Gelatin‐Hyaluronan Click‐Crosslinked Cryogels Elucidate Human Macrophage Invasion Behavior. (15th April 2021)

• Record Type: Journal Article
• Authors: Bahlmann, Laura C.; Baker, Alexander E. G.; Xue, Chang; Liu, Sophie; Meier‐Merziger, Moritz; Karakas, Danielle; Zhu, Luke; Co, Ileana; Zhao, Spencer; Chin, Allysia; McGuigan, Alison; Kuruvilla, John; Laister, Rob C.; Shoichet, Molly S.
• Is Part Of: Advanced functional materials. Volume 31:Number 28(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-04-15
• Subjects: cryogel -- extracellular matrix -- gelatin -- hyaluronan -- macrophage invasion; Materials -- Periodicals; Chemical vapor deposition -- Periodicals; 620.11
• DOI: 10.1002/adfm.202008400
• Languages: English
• ISSNs: 1616-301X

Abstract

Abstract: Hydrogel models of metastasis traditionally focus on the invasion of cancer cells; however, other cells in the tumor microenvironment that are associated with metastasis also have the ability to migrate. Macrophage phenotype plays a key role in the tumor microenvironment, yet understanding their migration within tunable 3D in vitro models has been limited. To gain a greater understanding of macrophage invasive behavior, stable and transparent oxime‐crosslinked cryogels comprised of click‐crosslinked gelatin‐oxyamine and hyaluronan‐aldehyde (GELox‐HAa) are synthesized. Fibronectin‐derived, oxyamine‐modified PHSRN‐RGDSP peptides are incorporated to further mimic the tumor extracellular matrix without impacting cryogel mechanics. It is found that primary human macrophages migrate to a greater depth in cryogels with greater porosity and pore size. To better understand the mechanism of migration, cells are treated with either inhibitors of matrix metalloproteinases (MMPs) or rho‐associated protein kinase (ROCK) and a predominantly MMP‐mediated mechanism of invasion is found. Macrophage polarization studies reveal that anti‐inflammatory, interleukin‐4/13 (IL4/IL13)‐treated macrophages migrate through cryogels to a greater extent than pro‐inflammatory, interferon‐gamma/lipopolysaccharide (IFNγ/LPS)‐treated cells. Interestingly, polarized macrophages move through cryogels using a combination of amoeboid and mesenchymal migration. These findings of macrophage invasion in this cryogel platform set the stage for their further study in a biomimetic tumor microenvironment. Abstract : Newly designed, tunable gelatin‐hyaluronan oxime‐crosslinked cryogels, with adhesive fibronectin‐derived peptides immobilized therein, enable human macrophage migration. Both cryogel physical properties, of pore size and stiffness, and macrophage polarization state affect extent of migration. Matrix‐metalloproteinase dependent migration is the dominant migration mode, similar to what is observed in the native tumor microenvironment. These studies validate the use of this cryogel to study tumor‐associated macrophage behavior.