title: Hydrogel biophysical properties instruct coculture-mediated osteogenic potential.
abstract: Cell-based approaches for bone formation require instructional cues from the surrounding environment. As an alternative to pharmacological strategies or transplanting single cell populations, one approach is to coimplant populations that can establish a new vasculature and differentiate to bone-forming osteoblasts. Mesenchymal stem/stromal cells (MSCs) possess osteogenic potential and produce numerous angiogenic growth factors. Endothelial colony-forming cells (ECFCs) are a subpopulation of endothelial progenitor cells capable of vasculogenesis in vivo and may provide endogenous cues to support MSC function. We investigated the contribution of the carrier biophysical properties to instruct entrapped human MSCs and ECFCs to simultaneously promote their osteogenic and proangiogenic potential. Compared with gels containing MSCs alone, fibrin gels engineered with increased compressive stiffness simultaneously increased the osteogenic and proangiogenic potential of entrapped cocultured cells. ECFCs produced bone morphogenetic protein-2 (BMP-2), a potent osteoinductive molecule, and increases in BMP-2 secretion correlated with gel stiffness. Coculture of MSCs with ECFCs transduced to knockdown BMP-2 production abrogated the osteogenic response to levels observed with MSCs alone. These results demonstrate that physical properties of engineered hydrogels modulate the function of cocultured cells in the absence of inductive cues, thus increasing the translational potential of coimplantation to speed bone formation and repair.
authors.affiliation: *Department of Biomedical Engineering and Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Davis, California, USA; and Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Kaitlin C
authors.initials: KC
authors.lastname: Murphy
authors.affiliation: *Department of Biomedical Engineering and Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Davis, California, USA; and Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Roberta S
authors.initials: RS
authors.lastname: Stilhano
authors.affiliation: *Department of Biomedical Engineering and Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Davis, California, USA; and Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Debika
authors.initials: D
authors.lastname: Mitra
authors.affiliation: *Department of Biomedical Engineering and Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Davis, California, USA; and Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Dejie
authors.initials: D
authors.lastname: Zhou
authors.affiliation: *Department of Biomedical Engineering and Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Davis, California, USA; and Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Samir
authors.initials: S
authors.lastname: Batarni
authors.affiliation: *Department of Biomedical Engineering and Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Davis, California, USA; and Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Silva
authors.affiliation: *Department of Biomedical Engineering and Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Davis, California, USA; and Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil jkleach@ucdavis.edu.
authors.forename: J Kent
authors.initials: JK
authors.lastname: Leach
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D066026:Endothelial Progenitor Cells / Q000378:metabolism; D005337:Fibrin / Q000494:pharmacology; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D017077:Culture Media, Conditioned; D020100:Hydrogels; D005337:Fibrin
keywords: BMP-2; ECFC; fibrin; mesenchymal stem cell; osteogenesis