title: Differential Effects of Small Molecule WNT Agonists on the Multilineage Differentiation Capacity of Human Mesenchymal Stem Cells.
abstract: Human bone marrow-derived mesenchymal stem cells (MSCs) are promising candidates for cell-based therapies, but loss of expansion and differentiation potential in vitro limits their applicability. Recently we showed that WNT3A protein promoted MSC proliferation and enhanced their chondrogenic potential, while simultaneously suppressing the propensity of the cartilage to undergo hypertrophic maturation. Since WNT3A protein is costly and rapidly loses its activity in culture, we investigated the possibility of replacing it with cheaper commercially available WNT agonists, specifically lithium chloride (LiCl), CHIR99021 (CHIR), SKL2001, and AMBMP. Of these, we found that only CHIR and LiCl stimulated MSC proliferation. Moreover, CHIR enhanced the chondrogenic capacity of MSCs, whereas LiCl predominantly increased the osteo- and adipogenic capacity. The different WNT agonists also differentially impacted the surface marker profile of the MSCs, possibly explaining the observed differences. Moreover, CHIR suppressed the hypertrophic propensity of the MSC-derived cartilage after in vivo implantation to an extent approaching that of WNT3A protein. These results indicate that CHIR may be a promising alternative for WNT3A protein for certain applications of human bone marrow-derived MSCs.
authors.affiliation: 1 Department of Orthopaedics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .
authors.forename: Roberto
authors.initials: R
authors.lastname: Narcisi
authors.affiliation: 1 Department of Orthopaedics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .
authors.forename: Ozan H
authors.initials: OH
authors.lastname: Arikan
authors.affiliation: 2 Department of Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .|3 Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .
authors.forename: Johannes
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: 3 Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .
authors.forename: Derk
authors.initials: D
authors.lastname: Ten Berge
authors.affiliation: 1 Department of Orthopaedics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .|2 Department of Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .
authors.forename: Gerjo J V M
authors.initials: GJ
authors.lastname: van Osch
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D064593:Heterografts; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008819:Mice, Nude; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D060509:Wnt3A Protein / Q000819:agonists* / Q000378:metabolism
chemical_list: C571720:5-furan-2yl-isoxazole-3-carboxylic acid (3-imidazol-1yl-propyl)-amide; C473711:Chir 99021; D007093:Imidazoles; D007555:Isoxazoles; D011725:Pyridines; D011743:Pyrimidines; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D018021:Lithium Chloride
keywords: CHIR; MSCs; WNT pathways; WNT3A; calcified matrix; chondrogenesis; lithium chloride