title: Wnt3a protein reduces growth factor-driven expansion of human hematopoietic stem and progenitor cells in serum-free cultures.
abstract: Ex vivo expansion of hematopoietic stem and progenitor cells (HSPC) is a promising approach to improve insufficient engraftment after umbilical cord blood stem cell transplantation (UCB-SCT). Although culturing HSPC with hematopoietic cytokines results in robust proliferation, it is accompanied with extensive differentiation and loss of self-renewal capacity. Wnt signaling has been implicated in regulating HSPC fate decisions in vivo and in promoting HSPC self-renewal by inhibition of differentiation, but the effects of Wnt on the ex vivo expansion of HSPC are controversial. Here, we demonstrate that exogenous Wnt3a protein suppresses rather than promotes the expansion of UCB-derived CD34+ cells in serum free expansion cultures. The reduced expansion was also observed in cultures initiated with Lin-CD34+CD38lowCD45RA-CD90+ cells which are highly enriched in HSC and was also observed in response to activation of beta-catenin signaling by GSK3 inhibition. The presence of Wnt3a protein during the culture reduced the frequency of multilineage CFU-GEMM and the long-term repopulation ability of the expanded HSPC. These data suggest that Wnt signaling reduces expansion of human HSPC in growth factor-driven expansion cultures by promoting differentiation of HSPC.
authors: Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Lucia E
authors: LE
authors: Duinhouwer
authors: Erasmus MC Stem Cell Institute, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Nesrin
authors: N
authors: Tüysüz
authors: Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Elwin W J C
authors: EW
authors: Rombouts
authors: Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Mariette N D
authors: MN
authors: Ter Borg
authors: Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Enrico
authors: E
authors: Mastrobattista
authors: Glycostem, Oss, The Netherlands.
authors: Jan
authors: J
authors: Spanholtz
authors: Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Jan J
authors: JJ
authors: Cornelissen
authors: Erasmus MC Stem Cell Institute, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Derk
authors: D
authors: Ten Berge
authors: Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors: Eric
authors: E
authors: Braakman
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000737:chemistry*; D005312:Fetal Blood / Q000166:cytology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D016688:Mice, Inbred NOD; D010300:Parkinson Disease / Q000628:therapy; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D016895:Culture Media, Serum-Free; D008081:Liposomes; D018336:Receptors, Aryl Hydrocarbon; D060509:Wnt3A Protein; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3