Human Cell Modeling for Cardiovascular Diseases

Abstract

The availability of appropriate and reliable in vitro cell models recapitulating human cardiovascular diseases has been the aim of numerous researchers, in order to retrace pathologic phenotypes, elucidate molecular mechanisms, and discover therapies using simple and reproducible techniques. In the past years, several human cell types have been utilized for these goals, including heterologous systems, cardiovascular and non-cardiovascular primary cells, and embryonic stem cells. The introduction of induced pluripotent stem cells and their differentiation potential brought new prospects for large-scale cardiovascular experiments, bypassing ethical concerns of embryonic stem cells and providing an advanced tool for disease modeling, diagnosis, and therapy. Each model has its advantages and disadvantages in terms of accessibility, maintenance, throughput, physiological relevance, recapitulation of the disease. A higher level of complexity in diseases modeling has been achieved with multicellular co-cultures. Furthermore, the important progresses reached by bioengineering during the last years, together with the opportunities given by pluripotent stem cells, have allowed the generation of increasingly advanced in vitro three-dimensional tissue-like constructs mimicking in vivo physiology. This review provides an overview of the main cell models used in cardiovascular research, highlighting the pros and cons of each, and describing examples of practical applications in disease modeling.

Aberrant PLN-R14del Protein Interactions Intensify SERCA2a Inhibition, Driving Impaired Ca2+ Handling and Arrhythmogenesis

“…Overall, this cascade of molecular and sub-cellular events is consistent with the increased aftercontractions and prolongation of the action potential duration that have been described in the PLN-R14del hearts. Although the use of heterologous expression systems such as HEK 293 or H9c2 cells as well as mouse models present with certain limitations, when aiming to unravel a human disease [53][54][55], they can and have offered valuable insights on pathogenetic mechanisms, which serve as the basis for subsequent, finely targeted studies in precious patient tissues. Collectively, our study provides the first evidence on the direct implications of the PLN-R14del mutation on its immediate interactions, and the impairment of those that may lead to a series of molecular aberrations associated with aberrant SR Ca 2+ handling and ultimately arrhythmogenesis.…”

Spectrum of Rare and Common Genetic Variants in Arrhythmogenic Cardiomyopathy Patients

“…Therefore, we can speculate that the above-mentioned genes, found mutated in our ACM patients, could be considered candidates for validation as new ACM-associated genes. Functional studies on the specific variants are awaited to confirm the pathogenic causative or contributory role in ACM [ 45 , 46 ].…”

Development of vascular disease models to explore disease causation and pathomechanisms of rare vascular diseases

“…With the ability to proliferate indefinitely and differentiate into most cell types, stem cells are an extremely useful tool for investigating pathomechanisms of any disease and are the ultimate tool for developing innovative research platforms for disease modeling, therapeutic targeting, high-throughput drug discovery, and regenerative therapies [ 10 ].…”

“…A critical need has been to establish an in vitro EC platform that can overcome the limited availability of patient-specific ECs. Human iPSC (hiPSC)-derived ECs (hiPSC-ECs) are a powerful tool not only for investigating pathomechanisms but also for drug screening and cell therapy [ 10 ]. There have been many reports of varying methods of differentiating hiPSCs into hiPSC-ECs [ 36 , 37 ] for a myriad of applications.…”

“…Patient-specific vascular disease models can be used in vitro, in vivo, or ex vivo, developed with the aim to recapitulate and recreate disease phenotypes. In vitro systems employ primary cells derived from a myriad of patient biospecimens, mesenchymal stem cells (MSCs), iPSCs, non-vascular cells, and blood-derived immune cells and progenitor cells [ 10 ]. These models range from simple two-dimensional monocultures and co-cultures to complex spherical organoids and four-dimensional vascular structures.…”