Browsing by Subject "Fetal Blood"

Now showing 1 - 8 of 8
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    Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock
    (Elsevier, 2015-06-18) Mantel, Charlie R.; O'Leary, Heather A.; Chitteti, Brahmananda R.; Huang, XinXin; Cooper, Scott; Hangoc, Giao; Brustovetsky, Nickolay; Srour, Edward F.; Lee, Man-Ryul; Messina-Graham, Steve; Haas, David M.; Falah, Nadia; Kapur, Reuben; Pelus, Louis M.; Bardeesy, Nabeel; Fitamant, Julien; Ivan, Mircea; Kim, Kye-Seong; Broxmeyer, Hal E.; Department of Microbiology & Immunology, IU School of Medicine
    Hematopoietic stem cells (HSCs) reside in hypoxic niches within bone marrow and cord blood. Yet, essentially all HSC studies have been performed with cells isolated and processed in non-physiologic ambient air. By collecting and manipulating bone marrow and cord blood in native conditions of hypoxia, we demonstrate that brief exposure to ambient oxygen decreases recovery of long-term repopulating HSCs and increases progenitor cells, a phenomenon we term extraphysiologic oxygen shock/stress (EPHOSS). Thus, true numbers of HSCs in the bone marrow and cord blood are routinely underestimated. We linked ROS production and induction of the mitochondrial permeability transition pore (MPTP) via cyclophilin D and p53 as mechanisms of EPHOSS. The MPTP inhibitor cyclosporin A protects mouse bone marrow and human cord blood HSCs from EPHOSS during collection in air, resulting in increased recovery of transplantable HSCs. Mitigating EPHOSS during cell collection and processing by pharmacological means may be clinically advantageous for transplantation.
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    Inhibiting HDAC for human hematopoietic stem cell expansion
    (American Society for Clinical Investigation, 2014-06) Broxmeyer, Hal E.; Department of Microbiology and Immunology, IU School of Medicine
    In this issue of the JCI, Chaurasia and colleagues report an impressive ex vivo expansion of HSCs from human cord blood (CB) using cytokines and altering epigenetic modifications. The application of this protocol provides information that has potential for clinical consideration. The enhanced expansion of CB HSCs is a substantial advance over recent work from the Chaurasia and Hoffman group, in which ex vivo production of human erythroid progenitor cells from CB was promoted by chromatin modification. Moreover, this study takes advantage of information from the rapidly emerging, but not yet fully elucidated, field of epigenetics.
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    Mild Heat Treatment Primes Human CD34(+) Cord Blood Cells for Migration Toward SDF-1α and Enhances Engraftment in an NSG Mouse Model
    (Wiley Blackwell (John Wiley & Sons), 2015-06) Capitano, Maegan L.; Hangoc, Giao; Cooper, Scott; Broxmeyer, Hal E.; Department of Microbiology and Immunology, IU School of Medicine
    Simple efforts are needed to enhance cord blood (CB) transplantation. We hypothesized that short-term exposure of CD34(+) CB cells to 39.5°C would enhance their response to stromal-derived factor-1 (SDF-1), by increasing lipid raft aggregation and CXCR4 expression, thus leading to enhanced engraftment. Mild hyperthermia (39.5°C) significantly increased the percent of CD34(+) CB that migrated toward SDF-1. This was associated with increased expression of CXCR4 on the cells. Mechanistically, mild heating increased the percent of CD34(+) cells with aggregated lipid rafts and enhanced colocalization of CXCR4 within lipid raft domains. Using methyl-β-cyclodextrin (MβCD), an agent that blocks lipid raft aggregation, it was determined that this enhancement in chemotaxis was dependent upon lipid raft aggregation. Colocalization of Rac1, a GTPase crucial for cell migration and adhesion, with CXCR4 to the lipid raft was essential for the effects of heat on chemotaxis, as determined with an inhibitor of Rac1 activation, NSC23766. Application-wise, mild heat treatment significantly increased the percent chimerism as well as homing and engraftment of CD34(+) CB cells in sublethally irradiated non-obese diabetic severe combined immunodeficiency IL-2 receptor gamma chain d (NSG) mice. Mild heating may be a simple and inexpensive means to enhance engraftment following CB transplantation in patients.
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    Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment
    (Nature Publishing Group, 2018-07-16) Huang, Xinxin; Guo, Bin; Liu, Sheng; Wan, Jun; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Enhancement of hematopoietic stem cell (HSC) homing and engraftment is clinically critical, especially for cord blood (CB) hematopoietic cell transplantation. Here we report that specific HDAC5 inhibition highly upregulates CXCR4 surface expression in human CB HSCs and progenitor cells (HPCs). This results in enhanced SDF-1/CXCR4-mediated chemotaxis and increased homing to the bone marrow environment, with elevated SCID-repopulating cell (SRC) frequency and enhanced long-term and secondary engraftment in NSG mice. HDAC5 inhibition increases acetylated p65 levels in the nucleus, which is important for CXCR4 transcription. Inhibition of nuclear factor-κB (NF-κB) signaling suppresses HDAC5-mediated CXCR4 upregulation, enhanced HSC homing, and engraftment. Furthermore, activation of the NF-κB signaling pathway via TNFα also results in significantly increased CXCR4 surface expression, enhanced HSC homing, and engraftment. These results demonstrate a previously unknown negative epigenetic regulation of HSC homing and engraftment by HDAC5, and allow for a new and simple translational strategy to enhance HSC transplantation.
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    Notch ligand Delta-like 1 promotes in vivo vasculogenesis in human cord blood-derived endothelial colony forming cells
    (Elsevier, 2015-05) Kim, Hyojin; Huang, Lan; Critser, Paul J.; Yang, Zhenyun; Chan, Rebecca J.; Wang, Lin; Carlesso, Nadia; Voytik-Harbin, Sherry L.; Bernstein, Irwin D.; Yoder, Mervin C.; Department of Pediatrics, IU School of Medicine
    BACKGROUND AIMS: Human cord blood (CB) is enriched in circulating endothelial colony forming cells (ECFCs) that display high proliferative potential and in vivo vessel forming ability. Because Notch signaling is critical for embryonic blood vessel formation in utero, we hypothesized that Notch pathway activation may enhance cultured ECFC vasculogenic properties in vivo. METHODS: In vitro ECFC stimulation with an immobilized chimeric Notch ligand (Delta-like1(ext-IgG)) led to significant increases in the mRNA and protein levels of Notch regulated Hey2 and EphrinB2 that were blocked by treatment with γ-secretase inhibitor addition. However, Notch stimulated preconditioning in vitro failed to enhance ECFC vasculogenesis in vivo. In contrast, in vivo co-implantation of ECFCs with OP9-Delta-like 1 stromal cells that constitutively expressed the Notch ligand delta-like 1 resulted in enhanced Notch activated ECFC-derived increased vessel density and enlarged vessel area in vivo, an effect not induced by OP9 control stromal implantation. RESULTS: This Notch activation was associated with diminished apoptosis in the exposed ECFC. CONCLUSIONS: We conclude that Notch pathway activation in ECFC in vivo via co-implanted stromal cells expressing delta-like 1 promotes vasculogenesis and augments blood vessel formation via diminishing apoptosis of the implanted ECFC.
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