Engineered Aging Cardiac Tissue Chip Model for Studying Cardiovascular Disease.
Engineered Aging Cardiac Tissue Chip Model for Studying Cardiovascular Disease.
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DOI：
10.1159/000516954
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Kannappan R
中科院分区：
文献类型：
--
作者：
Budhathoki S;Graham C;Sethu P;Kannappan R
由于全球老年人数量的快速增长以及心血管并发症的随之增加，迫切需要与年龄相关的心脏病建模和药物筛选平台。在本研究中，我们开发了一种心脏组织芯片模型，该模型结合了血流动力学负荷，并模仿了梗死老化心脏的基本方面。我们使用低剂量阿霉素处理诱导H9 c2成肌细胞的细胞衰老。然后，这些衰老细胞被用于设计心脏组织纤维，这些纤维受到与心脏中的压力-体积变化相关的血液动力学应力。通过缺氧处理在工程化心脏组织中模拟心肌缺血。我们的研究结果清楚地表明，急性低剂量阿霉素治疗诱导衰老，如形态学和分子标志物所证明的，包括扩大和扁平的细胞核，DNA损伤反应灶，和细胞周期抑制剂p16 INK 4a，p53和ROS的表达增加。在正常血流动力学负荷下，工程化心脏组织显示细胞排列并保留心脏细胞特性。我们的缺氧诱导的心肌梗死的衰老心脏组织模型概括了病理疾病的特征，如增加的细胞死亡和上调表达的ANP和BNP。总之，所描述的方法提供了一种新的方法来产生应激诱导的衰老心脏细胞表型和工程心脏组织芯片模型，以研究与衰老相关的心血管疾病病理学。
Due to the rapidly growing number of older people worldwide and the concomitant increase in cardiovascular complications, there is an urgent need for age-related cardiac disease modeling and drug screening platforms. In the present study, we developed a cardiac tissue chip model that incorporates hemodynamic loading and mimics essential aspects of the infarcted aging heart. We induced cellular senescence in H9c2 myoblasts using low-dose doxorubicin treatment. These senescent cells were then used to engineer cardiac tissue fibers, which were subjected to hemodynamic stresses associated with pressure-volume changes in the heart. Myocardial ischemia was modeled in the engineered cardiac tissue via hypoxic treatment. Our results clearly show that acute low dose doxorubicin treatment-induced senescence, as evidenced by morphological and molecular markers, including enlarged and flattened nuclei, DNA damage response foci, and increased expression of cell cycle inhibitor p16INK4a, p53, and ROS. Under normal hemodynamic load, the engineered cardiac tissues demonstrated cell alignment and retained cardiac cell characteristics. Our senescent cardiac tissue model of hypoxia-induced myocardial infarction recapitulated the pathological disease hallmarks such as increased cell death and upregulated expression of ANP and BNP. In summary, the described methodology provides a novel approach to generate stress-induced aging cardiac cell phenotypes and engineer cardiac tissue chip models to study the cardiovascular disease pathologies associated with aging.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
2.6
作者：
Kondo, Yoshitaka;Masutomi, Hirofumi;Noda, Yoshihiro;Ozawa, Yusuke;Takahashi, Keita;Handa, Setsuko;Maruyama, Naoki;Shimizu, Takahiko;Ishigami, Akihito
通讯作者：
Ishigami, Akihito
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
4.8
作者：
Kortlever, Roderik M.;Nijwening, Jeroen H.;Bernards, Rene
通讯作者：
Bernards, Rene
影响因子：
--
作者：
Burton, D. G. A.
通讯作者：
Burton, D. G. A.