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Gelatin-Hyaluronan Click-Crosslinked Cryogels Elucidate Human Macrophage Invasion Behavior

机译:明胶 - 透明化尼咔哒声冷冻凝胶酶阐明人巨噬细胞入侵行为

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摘要

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 (IFN gamma/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.
机译:水凝胶模型转移传统上专注于癌细胞的侵袭;然而,与转移相关的肿瘤微环境中的其他细胞也具有迁移的能力。巨噬细胞表型在肿瘤微环境中起着关键作用,但了解他们在体外模型中的可调3D内的迁移。为了更好地了解巨噬细胞侵入行为,合成由点击交联的明胶 - 氧基和透明质酸(Gelox-Haa)组成的稳定和透明的肟交联的冷冻胶质。掺入纤维蛋白衍生的氧杂环胺改性的pHSRN-RGDSP肽,以进一步模拟肿瘤细胞外基质而不撞击冷冻机械。发现初级人巨噬细胞以更大的孔隙率和孔径迁移到更大的浊度深度。为了更好地理解迁移机制,用基质金属蛋白酶(MMP)或RHO相关蛋白激酶(岩石)的任一种抑制剂治疗细胞,并且发现了主要的MMP介导的侵袭机制。巨噬细胞偏振化研究表明,抗炎,白细胞介素-4 / 13(IL4 / IL13) - 治疗巨噬细胞在更大程度上迁移到比促炎,干扰素-γ/脂多糖(IFNγ/ LPS) - 治疗细胞更大程度。有趣的是,偏振巨噬细胞使用作物和间充质迁移的组合来移动冷冻胶质。这些Cryogel平台中的巨噬细胞入侵的结果设定了他们在仿生肿瘤微环境中进一步研究的阶段。

著录项

  • 来源
    《Advanced Functional Materials》 |2021年第28期|2008400.1-2008400.18|共18页
  • 作者单位

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada|Univ Toronto Donnelly Ctr 160 Coll St Toronto ON M5S 3E1 Canada;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada|Univ Toronto Donnelly Ctr 160 Coll St Toronto ON M5S 3E1 Canada|Univ Toronto Dept Chem Engn & Appl Chem 200 Coll St Toronto ON M5S 3E5 Canada;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada|Univ Toronto Donnelly Ctr 160 Coll St Toronto ON M5S 3E1 Canada;

    Univ Toronto Dept Chem Engn & Appl Chem 200 Coll St Toronto ON M5S 3E5 Canada;

    Johannes Gutenberg Univ Mainz Dept Chem Duesbergweg 10-14 D-55128 Mainz Germany;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada|Univ Toronto Donnelly Ctr 160 Coll St Toronto ON M5S 3E1 Canada;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada|Univ Toronto Donnelly Ctr 160 Coll St Toronto ON M5S 3E1 Canada;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada|Univ Toronto Dept Chem Engn & Appl Chem 200 Coll St Toronto ON M5S 3E5 Canada;

    Univ Hlth Network Princess Margaret Canc Ctr 610 Univ Ave Toronto ON M5G 2C1 Canada;

    Univ Hlth Network Princess Margaret Canc Ctr 610 Univ Ave Toronto ON M5G 2C1 Canada;

    Inst Biomed Engn 164 Coll St Toronto ON M5S 3G9 Canada|Univ Toronto Donnelly Ctr 160 Coll St Toronto ON M5S 3E1 Canada|Univ Toronto Dept Chem Engn & Appl Chem 200 Coll St Toronto ON M5S 3E5 Canada|Univ Toronto Dept Chem 80 St George St Toronto ON M5S 3H6 Canada;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cryogel; extracellular matrix; gelatin; hyaluronan; macrophage invasion;

    机译:cryogel;细胞外基质;明胶;透明质酸;巨噬细胞入侵;

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