Macrophage phenotype and function are dependent upon the composition and biomechanics of the local cardiac tissue microenvironment.
Macrophage phenotype and function are dependent upon the composition and biomechanics of the local cardiac tissue microenvironment.
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DOI：
10.18632/aging.203054
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发表时间：
2021-05-17
期刊：
影响因子：
--
通讯作者：
Brown BN
中科院分区：
文献类型：
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作者：
Haschak M;LoPresti S;Stahl E;Dash S;Popovich B;Brown BN
巨噬细胞积聚和亚硝化应激是年龄相关的心血管病理和功能下降的已知机制。已知心肌微环境会随着年龄的增长而变化，但这些变化的直接影响还有待深入研究。本研究旨在更好地阐明心脏组织中的生物化学和生物力学改变在随年龄增长观察到的心脏驻留巨噬细胞的表型和功能改变中的作用。为了实现这一点，将来自年轻小鼠的幼稚骨髓来源的巨噬细胞接种到刚度范围为2kPA至64kPA的官能化聚二甲基硅氧烷水凝胶上或接种到组织培养塑料上，两者都涂覆有年轻或老年溶解的小鼠心脏细胞外基质（cECM）。生物力学和生物化学的改变被发现对巨噬细胞的极化和功能有显着的影响。发现增加的底物硬度促进与促炎性巨噬细胞活化相关的巨噬细胞形态，增加促炎性诱导型一氧化氮合酶蛋白的表达，增加一氧化氮分泌，以及减弱促炎性诱导型一氧化氮合酶活性和蛋白表达。此外，与年轻cECM处理的细胞相比，暴露于老化cECM促进了对典型促炎和抗炎细胞因子信号传导线索的减弱的响应性。这些结果表明，心血管系统中的生物力学和生物化学变化在促进与心血管疾病发展相关的促炎性巨噬细胞群体的年龄相关转变中起作用。
Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naïve bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.