Methods for Modeling Cardiac Diseases Using Human-Based In Vitro Models

TOPICAL COLLECTIONS

Guest Editor

Francesca Stillitano

University of Utrecht, University Medical Center, Division Heart and Lungs, Department of Cardiology, The Netherlands

Francesca Stillitano is an Assistant Professor at the Heart and Lung Division, Department of Cardiology, University of Medical Center, Utrecht (UMCU), Utrecht, The Netherlands. She has a broad background in cardiovascular biology focusing on the molecular basis of inherited and acquired cardiac diseases. Her primary research efforts focus on using iPSC-derived cardiomyocytes to (i) assess the capacity of these cells in recapitulating critical aspects of patient-specific cardiac phenotypes; (ii) investigate the molecular and cellular mechanisms underlying the development of cardiovascular defects; and (iii) evaluate drug-induced cardiac toxicity. They also combine iPSC technology and gene-editing techniques, such as CRISPR/Cas9 system, to correct/insert specific gene mutations that cause inherited cardiac diseases. She has expanded her research to include invivo studies and has applied potential gene therapy approaches. A combination of cellular and molecular biology, genome editing, and gene therapy approaches is used in invitro and invivo models to understand pathological processes better and develop novel therapeutic strategies.

Collection Overview

Cardiac disease modeling is vital to improve our knowledge on the mechanism of several cardiac diseases and to discover new therapeutic approaches, which have been hampered by the lack of appropriate models that accurately reflect the human disease phenotypes.

Human-induced Pluripotent Stem Cells (iPSCs) represent an innovative technology to reproduce a broad spectrum of human heart diseases in vitro. They can be generated by reprogramming any somatic cells, can self-renew indefinitely in culture, and differentiate into all specialized cells, including heart cells, for instance, cardiomyocytes, cardiac fibroblasts, smooth muscle cells, and endothelial cells.

iPSCs can be combined with precise gene editing, such as CRISPR\Cas approaches, to either introduce or correct disease-relevant mutations to create isogenic cells that differ from the parental lines only concerning the disease mutation. This allows investigation of specific molecular and cellular effects of pathogenic variants without complications from individual genetic background variability.

iPSC- and gene-edited iPSC-derived heart cells can be finally used to fabricate engineered cardiac tissues that more accurately recapitulate tissue- and organ-level disease pathophysiology.

This Methods Collection will provide robust protocols for generating adult-like cardiomyocytes, endothelial cells, cardiac fibroblasts, and smooth muscle cells from human iPSCs; it will include methods for generating gene-edited genes iPSC-derived cells well as for the fabrication of 3D cardiac tissues. Successful generation of these human models will help recapitulate in-vitro cardiac diseases, study the pathophysiological mechanisms, and subsequently develop suitable therapies.