Ex Vivo Models to Decipher the Molecular Mechanisms of Genetic Notch Cardiovascular Disorders.

Tommaso Ristori,Cecilia M Sahlgren,Marika Sjöqvist

doi:10.1089/ten.tec.2020.0327

Abstract

Notch is an evolutionary, conserved, cell–cell signaling pathway that is central to several biological processes, from tissue morphogenesis to homeostasis. It is therefore not surprising that several genetic mutations of Notch components cause inherited human diseases, especially cardiovascular disorders. Despite numerous efforts, current in vivo models are still insufficient to unravel the underlying mechanisms of these pathologies, hindering the development of utmost needed medical therapies. In this perspective review, we discuss the limitations of current murine models and outline how the combination of microphysiological systems (MPSs) and targeted computational models can lead to breakthroughs in this field. In particular, while MPSs enable the experimentation on human cells in controlled and physiological environments, in silico models can provide a versatile tool to translate the in vitro findings to the more complex in vivo setting. As a showcase example, we focus on Notch-related cardiovascular diseases, such as Alagille syndrome, Adams–Oliver syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).Impact statementIn this review, a comprehensive overview of the limitations of current in vivo models of genetic Notch cardiovascular diseases is provided, followed by a discussion over the potential of microphysiological systems and computational models in overcoming these limitations and in potentiating drug testing and modeling of these pathologies.

Highlights

Notch is a signaling pathway that relies on direct cell– cell interaction for its activation
After summarizing current in vivo models of Notch-related cardiovascular diseases, we propose that their limitations could be overcome by combining engineered in vitro models, providing a controlled environment to investigate specific aspects of the pathologies, together with in silico models, providing a digital twin for the in vivo setting
We recently developed a vessel wall on a chip, mimicking the physiological cell composition, organization, and hemodynamic environment of the arterial vessel wall, to study the impact of simultaneous shear stress and strain on endothelialVSMC signaling in tissue remodeling.[61]

Summary

Introduction

Notch is a signaling pathway that relies on direct cell– cell interaction for its activation. If coupled with simulations of blood vessel mechanics during aging, the model might shed light on the effects that age-related modifications have on Notch3-Jag[1] signaling and, in turn, on the appearance of CADASIL symptoms in young adults.[16] the Notch circuit model could be extended to include other Notch receptors, with different effects and behaviors, thereby enabling the investigation of ALGS dose sensitivity and Notch receptor specificity, which was discussed in the section on in vivo mouse models Conditional for their success, computational models need to be tightly coupled to experiments, which are strictly. Future efforts in this field should aim at potentiating the interplay between experiments and simulations by establishing more rigorous methods for the calibration and validation of in silico models based on cell experiments

Conclusion and Outlook

Findings

Funding Information