GSK-3β inhibition promotes early engraftment of ex vivo- expanded haematopoietic stem cells

被引：13
作者：
Dolnikov, A. [1 ,2 ]
Xu, N. [1 ,3 ]
Shen, S. [1 ,2 ]
Song, E. [1 ,2 ]
Holmes, T. [2 ]
Klamer, G. [2 ,3 ]
O'Brien, T. A. [1 ,2 ,3 ]
机构：
[1] Sydney Childrens Hosp, Sydney Cord & Marrow Transplant Lab, Randwick, NSW 2031, Australia
[2] Univ New S Wales, Sch Womens & Childrens Hlth, Sydney, NSW, Australia
[3] Univ New S Wales, Childrens Canc Inst Australia Med Res, Sydney, NSW, Australia
来源：
CELL PROLIFERATION | 2014年 / 47卷 / 02期
关键词：
BONE-MARROW; SHORT-TERM; PROGENITOR CELLS; CORD BLOOD; SELF-RENEWAL; MICE; EXPANSION; TRANSPLANTATION; INTEGRIN; GLYCOGEN-SYNTHASE-KINASE-3-BETA;
D O I：
10.1111/cpr.12092
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
ObjectivesUmbilical cord blood (UCB) is a source of stem cells used for allogeneic transplantation, in addition to bone marrow and peripheral blood. Limited numbers of stem cells in a single UCB unit is associated with slow haematopoietic recovery and high risk of graft failure, particularly in adult patients. UCB stem cells can be expanded ex vivo; however, rapid differentiation reduces their regenerative potential. We have recently shown that Wnt/-catenin signalling is down-regulated in ex vivo-expanded stem cells; therefore, we propose that re-activation of Wnt signalling using GSK-3 inhibition may act to improve regenerative potential of these ex vivo-expanded stem cells. Materials and methodsImmunocompromised mice were employed in transplantation studies to determine stem-cell engraftment. Flow cytometry was used to phenotype the engrafted human cells. Retroviral gene transfer was used to examine the role of Myc gene up-regulated by GSK-3 inhibition, in ex vivo-expanded stem cells. ResultsTreatment with GSK-3 inhibitor, 6-bromoindirubin 3-oxime (BIO) improved early human cell engraftment in the mice and elevated the numbers of myeloid progenitor cells in cytokine-stimulated culture. BIO up-regulated -catenin and c-myc in ex vivo-expanded stem cells. Ectopic expression of Myc acted to increase clonogenic potential and to delay differentiation of haematopoietic progenitor cells, suggesting the potential mechanism to improve regenerative potential of ex vivo-expanded grafts. ConclusionsPharmacological inhibition of GSK-3 provided a novel approach to improve early engraftment of ex vivo-expanded haematopoietic progenitor cells.
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页码：113 / 123
页数：11
相关论文
共 23 条
[1]   Ex vivo expansion of human hematopoietic stem and progenitor cells [J].
Dahlberg, Ann ;
Delaney, Colleen ;
Bernstein, Irwin D. .
BLOOD, 2011, 117 (23) :6083-6090
[2]   V-myc in a simple, single gene retroviral vector causes rapid induction of leukemia and concomitant apoptosis following bone marrow transplantation [J].
Dolnikov, A ;
Shounan, Y ;
Millington, M ;
Mackenzie, K ;
Symonds, G .
LEUKEMIA, 1998, 12 (04) :542-553
[3]   Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo [J].
Fleming, Heather E. ;
Janzen, Viktor ;
Lo Celso, Cristina ;
Guo, Jun ;
Leahy, Kathleen M. ;
Kronenberg, Henry M. ;
Scadden, David T. .
CELL STEM CELL, 2008, 2 (03) :274-283
[4]   Anti-α4β1 integrin antibody induces receptor internalization and does not impair the function of circulating neutrophilic leukocytes [J].
Fleming, Jennifer C. ;
Bao, Feng ;
Cepinskas, Gediminas ;
Weaver, Lynne C. .
INFLAMMATION RESEARCH, 2010, 59 (08) :647-657
[5]   Ex vivo expansion of hematopoietic progenitor cells is associated with downregulation of α4 integrin- and CXCR4-mediated engraftment in NOD/SCID β2-microglobulin-null mice [J].
Foguenne, Jacques ;
Di Stefano, Ivano ;
Giet, Olivier ;
Beguln, Yves ;
Gothot, Andre .
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, 2009, 94 (02) :185-194
[6]   Murine hematopoietic reconstitution after tagging and selection of retrovirally transduced bone marrow cells [J].
GarciaHernandez, B ;
Castellanos, A ;
Lopez, A ;
Orfao, A ;
SanchezGarcia, I .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (24) :13239-13244
[7]   Previously undetected human hematopoietic cell populations with short-term repopulating activity selectively engraft NOD/SCID-β2 microglobulin-null mice [J].
Glimm, H ;
Eisterer, W ;
Lee, K ;
Cashman, J ;
Holyoake, TL ;
Nicolini, F ;
Shultz, LD ;
von Kalle, C ;
Eaves, CJ .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (02) :199-206
[8]   Reduced Mortality after Allogeneic Hematopoietic-Cell Transplantation. [J].
Gooley, Ted A. ;
Chien, Jason W. ;
Pergam, Steven A. ;
Hingorani, Sangeeta ;
Sorror, Mohamed L. ;
Boeckh, Michael ;
Martin, Paul J. ;
Sandmaier, Brenda M. ;
Marr, Kieren A. ;
Appelbaum, Frederick R. ;
Storb, Rainer ;
McDonald, George B. .
NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (22) :2091-2101
[9]   The proto-oncogene c-myc in hematopoietic development and leukemogenesis [J].
Hoffman, B ;
Amanullah, A ;
Shafarenko, M ;
Liebermann, DA .
ONCOGENE, 2002, 21 (21) :3414-3421
[10]   The role of glycogen synthase kinase-3β in normal haematopoiesis, angiogenesis and leukaemia [J].
Holmes, T. ;
O'Brien, T. A. ;
Knight, R. ;
Lindeman, R. ;
Symonds, G. ;
Dolnikov, A. .
CURRENT MEDICINAL CHEMISTRY, 2008, 15 (15) :1493-1499
123