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Review
. 2020 Oct 28:8:550504.
doi: 10.3389/fcell.2020.550504. eCollection 2020.

Aortic "Disease-in-a-Dish": Mechanistic Insights and Drug Development Using iPSC-Based Disease Modeling

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Review

Aortic "Disease-in-a-Dish": Mechanistic Insights and Drug Development Using iPSC-Based Disease Modeling

Hongorzul Davaapil et al. Front Cell Dev Biol. .

Abstract

Thoracic aortic diseases, whether sporadic or due to a genetic disorder such as Marfan syndrome, lack effective medical therapies, with limited translation of treatments that are highly successful in mouse models into the clinic. Patient-derived induced pluripotent stem cells (iPSCs) offer the opportunity to establish new human models of aortic diseases. Here we review the power and potential of these systems to identify cellular and molecular mechanisms underlying disease and discuss recent advances, such as gene editing, and smooth muscle cell embryonic lineage. In particular, we discuss the practical aspects of vascular smooth muscle cell derivation and characterization, and provide our personal insights into the challenges and limitations of this approach. Future applications, such as genotype-phenotype association, drug screening, and precision medicine are discussed. We propose that iPSC-derived aortic disease models could guide future clinical trials via "clinical-trials-in-a-dish", thus paving the way for new and improved therapies for patients.

Keywords: Loeys-Dietz; Marfan; aortic aneurysm; disease-in-a-dish; induced pluripotent stem cell; vascular smooth muscle.

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Figures

FIGURE 1
FIGURE 1
Summary of aortic disease phenotype recapitulated in MFS iPSC model (Granata et al., 2017).
FIGURE 2
FIGURE 2
The different regions of the thoracic aorta and their disease susceptibilities. The descending aorta comprises VSMCs from paraxial mesoderm, the aortic arch from neural crest, and the aortic root from lateral plate mesoderm. The boundary between the arch and descending aorta is clearly defined, whereas there is overlap between the VSMCs from NC and LM at the aortic root, as denoted by the dotted lines.
FIGURE 3
FIGURE 3
Approaches to improving homogeneity of VSMC differentiations by using (A) direct or forward reprogramming methods, (B) automation, or (C) improved quality control and simplification of media components.
FIGURE 4
FIGURE 4
Currently, successful use of a drug in animal models is the prerequisite for use in clinical trials (A); this may lead to an amelioration in disease phenotype in some individuals, but not all. “Clinical-trials-in-a-dish” can be performed, where the effects of a combination of drugs at low doses is tested on patient-derived VSMCs, allowing us to target multiple de-regulated pathways (B). This combination therapy could then be validated in rodent models prior to use in clinical trials, and may have an effect in more patients (C).

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