Engineered Aging Cardiac Tissue Chip Model for Studying Cardiovascular Disease

Abstract

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 p16<sup>INK4a</sup>, 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 conclusion, 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.

Microphysiological systems for human aging research

“…An aging cardiac tissue chip model was invented to study age‐related cardiac diseases and drug screening (Budhathoki et al., 2022 ). H9c2 myoblasts treated with low‐dose doxorubicin were found to drive cellular senescence with characteristics of DNA damage response, flattened and large nuclei, and elevated expression of cell cycle inhibitors, such as p53, p16 INK4a , and ROS.…”

Experimental models of myocardial ischemia: classical approaches and innovations (review)

“…Методы тканевой инженерии позволяют создавать модели ткани сердца, воспроизводящие стареющее сердце, и впоследствии моделировать изменения при ИМ в сконструированных волокнах путем обработки гипоксической газовой смесью [17]. Перспективным направлением является дальнейшее совершенствование моделей «сердца-на-чипе» и добавление в модель иммунных и сосудистых клеток для изучения взаимодействия воспалительных процессов и ангиогенеза при ишемии миокарда.…”

Advances in the design, generation, and application of tissue-engineered myocardial equivalents

“…Apart from metabolic and infective forms, cardiovascular diseases might onset with aging, which is a well-recognized agent of progressive and irreversible deterioration of biological processes and, hence, body function. The pathological effects of aging could be well studied with cardiac engineered tissue models, as shown recently by two independent groups using heart-on-a-chip platforms ( Acun et al, 2019 ; Budhathoki et al, 2022 ). Despite the physiological differences between women and men being recognized, gender medicine is an insufficiently explored branch of Modern Medicine, and treatments remain generally established for a male subject with around 70 kg of weight.…”