Browsing by Subject "Hematopoietic progenitor cells"

Now showing 1 - 7 of 7
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    Concise Review: A Role for DEK in Stem/Progenitor Cell Biology
    (Oxford University Press, 2013) Broxmeyer, Hal E.; Mor-Vaknin, Nirit; Kappes, Ferdinand; Legendre, Maureen; Saha, Anjan K.; Ou, Xuan; O’Leary, Heather; Capitano, Maegan; Cooper, Scott; Markovitz, David M.; Microbiology and Immunology, School of Medicine
    Understanding the factors that regulate hematopoiesis opens up the possibility of modifying these factors and their actions for clinical benefit. DEK, a non-histone nuclear phosphoprotein initially identified as a putative proto-oncogene, has recently been linked to regulate hematopoiesis. DEK has myelosuppressive activity in vitro on proliferation of human and mouse hematopoietic progenitor cells and enhancing activity on engraftment of long-term marrow repopulating mouse stem cells, has been linked in coordinate regulation with the transcription factor C/EBPα, for differentiation of myeloid cells, and apparently targets a long-term repopulating hematopoietic stem cell for leukemic transformation. This review covers the uniqueness of DEK, what is known about how it now functions as a nuclear protein and also as a secreted molecule that can act in paracrine fashion, and how it may be regulated in part by dipeptidylpeptidase 4, an enzyme known to truncate and modify a number of proteins involved in activities on hematopoietic cells. Examples are provided of possible future areas of investigation needed to better understand how DEK may be regulated and function as a regulator of hematopoiesis, information possibly translatable to other normal and diseased immature cell systems.
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    Enhanced Collection of Phenotypic and Engrafting Human Cord Blood Hematopoietic Stem Cells at 4°C
    (Oxford University Press, 2020-10) Broxmeyer, Hal E.; Cooper, Scott; Capitano, Maegan L.; Microbiology and Immunology, School of Medicine
    The number of hematopoietic stem cells (HSCs) collected in cord blood (CB) at the birth of a baby is a limiting factor for efficacious use of CB in hematopoietic cell transplantation (HCT). We now demonstrate that collecting and processing of human CB at 4°C within minutes of the baby's birth results in significantly enhanced numbers of rigorously defined phenotypic HSC and self-renewing NSG immune-deficient mouse engrafting and SCID-repopulating cells. This was associated with decreased numbers of hematopoietic progenitor cells (HPC), as noted previously for hypoxia collected/processed cells blocking ambient air induced differentiation of HSC to HPC. We have thus defined a simple, cost-effective, means to collect increased numbers of CB HSC, of potential use for clinical CB HCT.
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    Expression of gilt acts as a positive regulator of mouse hematopoietic progenitor cells
    (Elsevier, 2021) Broxmeyer, Hal E.; Cooper, Scott; Blum, Janice S.; Microbiology and Immunology, School of Medicine
    Gamma interferon inducible lysosomal thiol reductase (GILT), is known to be involved in immunity, but its role in hematopoiesis has not been previously reported. Herein, we demonstrate using gilt knockout (-/-) mice that loss of gilt associates with decreased numbers and cycling status of femoral hematopoietic progenitor cells (CFU-GM, BFU-E, and CFU-GEMM) with more modest effects on splenic progenitor cells. Thus, GILT is associated with positive regulation of hematopoietic progenitor cells in mice, mainly in bone marrow.
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    The IL-33 Receptor/ST2 acts as a positive regulator of functional mouse bone marrow hematopoietic stem and progenitor cells
    (Elsevier, 2020-09) Capitano, Maegan L.; Griesenauer, Brad; Guo, Bin; Cooper, Scott; Paczesny, Sophie; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    There is a paucity of information on a potential role for the IL-33 receptor/ST2 in the regulation of mouse bone marrow (BM) hematopoietic stem (HSC) and progenitor (HPC) cells. Comparing the BM of st2-/- and wild type (WT) control mice using functional assays, it was found that st2-/- BM cells had poorer engrafting capacity than WT BM in a competitive repopulating assay using congenic mice, with no changes in reconstitution of B-, T- and myeloid cells following transplantation. The BM of st2-/- mice also had fewer granulocyte-macrophage, erythroid, and multipotential progenitors than that of WT BM and these st2-/- HPC were in a slow cycling state compared to that of the rapidly cycling HPC of the WT mice. While functional assessment of HSC and HPC demonstrated that ST2 has a positive influence on regulation of HSC, we could not pick up differences in st2-/- compared to WT BM using only phenotypic analysis of HSC and HPC populations prior to transplantation, again demonstrating that phenotypic analysis of HSC and HPC do not always recapitulate the functional assessments of these immature hematopoietic cells.
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    Insights into highly engraftable hematopoietic cells from 27-year cryopreserved umbilical cord blood
    (Elsevier, 2023) Broxmeyer, Hal E.; Luchsinger, Larry L.; Singer Weinberg, Rona; Jimenez, Alexandra; Masson Frenet, Emeline; Van't Hof, Wouter; Capitano, Maegan L.; Hillyer, Christopher D.; Kaplan, Mark H.; Cooper, Scott; Ropa, James; Microbiology and Immunology, School of Medicine
    Umbilical cord blood transplantation is a life-saving treatment for malignant and non-malignant hematologic disorders. It remains unclear how long cryopreserved units remain functional, and the length of cryopreservation is often used as a criterion to exclude older units. We demonstrate that long-term cryopreserved cord blood retains similar numbers of hematopoietic stem and progenitor cells compared with fresh and recently cryopreserved cord blood units. Long-term cryopreserved units contain highly functional cells, yielding robust engraftment in mouse transplantation models. We also leverage differences between units to examine gene programs associated with better engraftment. Transcriptomic analyses reveal that gene programs associated with lineage determination and oxidative stress are enriched in high engrafting cord blood, revealing potential molecular markers to be used as potency markers for cord blood unit selection regardless of length of cryopreservation. In summary, cord blood units cryopreserved for extended periods retain engrafting potential and can potentially be used for patient treatment.
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    Leukemia Inhibitory Factor Promotes Survival of Hematopoietic Progenitors Ex Vivo and Is Post-Translationally Regulated by DPP4
    (Oxford University Press, 2022) Ropa, James; Cooper, Scott; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Hematopoietic cells are regulated in part by extracellular cues from cytokines. Leukemia inhibitory factor (LIF) promotes survival, self-renewal, and pluripotency of mouse embryonic stem cells (mESC). While genetic deletion of LIF affects hematopoietic progenitor cells (HPCs), the direct effect of LIF protein exposure on HPC survival is not known. Furthermore, post-translational modifications (PTM) of LIF and their effects on its function have not been evaluated. We demonstrate that treatment with recombinant LIF preserves mouse and human HPC numbers in stressed conditions when growth factor addition is delayed ex vivo. We show that Lif is upregulated in response to irradiation-induced stress. We reveal novel PTM of LIF where it is cleaved twice by dipeptidyl peptidase 4 (DPP4) protease so that it loses its 4 N-terminal amino acids. This truncation of LIF down-modulates LIF’s ability to preserve functional HPC numbers ex vivo following delayed growth factor addition. DPP4-truncated LIF blocks the ability of full-length LIF to preserve functional HPC numbers. This LIF role and its novel regulation by DPP4 have important implications for normal and stress hematopoiesis, as well as for other cellular contexts in which LIF and DPP4 are implicated.
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    Quickly attainable and highly engrafting hematopoietic stem cells
    (Wolters Kluwer, 2019-09-17) Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine