title: Hydrogels with tunable stress relaxation regulate stem cell fate and activity.
abstract: Natural extracellular matrices (ECMs) are viscoelastic and exhibit stress relaxation. However, hydrogels used as synthetic ECMs for three-dimensional (3D) culture are typically elastic. Here, we report a materials approach to tune the rate of stress relaxation of hydrogels for 3D culture, independently of the hydrogel's initial elastic modulus, degradation, and cell-adhesion-ligand density. We find that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation. Strikingly, MSCs form a mineralized, collagen-1-rich matrix similar to bone in rapidly relaxing hydrogels with an initial elastic modulus of 17 kPa. We also show that the effects of stress relaxation are mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Our findings highlight stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Mechanical Engineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Ovijit
authors.initials: O
authors.lastname: Chaudhuri
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Luo
authors.initials: L
authors.lastname: Gu
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Orthopedic Surgery, Research Institute MOVE, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
authors.forename: Darinka
authors.initials: D
authors.lastname: Klumpers
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Darnell
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Sidi A
authors.initials: SA
authors.lastname: Bencherif
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Weaver
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Huebsch
authors.affiliation: Department of Mechanical Engineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Hong-Pyo
authors.initials: HP
authors.lastname: Lee
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts 02138, USA.|Julius Wolff Institute, Charité-Universitätsmedizin Berlin and Berlin-Brandenburg Center for Regenerative Therapies, 13353 Berlin, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Lippens
authors.affiliation: Julius Wolff Institute, Charité-Universitätsmedizin Berlin and Berlin-Brandenburg Center for Regenerative Therapies, 13353 Berlin, Germany.
authors.forename: Georg N
authors.initials: GN
authors.lastname: Duda
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
mesh_terms: D000464:Alginates / Q000737:chemistry; D001696:Biomechanical Phenomena; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D005109:Extracellular Matrix; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D020100:Hydrogels; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D000464:Alginates; D006603:Hexuronic Acids; D020100:Hydrogels; D020723:Glucuronic Acid