four groups of cells. The SP cells with lowest efflux of Hoechst dye contained the highest progenitor activity (day-7-14 CAFC). The highest day-35 CAFC frequencies, nearly 6000 times those of normal marrow, were seen in the SP cells with the greatest efflux of the Hoechst dye.
Murine SP cells contain both progenitor and primitive populations of hematopoietic stem cells. The most primitive stem cells measured in the in vitro CAFC assay mark for Sca(+) and CD34(-) and have a high ability to efflux Hoechst dye. Isolation of these cells may provide the means to directly study mechanisms of primitive stem cell damage.
Experimental Hematology 04/2003; 31(3):244-50. · 2.90 Impact Factor
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ABSTRACT: Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis.
