title: GSK-3β inhibition promotes early engraftment of ex vivo-expanded haematopoietic stem cells.
abstract: OBJECTIVE
  Umbilical 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/β-catenin signalling is down-regulated in ex vivo-expanded stem cells; therefore, we propose that re-activation of Wnt signalling using GSK-3β inhibition may act to improve regenerative potential of these ex vivo-expanded stem cells.
  
  
  METHODS
  Immunocompromised 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-3β inhibition, in ex vivo-expanded stem cells.
  
  
  RESULTS
  Treatment with GSK-3β 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 β-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.
  
  
  CONCLUSIONS
  Pharmacological inhibition of GSK-3β provided a novel approach to improve early engraftment of ex vivo-expanded haematopoietic progenitor cells.
authors: Sydney Cord & Marrow Transplant Laboratory, Sydney Children's Hospital, Randwick, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
authors: A
authors: A
authors: Dolnikov
authors: N
authors: N
authors: Xu
authors: S
authors: S
authors: Shen
authors: E
authors: E
authors: Song
authors: T
authors: T
authors: Holmes
authors: G
authors: G
authors: Klamer
authors: T A
authors: TA
authors: O'Brien
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods; D005353:Fibronectins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006085:Graft Survival / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010091:Oximes / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C483321:6-bromoindirubin-3'-oxime; D005353:Fibronectins; C507942:Il2rg protein, mouse; D007211:Indoles; D053631:Interleukin Receptor Common gamma Subunit; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C545354:retronectin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3