Modular GAG-matrices to promote mammary epithelial morphogenesis in vitro

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• 作者：Mirko Nowak^a ; Uwe Freudenberg^a ; Mikhail V. Tsurkan^a ; Carsten Werner^a ; Kandice R. Levental^a ; ^b ; ^{kandice.r.levental@uth.tmc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Mammary epithelium ; Cell-material interaction ; Organoid morphogenesis ; Heparin ; Biomimetic material
• 刊名：Biomaterials
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：112
• 期：Complete
• 页码：20-30
• 全文大小：2889 K

文摘

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.