title: Modular GAG-matrices to promote mammary epithelial morphogenesis in vitro.
abstract: Matrix systems used to study complex three-dimensional (3D) cellular processes like mammary epithelial tissue morphogenesis and tumorigenesis ex vivo often require ill-defined biological components, which lead to poor reproducibility and a lack of control over physical parameters. In this study, a well-defined, tunable synthetic biohybrid hydrogel composed of the glycosaminoglycan heparin, star-shaped poly(ethylene glycol) (starPEG), and matrix metalloproteinase- (MMP-) cleavable crosslinkers was applied to dissect the biophysical and biochemical signals promoting human mammary epithelial cell (MEC) morphogenesis. We show that compliant starPEG-heparin matrices promote the development of polarized MEC acini. Both the presence of heparin and MMP-cleavable crosslinks are essential in facilitating MEC morphogenesis without supplementation of exogenous adhesion ligands. In this system, MECs secrete and organize laminin in basement membrane-like assemblies to promote integrin signaling and drive acinar development. Therefore, starPEG-heparin hydrogels provide a versatile platform to study mammary epithelial tissue morphogenesis in a chemically defined and precisely tunable 3D in vitro microenvironment. The system allows investigation of biophysical and biochemical aspects of mammary gland biology and potentially a variety of other organoid culture studies.
authors.affiliation: Leibniz Institute of Polymer Research Dresden e.V., Max Bergmann Center of Biomaterials Dresden, Center for Regenerative Therapies Dresden, TU Dresden, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Nowak
authors.affiliation: Leibniz Institute of Polymer Research Dresden e.V., Max Bergmann Center of Biomaterials Dresden, Center for Regenerative Therapies Dresden, TU Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Freudenberg
authors.affiliation: Leibniz Institute of Polymer Research Dresden e.V., Max Bergmann Center of Biomaterials Dresden, Center for Regenerative Therapies Dresden, TU Dresden, Germany.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Tsurkan
authors.affiliation: Leibniz Institute of Polymer Research Dresden e.V., Max Bergmann Center of Biomaterials Dresden, Center for Regenerative Therapies Dresden, TU Dresden, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Werner
authors.affiliation: Leibniz Institute of Polymer Research Dresden e.V., Max Bergmann Center of Biomaterials Dresden, Center for Regenerative Therapies Dresden, TU Dresden, Germany; Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address: kandice.r.levental@uth.tmc.edu.
authors.forename: Kandice R
authors.initials: KR
authors.lastname: Levental
mesh_terms: D040761:Biomimetic Materials / Q000737:chemistry; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology*; D005109:Extracellular Matrix / Q000737:chemistry*; D006025:Glycosaminoglycans / Q000737:chemistry*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D042361:Mammary Glands, Human / Q000166:cytology* / Q000254:growth & development*; D009024:Morphogenesis / Q000502:physiology*; D009924:Organ Culture Techniques / Q000295:instrumentation / Q000379:methods; D066330:Printing, Three-Dimensional; D023822:Tissue Engineering / Q000295:instrumentation / Q000379:methods; D054457:Tissue Scaffolds
chemical_list: D006025:Glycosaminoglycans; D020100:Hydrogels
keywords: Biomimetic material; Cell-material interaction; Heparin; Mammary epithelium; Organoid morphogenesis