Biomimetic cardiac tissue chip and murine arteriovenous fistula models for recapitulating clinically relevant cardiac remodeling under volume overload conditions.
Biomimetic cardiac tissue chip and murine arteriovenous fistula models for recapitulating clinically relevant cardiac remodeling under volume overload conditions.
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DOI：
10.3389/fbioe.2023.1101622
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发表时间：
2023
影响因子：
5.7
通讯作者：
Lee, Timmy
中科院分区：
文献类型：
--
作者：
Waldrop, Tatyana Isayeva;Graham, Caleb;Gard, William;Ingle, Kevin;Ptacek, Travis;Nguyen, Nguyen;Lose, Bailey;Sethu, Palaniappan;Lee, Timmy
关键词：
心血管事件是透析患者死亡的主要原因。虽然动静脉瘘(AVF)是血液透析患者的首选途径，但AVF的产生会导致心脏出现容量超负荷(VO)状态。我们开发了一种具有可调压力和拉伸的三维(3D)心脏组织芯片(CTC)来模拟与AVF创建相关的急性血流动力学变化，以补充我们的VO小鼠AVF模型。在这项研究中，我们的目标是在体外复制小鼠AVF模型的血流动力学，并假设如果3D心脏组织结构受到“容量超负荷”条件的影响，它们将出现纤维化和关键基因表达的变化，在AVF小鼠中可见。小鼠接受了AVF或Sham手术，并在28天时被处死。将h9c2大鼠心肌成肌细胞和正常成人真皮成纤维细胞在水凝胶中构建的心脏组织接种到装置中，在1 GHz频率下暴露于100 mg/10 mm Hg压力(0.4°S/0.6°S)下96h，对照组暴露于“正常”拉伸，实验组暴露于“容量超负荷”。对构建的组织结构和小鼠左心室(LV)进行RT-PCR和组织学检测，并对小鼠LV进行转录。我们的组织结构和小鼠LV分别与对照组织结构和假手术小鼠相比，都显示出心脏纤维化。我们的组织结构和小鼠LV中的基因表达研究表明，与对照组相比，VO条件下与细胞外基质产生、氧化应激、炎症和纤维化相关的基因表达增加。我们的转录组学研究表明，激活的上游调控因子与纤维化、炎症和氧化应激相关，如1型胶原复合体、TGFB1、CCR2和VEGFA，以及与动静脉瘘小鼠左室线粒体生物发生相关的失活调控因子。综上所述，我们的CTC模型产生了与我们的小鼠AVF模型相似的纤维化相关组织学和基因表达谱。因此，CTC可能在了解VO状态的心脏病理生物学方面发挥关键作用，类似于AVF创建后的情况，并可能被证明在评估治疗方面是有用的。
Cardiovascular events are the primary cause of death among dialysis patients. While arteriovenous fistulas (AVFs) are the access of choice for hemodialysis patients, AVF creation can lead to a volume overload (VO) state in the heart. We developed a three-dimensional (3D) cardiac tissue chip (CTC) with tunable pressure and stretch to model the acute hemodynamic changes associated with AVF creation to complement our murine AVF model of VO. In this study, we aimed to replicate the hemodynamics of murine AVF models in vitro and hypothesized that if 3D cardiac tissue constructs were subjected to “volume overload” conditions, they would display fibrosis and key gene expression changes seen in AVF mice. Mice underwent either an AVF or sham procedure and were sacrificed at 28 days. Cardiac tissue constructs composed of h9c2 rat cardiac myoblasts and normal adult human dermal fibroblasts in hydrogel were seeded into devices and exposed to 100 mg/10 mmHg pressure (0.4 s/0.6 s) at 1 Hz for 96 h. Controls were exposed to “normal” stretch and experimental group exposed to “volume overload”. RT-PCR and histology were performed on the tissue constructs and mice left ventricles (LVs), and transcriptomics of mice LVs were also performed. Our tissue constructs and mice LV both demonstrated cardiac fibrosis as compared to control tissue constructs and sham-operated mice, respectively. Gene expression studies in our tissue constructs and mice LV demonstrated increased expression of genes associated with extracellular matrix production, oxidative stress, inflammation, and fibrosis in the VO conditions vs. control conditions. Our transcriptomics studies demonstrated activated upstream regulators related to fibrosis, inflammation, and oxidative stress such as collagen type 1 complex, TGFB1, CCR2, and VEGFA and inactivated regulators related to mitochondrial biogenesis in LV from mice AVF. In summary, our CTC model yields similar fibrosis-related histology and gene expression profiles as our murine AVF model. Thus, the CTC could potentially play a critical role in understanding cardiac pathobiology of VO states similar to what is present after AVF creation and may prove useful in evaluating therapies.
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