IU Indianapolis ScholarWorks :: Browsing by Subject "Hematopoiesis"

Browsing by Subject "Hematopoiesis"

Now showing 1 - 10 of 54

An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia
(Ferrata Storti Foundation, 2017-06) Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D.; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A.; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D. Wade; Yang, Feng-Chun; Pediatrics, School of Medicine
Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.
Age and Sex Divergence in Hematopoietic Radiosensitivity in Aged Mouse Models of the Hematopoietic Acute Radiation Syndrome
(BioOne, 2022) Patterson, Andrea M.; Vemula, Sasidhar; Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Fisher, Alexa; Wu, Tong; Sellamuthu, Rajendran; Feng, Hailin; Katz, Barry P.; DesRosiers, Colleen M.; Pelus, Louis M.; Cox, George N.; MacVittie, Thomas J.; Orschell, Christie M.; Medicine, School of Medicine
The hematopoietic system is highly sensitive to stress from both aging and radiation exposure, and the hematopoietic acute radiation syndrome (H-ARS) should be modeled in the geriatric context separately from young for development of age-appropriate medical countermeasures (MCMs). Here we developed aging murine H-ARS models, defining radiation dose response relationships (DRRs) in 12-month-old middle-aged and 24-month-old geriatric male and female C57BL/6J mice, and characterized diverse factors affecting geriatric MCM testing. Groups of approximately 20 mice were exposed to ∼10 different doses of radiation to establish radiation DRRs for estimation of the LD50/30. Radioresistance increased with age and diverged dramatically between sexes. The LD50/30 in young adult mice averaged 853 cGy and was similar between sexes, but increased in middle age to 1,005 cGy in males and 920 cGy in females, with further sex divergence in geriatric mice to 1,008 cGy in males but 842 cGy in females. Correspondingly, neutrophils, platelets, and functional hematopoietic progenitor cells were all increased with age and rebounded faster after irradiation. These effects were higher in aged males, and neutrophil dysfunction was observed in aged females. Upstream of blood production, hematopoietic stem cell (HSC) markers associated with age and myeloid bias (CD61 and CD150) were higher in geriatric males vs. females, and sex-divergent gene signatures were found in HSCs relating to cholesterol metabolism, interferon signaling, and GIMAP family members. Fluid intake per gram body weight decreased with age in males, and decreased after irradiation in all mice. Geriatric mice of substrain C57BL/6JN sourced from the National Institute on Aging were significantly more radiosensitive than C57BL/6J mice from Jackson Labs aged at our institution, indicating mouse source and substrain should be considered in geriatric radiation studies. This work highlights the importance of sex, vendor, and other considerations in studies relating to hematopoiesis and aging, identifies novel sex-specific functional and molecular changes in aging hematopoietic cells at steady state and after irradiation, and presents well-characterized aging mouse models poised for MCM efficacy testing for treatment of acute radiation effects in the elderly.
Arid3b Is Critical for B Lymphocyte Development
(Plos, 2016-08-18) Kurkewich, Jeffrey L.; Klopfenstein, Nathan; Hallas, William M.; Wood, Christian; Sattler, Rachel A.; Das, Chhaya; Tucker, Haley; Dahl, Richard; Dahl, Karen D. Cowden; Department of Biochemistry & Molecular Biology, IU School of Medicine
Arid3a and Arid3b belong to a subfamily of ARID (AT-rich interaction domain) transcription factors. The Arid family is involved in regulating chromatin accessibility, proliferation, and differentiation. Arid3a and Arid3b are closely related and share a unique REKLES domain that mediates their homo- and hetero-multimerization. Arid3a was originally isolated as a B cell transcription factor binding to the AT rich matrix attachment regions (MARS) of the immunoglobulin heavy chain intronic enhancer. Deletion of Arid3a results in a highly penetrant embryonic lethality with severe defects in erythropoiesis and hematopoietic stem cells (HSCs). The few surviving Arid3a-/- (<1%) animals have decreased HSCs and early progenitors in the bone marrow, but all mature lineages are normally represented in the bone marrow and periphery except for B cells. Arid3b-/- animals die around E7.5 precluding examination of hematopoietic development. So it is unclear whether the phenotype of Arid3a loss on hematopoiesis is dependent or independent of Arid3b. In this study we circumvented this limitation by also examining hematopoiesis in mice with a conditional allele of Arid3b. Bone marrow lacking Arid3b shows decreased common lymphoid progenitors (CLPs) and downstream B cell populations while the T cell and myeloid lineages are unchanged, reminiscent of the adult hematopoietic defect in Arid3a mice. Unlike Arid3a-/- mice, HSC populations are unperturbed in Arid3b-/- mice. This study demonstrates that HSC development is independent of Arid3b, whereas B cell development requires both Arid3a and Arid3b transcription factors.
ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis
(American Association for the Advancement of Science, 2017-01-20) Li, Zhaomin; Zhang, Peng; Yan, Aimin; Guo, Zhengyu; Ban, Yuguang; Li, Jin; Chen, Shi; Yang, Hui; He, Yongzheng; Li, Jianping; Guo, Ying; Zhang, Wen; Hajiramezanali, Ehsan; An, Huangda; Fajardo, Darlene; Harbour, J. William; Ruan, Yijun; Nimer, Stephen D.; Yu, Peng; Chen, Xi; Xu, Mingjiang; Yang, Feng-Chun; Department of Pediatrics, IU School of Medicine
ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin-cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.
BATF sustains homeostasis and functionality of bone marrow Treg cells to preserve homeostatic regulation of hematopoiesis and development of B cells
(Frontiers Media, 2023-02-22) Tikka, Chiranjeevi; Beasley, Lindsay; Xu, Chengxian; Yang, Jing; Cooper, Scott; Lechner, Joseph; Gutch, Sarah; Kaplan, Mark H.; Capitano, Maegan; Yang, Kai; Pediatrics, School of Medicine
Bone marrow Treg cells (BM Tregs) orchestrate stem cell niches crucial for hematopoiesis. Yet little is known about the molecular mechanisms governing BM Treg homeostasis and function. Here we report that the transcription factor BATF maintains homeostasis and functionality of BM Tregs to facilitate homeostatic regulation of hematopoiesis and B cell development. Treg-specific ablation of BATF profoundly compromised proportions of BM Tregs associated with reduced expression of Treg effector molecules, including CD44, ICOS, KLRG1, and TIGIT. Moreover, BATF deficiency in Tregs led to increased numbers of hematopoietic stem cells (HSCs), multipotent progenitors (MPPs), and granulocyte-macrophage progenitors (GMPs), while reducing the functionality of myeloid progenitors and the generation of common lymphoid progenitors. Furthermore, Tregs lacking BATF failed to support the development of B cells in the BM. Mechanistically, BATF mediated IL-7 signaling to promote expression of effector molecules on BM Tregs and their homeostasis. Our studies reveal a previously unappreciated role for BATF in sustaining BM Treg homeostasis and function to ensure hematopoiesis.
Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression
(Springer Nature, 2019-03) Ni, Fang; Yu, Wen-Mei; Li, Zhiguo; Graham, Douglas K.; Jin, Lingtao; Kang, Sumin; Rossi, Michael R.; Li, Shiyong; Broxmeyer, Hal E.; Qu, Cheng-Kui; Microbiology and Immunology, School of Medicine
Amino acid (AA) metabolism is involved in diverse cellular functions, including cell survival and growth, however it remains unclear how it regulates normal hematopoiesis versus leukemogenesis. Here, we report that knockout of Slc1a5 (ASCT2), a transporter of neutral AAs, especially glutamine, results in mild to moderate defects in bone marrow and mature blood cell development under steady state conditions. In contrast, constitutive or induced deletion of Slc1a5 decreases leukemia initiation and maintenance driven by the oncogene MLL-AF9 or Pten deficiency. Survival of leukemic mice is prolonged following Slc1a5 deletion, and pharmacological inhibition of ASCT2 also decreases leukemia development and progression in xenograft models of human acute myeloid leukemia. Mechanistically, loss of ASCT2 generates a global effect on cellular metabolism, disrupts leucine influx and mTOR signaling, and induces apoptosis in leukemic cells. Given the substantial difference in reliance on ASCT2-mediated AA metabolism between normal and malignant blood cells, this in vivo study suggests ASCT2 as a promising therapeutic target for the treatment of leukemia.
CXXC finger protein 1 is important for hematopoiesis
(2005) Young, Suzanne R.L.
Definitive Hematopoiesis in the Yolk Sac Emerges from Wnt-Responsive Hemogenic Endothelium Independently of Circulation and Arterial Identity
(Wiley, 2016-02) Frame, Jenna M.; Fegan, Katherine H.; Conway, Simon J.; McGrath, Kathleen E.; Palis, James; Department of Pediatrics, IU School of Medicine
Adult-repopulating hematopoietic stem cells (HSCs) emerge in low numbers in the midgestation mouse embryo from a subset of arterial endothelium, through an endothelial-to-hematopoietic transition. HSC-producing arterial hemogenic endothelium relies on the establishment of embryonic blood flow and arterial identity, and requires β-catenin signaling. Specified prior to and during the formation of these initial HSCs are thousands of yolk sac-derived erythro-myeloid progenitors (EMPs). EMPs ensure embryonic survival prior to the establishment of a permanent hematopoietic system, and provide subsets of long-lived tissue macrophages. While an endothelial origin for these HSC-independent definitive progenitors is also accepted, the spatial location and temporal output of yolk sac hemogenic endothelium over developmental time remain undefined. We performed a spatiotemporal analysis of EMP emergence, and document the morphological steps of the endothelial-to-hematopoietic transition. Emergence of rounded EMPs from polygonal clusters of Kit(+) cells initiates prior to the establishment of arborized arterial and venous vasculature in the yolk sac. Interestingly, Kit(+) polygonal clusters are detected in both arterial and venous vessels after remodeling. To determine whether there are similar mechanisms regulating the specification of EMPs with other angiogenic signals regulating adult-repopulating HSCs, we investigated the role of embryonic blood flow and Wnt/β-catenin signaling during EMP emergence. In embryos lacking a functional circulation, rounded Kit(+) EMPs still fully emerge from unremodeled yolk sac vasculature. In contrast, canonical Wnt signaling appears to be a common mechanism regulating hematopoietic emergence from hemogenic endothelium. These data illustrate the heterogeneity in hematopoietic output and spatiotemporal regulation of primary embryonic hemogenic endothelium.
Distinct sources of hematopoietic progenitors emerge before HSCs and provide functional blood cells in the mammalian embryo
(Elsevier B.V., 2015-06-30) McGrath, Kathleen E.; Frame, Jenna M.; Fegan, Katherine H.; Bowen, James R.; Conway, Simon J.; Catherman, Seana C.; Kingsley, Paul D.; Koniski, Anne D.; Palis, James; Department of Pediatrics, IU School of Medicine
Hematopoietic potential arises in mammalian embryos before adult-repopulating hematopoietic stem cells (HSCs). At E9.5, we show the first murine definitive erythro-myeloid progenitors (EMPs) have an immunophenotype distinct from primitive hematopoietic progenitors, maturing megakaryocytes and macrophages, and rare B cell potential. EMPs emerge in the yolk sac with erythroid and broad myeloid, but not lymphoid, potential. EMPs migrate to the fetal liver and rapidly differentiate including production of circulating neutrophils by E11.5. While the surface markers, transcription factors and lineage potential associated with EMPs overlap with those found in adult definitive hematopoiesis, they are present in unique combinations or proportions that result in a specialized definitive embryonic progenitor. Further, we find that ES cell -derived hematopoiesis recapitulates early yolk sac hematopoiesis, including primitive, EMP and rare B cell potential. EMPs do not have long term potential when transplanted in immunocompromised adults, but can provide transient adult-like RBC reconstitution.
Eicosanoid Regulation of Hematopoietic Stem and Progenitor Cell Function
(2010-07-21T19:13:29Z) Hoggatt, Jonathan G.; Pelus, Louis M.; Broxmeyer, Hal E.; Clapp, D. Wade; Srour, Edward
Adult hematopoietic stem cells (HSC) are routinely used to reconstitute hematopoiesis after myeloablation; however, transplantation efficacy and multilineage reconstitution can be limited by inadequate HSC number, or poor homing, engraftment or self-renewal. We have demonstrated that mouse and human HSC express prostaglandin E2 (PGE2) receptors, and that short-term ex vivo exposure of HSC to PGE2 enhances their homing, survival and proliferation, resulting in increased long-term repopulating cell and competitive repopulating unit (CRU) frequency. HSC pulsed with PGE2 are more competitive, as determined by head-to-head comparison in a competitive transplantation model. Enhanced HSC frequency and competitive advantage is stable and maintained upon multiple serial transplantations, with full multi-lineage reconstitution. PGE2 increases HSC CXCR4 mRNA and surface expression and enhances their migration to SDF-1α in vitro and homing to bone marrow in vivo and stimulates HSC entry into and progression through cell cycle. In addition, PGE2 enhances HSC survival, associated with an increase in Survivin mRNA and protein expression and reduction in intracellular active caspase-3. While PGE2 pulse of HSC promotes HSC self-renewal, blockade of PGE2 biosynthesis with non-steroidal anti-inflammatory drugs (NSAIDs) results in expansion of bone marrow hematopoietic progenitor cells (HPC). We co-administered NSAIDs along with the mobilizing agent granulocyte-colony stimulating factor (G-CSF) and evaluations of limiting dilution transplants, assays monitoring neutrophil and platelet recoveries, and secondary transplantations, clearly indicate that NSAIDs facilitate mobilization of a hematopoietic graft with superior functional activity compared to the graft mobilized by G-CSF alone. Enhanced mobilization has also been confirmed in baboons mobilized with G-CSF and a NSAID. Increases in mobilization are the result of a reduction of signaling through the PGE2 receptor EP4, which results in marrow expansion and reduction in the osteoblastic HSC niche. We also identify a new role for cannabinoids, an eicosanoid with opposing functions to PGE2, in hematopoietic mobilization. Additionally, we demonstrate increased survival in lethally irradiated mice treated with PGE2, NSAIDs, or the hypoxia mimetic cobalt chloride. Our results define novel mechanisms of action whereby eicosanoids regulate HSC and HPC function, and characterize novel translational strategies for hematopoietic therapies.

Browsing by Subject "Hematopoiesis"

Results Per Page

Sort Options