title: Role of WNT-5a in the determination of human mesenchymal stem cells into preadipocytes.
abstract: Increasing adipocyte size as well as numbers is important in the development of obesity and type 2 diabetes, with adipocytes being generated from mesenchymal precursor cells. This process includes the determination of mesenchymal stem cells (MSC) into preadipocytes (PA) and the differentiation of PA into mature fat cells. Although the process of differentiation has been highly investigated, the determination in humans is poorly understood. In this study, we compared human MSC and human committed PA on a cellular and molecular level to gain further insights into the regulatory mechanisms in the determination process. Both cell types showed similar morphology and expression patterns of common mesenchymal and hematopoietic surface markers. However, although MSC were able to differentiate into adipocytes and osteocytes, PA were only able to undergo adipogenesis, indicating that PA lost their multipotency during determination. WNT-5a expression showed significantly higher levels in MSC compared with PA suggesting that WNT-5a down-regulation might be important in the determination process. Indeed, incubation of human MSC in medium containing neutralizing WNT-5a antibodies abolished their ability to undergo osteogenesis, although adipogenesis was still possible. An opposite effect was achieved using recombinant WNT-5a protein. On a molecular level, WNT-5a was found to promote c-Jun N-terminal kinase-dependent intracellular signaling in MSC. Activation of this noncanonical pathway resulted in the induction of osteopontin expression further indicating pro-osteogenic effects of WNT-5a. Our data suggest that WNT-5a is necessary to maintain osteogenic potential of MSC and that inhibition of WNT-5a signaling therefore plays a role in their determination into PA in humans.
authors.affiliation: Department of Internal Medicine II and Centre of Molecular Medicine, University of Cologne, Kerpener Strasse 62, 50937 Köln, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Bilkovski
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Schulte
authors.forename: Frank
authors.initials: F
authors.lastname: Oberhauser
authors.forename: Matthias
authors.initials: M
authors.lastname: Gomolka
authors.forename: Michael
authors.initials: M
authors.lastname: Udelhoven
authors.forename: Moritz M
authors.initials: MM
authors.lastname: Hettich
authors.forename: Bernhard
authors.initials: B
authors.lastname: Roth
authors.forename: Axel
authors.initials: A
authors.lastname: Heidenreich
authors.forename: Christian
authors.initials: C
authors.lastname: Gutschow
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krone
authors.forename: Matthias
authors.initials: M
authors.lastname: Laudes
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis; D002454:Cell Differentiation; D019070:Cell Lineage; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010011:Osteocytes / Q000166:cytology; D010012:Osteogenesis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein