title: Instructing Human Macrophage Polarization by Stiffness and Glycosaminoglycan Functionalization in 3D Collagen Networks.
abstract: Dynamic alterations of composition and mechanics of the extracellular matrix are suggested to modulate cellular behavior including plasticity of macrophages (MPhs) during wound healing. In this study, engineered 3D fibrillar matrices based on naturally occurring biopolymers (collagen I, glycosaminoglycans (GAGs)) are used to mimic matrix stiffening as well as modification by sulfated and nonsulfated GAGs at different stages of wound healing. Human MPhs are found to sensitively respond to these microenvironmental cues in terms of polarization toward proinflammatory or wound healing phenotypes over 6 days in vitro. MPhs exhibit a wound healing phenotype in stiffer matrices as determined by protein and gene expression of relevant cytokines (IL10, IL12, and TNFα). Presence of sulfated and nonsulfated GAGs inhibits this polarization effect. Furthermore, control experiments on 2D matrices stress the relevance of using stiffness-controlled 3D matrices, as MPhs show a reciprocal polarization behavior depending on GAG presence. Hence, the results indicate a strong influence of dimensionality, stiffness, and GAG presence of the biomaterial scaffold on MPh polarization and emphasize the need for matrices closely mimicking the 3D in vivo context with a variable stiffness and GAG composition in in vitro studies.
authors.affiliation: Institute of Biochemistry, Universität Leipzig, 04103, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Friedemann
authors.affiliation: Institute of Biochemistry, Universität Leipzig, 04103, Leipzig, Germany.
authors.forename: Liv
authors.initials: L
authors.lastname: Kalbitzer
authors.affiliation: Department of Dermatology, Venerology and Allergology, Universitätsklinikum Leipzig, 04103, Leipzig, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Franz
authors.affiliation: Biomaterials Department, INNOVENT e. V., 07745, Jena, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moeller
authors.affiliation: Biomaterials Department, INNOVENT e. V., 07745, Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schnabelrauch
authors.affiliation: Department of Dermatology, Venerology and Allergology, Universitätsklinikum Leipzig, 04103, Leipzig, Germany.
authors.forename: Jan-Christoph
authors.initials: JC
authors.lastname: Simon
authors.affiliation: Institute of Biochemistry, Universität Leipzig, 04103, Leipzig, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Pompe
authors.affiliation: Institute of Biochemistry, Universität Leipzig, 04103, Leipzig, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Franke
mesh_terms: D024042:Collagen Type I / Q000737:chemistry*; D005109:Extracellular Matrix / Q000737:chemistry*; D005260:Female; D006025:Glycosaminoglycans / Q000737:chemistry*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D015846:Monokines / Q000096:biosynthesis*
chemical_list: D024042:Collagen Type I; D006025:Glycosaminoglycans; D015846:Monokines
keywords: collagen; extracellular matrix; glycosaminoglycan; human macrophages; stiffness