Understanding genomic medicine for thoracic aortic disease through the lens of induced pluripotent stem cells

Abstract

Thoracic aortic disease (TAD) is often silent until a life-threatening complication occurs. However, genetic information can inform both identification and treatment at an early stage. Indeed, a diagnosis is important for personalised surveillance and intervention plans, as well as cascade screening of family members. Currently, only 20% of heritable TAD patients have a causative mutation identified and, consequently, further advances in genetic coverage are required to define the remaining molecular landscape. The rapid expansion of next generation sequencing technologies is providing a huge resource of genetic data, but a critical issue remains in functionally validating these findings. Induced pluripotent stem cells (iPSCs) are patient-derived, reprogrammed cell lines which allow mechanistic insights, complex modelling of genetic disease and a platform to study aortic genetic variants. This review will address the need for iPSCs as a frontline diagnostic tool to evaluate variants identified by genomic discovery studies and explore their evolving role in biological insight through to drug discovery.

Keywords: 3D models; aortic aneurysm; aortic dissection; disease modelling; genetic variants; induced pluripotent stem cells; thoracic aortic disease.

Figure 1

Graphical summary demonstrating the utility of induced pluripotent stem cells (iPSC) in understanding thoracic aortic disease (TAD) variants of unknown significance (VUS). iPSCs can be generated from a TAD patient or an established iPSC line genetically edited to carry a VUS. These can be differentiated in to vascular smooth muscle cell (VSMC) or endothelial cell (EC) in the form of a 2-dimensional (2D) culture or 3-dimensional (3D) culture system including vascular organoids (VO), vessel on a chip (VoC) and vascular ring. These models can proceed to multiomic evaluation, be used for drug or CRISPR screening, and then followed by assessment of drug response in high throughput manner. Such an approach allows for personalised management of the TAD patient and allow determination for need of cascade screening of family members. Figure created with BioRender.com. Publication licence granted by BioRender. Agreement number UH266AGKA0.