title: Disruption of cell-cell contact-mediated notch signaling via hydrogel encapsulation reduces mesenchymal stem cell chondrogenic potential: winner of the Society for Biomaterials Student Award in the Undergraduate Category, Charlotte, NC, April 15 to 18, 2015.
abstract: Cell-cell contact-mediated Notch signaling is essential for mesenchymal stem cell (MSC) chondrogenesis during development. However, subsequent deactivation of Notch signaling is also required to allow for stem cell chondrogenic progression. Recent literature has shown that Notch signaling can also influence Wnt/β-catenin signaling, critical for MSC differentiation, through perturbations in cell-cell contacts. Traditionally, abundant cell-cell contacts, consistent with development, are emulated in vitro using pellet cultures for chondrogenesis. However, cells are often encapsulated within biomaterials-based scaffolds, such as hydrogels, to improve therapeutic cell localization in vivo. To explore the role of Notch and Wnt/β-catenin signaling in the context of hydrogel-encapsulated MSC chondrogenesis, we compared signaling and differentiation capacity of MSCs in both hydrogels and traditional pellet cultures. We demonstrate that encapsulation within poly(ethylene glycol) hydrogels reduces cell-cell contacts, and both Notch (7.5-fold) and Wnt/β-catenin (84.7-fold) pathway activation. Finally, we demonstrate that following establishment of cell-cell contacts and transient Notch signaling in pellet cultures, followed by Notch signaling deactivation, resulted in a 1.5-fold increase in MSC chondrogenesis. Taken together, these findings support that cellular condensation, and establishment of initial cell-cell contacts is critical for MSC chondrogenesis, and this process is inhibited by hydrogel encapsulation.
authors.affiliation: Department of Biomedical Engineering, University of Rochester, 207 Robert B. Goergen Hall, Box 270168, Rochester, New York, 14627-0168.
authors.forename: Amanda X
authors.initials: AX
authors.lastname: Chen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hoffman
authors.forename: Caressa S
authors.initials: CS
authors.lastname: Chen
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Shubin
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Reynolds
authors.forename: Danielle S W
authors.initials: DS
authors.lastname: Benoit
mesh_terms: D000818:Animals; D001363:Awards and Prizes; D002450:Cell Communication / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018914:Cells, Immobilized / Q000166:cytology; D020219:Chondrogenesis / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013334:Students; D060449:Wnt Signaling Pathway
chemical_list: D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols
keywords: cell-cell contacts; hydrogels; mesenchymal stem cells; notch signaling; wnt signaling