Immunomodulatory polymeric scaffold enhances extracellular matrix production in cell co-cultures under dynamic mechanical stimulation
Immunomodulatory polymeric scaffold enhances extracellular matrix production in cell co-cultures under dynamic mechanical stimulation
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DOI：
10.1016/j.actbio.2015.05.038
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发表时间：
2015-09-15
影响因子：
9.7
通讯作者：
Santerre, J. P.
中科院分区：
文献类型：
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作者：
Battiston, K. G.;Labow, R. S.;Santerre, J. P.
尽管免疫细胞在调节创伤后的伤口愈合过程中很重要，但具有推动人体免疫细胞向促再生表型转变的合成生物材料的例子很少，旨在实现这种免疫调节特性的更少。虽然单核细胞及其衍生的巨噬细胞被认为是体内组织重塑的重要贡献者，但这主要被认为是由于它们调节其他细胞类型的能力。然而，单核细胞和巨噬细胞本身产生组织产品的能力目前在组织再生领域并没有得到很好的认识。此外，虽然在承受机械载荷的重塑组织中发现了单核/巨噬细胞，但由于体内环境涉及的许多因素的复杂性，这种生物力学应变对单核/巨噬细胞及其调节组织特异性细胞活动的能力的影响尚不清楚，因此有必要使用受控的体外培养平台来研究这一现象。在这项研究中，人单核细胞与人冠状动脉平滑肌细胞(VSMCs)共培养在管状(3 Mm ID)可降解聚氨酯支架上，结合了非离子、疏水和离子化学(D-PHI)。目的是确定这样的合成基质是否可以与动态生物力学刺激(10%周向应变，1赫兹)一起用于共培养系统，以指导单核细胞促进组织生成，并更好地理解单核细胞/巨噬细胞可能促进新组织产生的不同方式。机械应变和单核细胞共培养对VSMC的生长有互补和非抑制作用。与静态对照相比，共培养样品显示硫酸糖胺多聚糖(GAG)和弹性蛋白的沉积增加，以及促进VSMC生长的生长因子FGF-2的释放增加，而动态培养支持I型和III型胶原的增加以及机械性能(弹性模数、拉伸强度)的增加。被测试的生物材料或培养条件并没有促进巨噬细胞向M1状态的极化。在D-PHI上培养的单核/巨噬细胞也能产生血管细胞外基质成分，包括I型胶原、III型胶原、弹性蛋白和GAG。这项研究强调了在组织工程策略中使用具有免疫调节特性的合成生物材料来促进细胞和组织的生长，并确认单核/巨噬细胞的ECM沉积是这种新组织的意想不到的来源。意义陈述生物材料调节巨噬细胞激活以适应伤口愈合表型的能力最近被证明支持积极的组织再生。然而，免疫调节生物材料在体外利用单核/巨噬细胞活性来支持组织工程策略的能力具有巨大的潜力，尚未得到研究。本研究采用单核细胞与可降解的聚亚安酯(D-PHI)共培养的方法，在血管组织工程的背景下，结合生物力学应变来调节VSMCs的反应。结果表明，支持理想的巨噬细胞激活状态的免疫调节生物材料，如D-PHI，可以与生物力学应变相结合，在体外增加血管组织的产生，部分原因是单核/巨噬细胞本身产生血管ECM蛋白的新的和意想不到的贡献。(C)2015 Acta Materialia Inc.由爱思唯尔有限公司出版。版权所有。
Despite the importance of immune cells in regulating the wound healing process following injury, there are few examples of synthetic biomaterials that have the capacity to push the body's immune cells toward pro-regeneration phenotypes, and fewer still that are designed with the intention of achieving this immunomodulatory character. While monocytes and their derived macrophages have been recognized as important contributors to tissue remodeling in vivo, this is primarily believed to be due to their ability to regulate other cell types. The ability of monocytes and macrophages to generate tissue products themselves, however, is currently not well appreciated within the field of tissue regeneration. Furthermore, while monocytes/macrophages are found in remodeling tissue that is subjected to mechanical loading, the effect this biomechanical strain on monocytes/macrophages and their ability to regulate tissue-specific cellular activity has not been understood due to the complexity of the many factors involved in the in vivo setting, hence necessitating the use of controlled in vitro culture platforms to investigate this phenomenon. In this study, human monocytes were co-cultured with human coronary artery smooth muscle cells (VSMCs) on a tubular (3 mm ID) degradable polyurethane scaffold, with a unique combination of non-ionic polar, hydrophobic and ionic chemistry (D-PHI). The goal was to determine if such a synthetic matrix could be used in a co-culture system along with dynamic biomechanical stimulus (10% circumferential strain, 1 Hz) conditions in order to direct monocytes to enhance tissue generation, and to better comprehend the different ways in which monocytes/macrophages may contribute to new tissue production. Mechanical strain and monocyte co-culture had a complementary and non-mitigating effect on VSMC growth. Co-culture samples demonstrated increased deposition of sulphated glycosaminoglycans (GAGs) and elastin, as well as increases in the release of FGF-2, a growth factor that can stimulate VSMC growth, while dynamic culture supported increases in collagen I and III as well as increased mechanical properties (elastic modulus, tensile strength) vs. static controls. Macrophage polarization toward an M1 state was not promoted by the biomaterial or culture conditions tested. Monocytes/macrophages cultured on D-PHI were also shown to produce vascular extracellular matrix components, including collagen I, collagen III, elastin, and GAGs. This study highlights the use of synthetic biomaterials having immunomodulatory character in order to promote cell and tissue growth when used in tissue engineering strategies, and identifies ECM deposition by monocytes/macrophages as an unexpected source of this new tissue.Statement of SignificanceThe ability of biomaterials to regulate macrophage activation towards a wound healing phenotype has recently been shown to support positive tissue regeneration. However, the ability of immunomodulatory biomaterials to harness monocyte/macrophage activity to support tissue engineering strategies in vitro holds enormous potential that has yet to be investigated. This study used a monocyte co-culture on a degradable polyurethane (D-PHI) to regulate the response of VSMCs in combination with biomechanical strain in a vascular tissue engineering context. Results demonstrate that immunomodulatory biomaterials, such as D-PHI, that support a desirable macrophage activation state can be combined with biomechanical strain to augment vascular tissue production in vitro, in part due to the novel and unexpected contribution of monocytes/macrophages themselves producing vascular ECM proteins. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.