Modeling aortic diseases using induced pluripotent stem cells

Abstract

Induced pluripotent stem cells (iPSCs) offer an effective platform for studies of human physiology and have revealed new possibilities for disease modeling at the cellular level. These cells also have the potential to be leveraged in the practice of precision medicine, including personalized drug testing. Aortic diseases result in significant morbidity and mortality and pose a global burden to healthcare. Their pathogenesis is mostly associated with functional alterations of vascular components, such as endothelial cells and vascular smooth muscle cells. Drugs that have been proven to be effective in animal models often fail to protect patients from adverse aortic events in clinical studies, provoking researchers to develop reliable in vitro models using human cells. In this review, we summarize the patient iPSC‐derived aortic cells that have been utilized to model aortic diseases in vitro. In advanced models, hemodynamic factors, such as blood flow‐induced shear stress and cyclic strain, have been added to the systems to replicate cellular microenvironments in the aortic wall. Examples of the utility of such factors in modeling various aortopathies, such as Marfan syndrome, Loeys‐Dietz syndrome, and bicuspid aortic valve‐related aortopathy, are also described. Overall, the iPSC‐based in vitro cell models have shown the potential to promote the development and practice of precision medicine in the treatment of aortic diseases.

A hiPSC-derived lineage-specific vascular smooth muscle cell-on-a-chip identifies aortic heterogeneity across segments

“…The application of hiPSC-SMCs in cardiovascular research and pharmaceutical purposes calls for a bioengineered system that mimics physiological responses. 35,36 Here, for investigating the aortic heterogeneity across segments, we report lineage-specific LM-SMCs, NC-SMCs, and PM-SMCs generated from hiPSCs representing SMCs in distinct aortic segments, including the aortic root, tubular ascending aorta, and aortic arch, descending thoracic aorta, and abdominal aorta. Microfluid technology was used to connect the three different types of SMCs-on-chips as an entire SMC organ-ona-chip.…”

Mechanosignals in abdominal aortic aneurysms

“…In order to understand the mechanism by which cells respond to mechanical stress and the mechanotransduction signaling that drives AAA at the subcellular level, a stringent in vitro system is necessary to mimic in vivo conditions, which remain a challenge considering cells in culture are not subjected to constant stress, ECM microenvironment and physical forces observed in vivo (107). Several studies have tackled such issues by creating a multi-layered 3D-vascular scaffold that can mimic the biological vasculature as opposed to the traditional 2D culture of SMCs or ECs (108)(109)(110). Organ-on-chip platforms have been utilized to characterize the interactions between ECs and SMCs.…”

“…Organ-on-chip platforms have been utilized to characterize the interactions between ECs and SMCs. Using a platform bioprinted into a microfluidic device, SMCs and ECs can be cocultured on a porous, tensile membrane that underwent mechanical stretch and shear stress, making this system suitable to delve into the mechanical mechanisms in AAA and for the testing of high-throughput drug candidates ( 110 ). Using this model, Chen et al replicated the cyclic stretch of human pluripotent stem cell-derived aortic smooth muscle cells (hPSC-HASMCs) to study the effect of metformin in aortic aneurysm development.…”

Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy

“…And the PTEN/PI3K/AKT/mTOR pathways. Activating mutations of Ras and Raf frequently leading to activation of their downstream targets MEK1/2 and ERK1/2 [ 44 ]. Similarly, in the PI3K/AKT/mTOR pathway, mutation/inactivation of PTEN resulting in activation of PI3K and its downstream targets AKT and mTOR [ 45 ].…”

“…4 The use of a UV-patterned substrate to facilitate long-term culture of cells. Panel A shows an overlay of phase-contrast and fluorescent images downstream targets MEK1/2 and ERK1/2 [44]. Similarly, in the PI3K/AKT/mTOR pathway, mutation/inactivation of PTEN resulting in activation of PI3K and its downstream targets AKT and mTOR [45].…”