title: Bioactive nanofibers enable the identification of thrombospondin 2 as a key player in enamel regeneration.
abstract: Tissue regeneration and development involves highly synchronized signals both between cells and with the extracellular environment. Biomaterials can be tuned to mimic specific biological signals and control cell response(s). As a result, these materials can be used as tools to elucidate cell signaling pathways and candidate molecules involved with cellular processes. In this work, we explore enamel-forming cells, ameloblasts, which have a limited regenerative capacity. By exposing undifferentiated cells to a self-assembling matrix bearing RGDS epitopes, we elicited a regenerative signal at will that subsequently led to the identification of thrombospondin 2 (TSP2), an extracellular matrix protein that has not been previously recognized as a key player in enamel development and regeneration. Targeted disruption of the thrombospondin 2 gene (Thbs2) resulted in enamel formation with a disordered architecture that was highly susceptible to wear compared to their wild-type counterparts. To test the regenerative capacity, we injected the bioactive matrix into the enamel organ and discovered that the enamel organic epithelial cells in TSP-null mice failed to polarize on the surface of the artificial matrix, greatly reducing integrin β1 and Notch1 expression levels, which represent signaling pathways known to be associated with TSP2. These results suggest TSP2 plays an important role in regulating cell-matrix interactions during enamel formation. Exploiting the signaling pathways activated by biomaterials can provide insight into native signaling mechanisms crucial for tooth development and cell-based strategies for enamel regeneration.
authors.affiliation: Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry of USC, The University of Southern California, Los Angeles, CA, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Newcomb
authors.affiliation: Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry of USC, The University of Southern California, Los Angeles, CA, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry of USC, The University of Southern California, Los Angeles, CA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Bornstein
authors.affiliation: Craniofacial Anomalies Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Amendt
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA; Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA; Department of Chemistry, Northwestern University, Evanston, IL, USA; Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA; Department of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Stupp
authors.affiliation: Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry of USC, The University of Southern California, Los Angeles, CA, USA. Electronic address: mlsnead@usc.edu.
authors.forename: Malcolm L
authors.initials: ML
authors.lastname: Snead
mesh_terms: D000565:Ameloblasts / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D000818:Animals; D003743:Dental Enamel / Q000166:cytology / Q000502:physiology*; D048091:Guided Tissue Regeneration / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D057139:Nanofibers / Q000737:chemistry*; D012038:Regeneration / Q000502:physiology*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D000099262:Thrombospondin 2
chemical_list: D019699:Thrombospondins; D000099262:Thrombospondin 2
keywords: Enamel regeneration; Nano-fabricated artificial matrix; Peptide amphiphile; Signaling pathway; Thrombospondin 2