title: Different Balance of Wnt Signaling in Adult and Fetal Bone Marrow-Derived Mesenchymal Stromal Cells.
abstract: Mesenchymal stromal cells (MSCs) are applied as novel therapeutics for their regenerative and immune-suppressive capacities. Clinical applications, however, require extensive expansion of MSCs. Fetal bone marrow-derived MSCs (FBMSCs) proliferate faster than adult bone marrow-derived MSC (ABMSCs). To optimize expansion and function of MSC in general, we explored the differences between ABMSC and FBMSC. Gene expression profiling implicated differential expression of genes encoding proteins in the Wnt signaling pathway, including excreted inhibitors of Wnt signaling, particularly by ABMSC. Both MSC types had a similar basal level of canonical Wnt signaling. Abrogation of autocrine Wnt production by inhibitor of Wnt production-2 (IWP2) reduced canonical Wnt signaling and cell proliferation of FBMSCs, but hardly affected ABMSC. Addition of exogenous Wnt3a, however, induced expression of the target genes lymphocyte enhancer-binding factor (LEF) and T-cell factor (TCF) faster and at lower Wnt3a levels in ABMSC compared to FBMSC. Medium replacement experiments indicated that ABMSC produce an inhibitor of Wnt signaling that is effective on ABMSC itself but not on FBMSC, whereas FBMSC excrete (Wnt) factors that stimulate proliferation of ABMSC. In contrast, FBMSC were not able to support hematopoiesis, whereas ABMSC displayed hematopoietic support sensitive to IWP2, the inhibitor of Wnt factor excretion. In conclusion, ABMSC and FBMSC differ in their Wnt signature. While FBMSC produced factors, including Wnt signals, that enhanced MSC proliferation, ABMSC produced Wnt factors in a setting that enhanced hematopoietic support. Thus, further unraveling the molecular basis of this phenomenon may lead to improvement of clinical expansion protocols of ABMSCs.
authors.affiliation: 1 Department of Hematopoiesis, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .
authors.forename: Maja M
authors.initials: MM
authors.lastname: Paciejewska
authors.affiliation: 1 Department of Hematopoiesis, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .|2 Department of Experimental Immunohematology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .
authors.forename: Marijke W
authors.initials: MW
authors.lastname: Maijenburg
authors.affiliation: 3 Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands .
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: 1 Department of Hematopoiesis, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .
authors.forename: Marion
authors.initials: M
authors.lastname: Kleijer
authors.affiliation: 1 Department of Hematopoiesis, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .
authors.forename: Kim
authors.initials: K
authors.lastname: Vermeul
authors.affiliation: 4 Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .
authors.forename: Kees
authors.initials: K
authors.lastname: Weijer
authors.affiliation: 3 Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands .
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: 1 Department of Hematopoiesis, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .|5 Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.affiliation: 2 Department of Experimental Immunohematology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .|5 Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.affiliation: 1 Department of Hematopoiesis, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .|2 Department of Experimental Immunohematology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands .
authors.forename: Carlijn
authors.initials: C
authors.lastname: Voermans
mesh_terms: D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005333:Fetus / Q000166:cytology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012995:Solubility; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D051153:Wnt Proteins