Page 50 - Rappaport Institute Magazine 2024

PHYSIOLOGY, BIOPHYSICS AND SYSTEMS BIOLOGY
Lior Gepstein, MD, PhD
Professor of Physiology and Medicine (Cardiology)
MD, 1996 – Technion, Israel. PhD, 1999 – Technion, Israel
Use of Advanced Biological Techniques for the Study and Treatment of Cardiac Disorders
Research in the Gepstein laboratory focuses on utilization of advanced biological techniques (such as pluripotent stem cells, tissue engineering, 3D bioprinting, gene editing, optogenetics and chemogenetics) for the study and treatment of cardiac disorders. These emerging experimental tools are used: (1) in the emerging field of cardiovascular regenerative medicine (for the treatment of heart failure and arrhythmias), (2) for drug screening and discovery, and (3) for cardiac disease modeling. For the latter application, human induced pluripotent stem cells (hiPSCs) are established from patients with different types of inherited cardiomyopathies (such as dilated, hypertrophic and metabolic cardiomyopathies) or arrhythmogenic syndromes. These disease states may lead to the development of malignant arrhythmias and sudden cardiac death in otherwise healthy individuals. The patient- specific hiPSCs lines generated are coaxed to differentiate into different cardiomyocyte subtypes, used to establish advanced cardiac tissue models, and then characterized using cutting-edge molecular, structural, and functional assays. These studies are expected to provide new mechanistic insights into inherited cardiac disorders, to allow optimization of patient-specific therapies (precision-medicine), and to facilitate development of new therapies.
Selected Publications
ˆ Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, Feldman O, Gepstein A, Arbel A, Hammerman H, Boulos M, Gepstein L. Modelling the long QT syndrome with induced pluripotent stem cells. Nature. 471:225-229, 2011.
ˆ Nussinovitch U, Gepstein L. Optogenetics for in vivo cardiac pacing and resynchronization therapies. Nature Biotechnology. 33:750-4, 2015.
ˆ Goldfracht I, Protze S, Shiti A, Gruber A, Shaheen N, Setter N, Nartiss Y, Keller G, Gepstein L. Generating ring-shaped engineered heart tissues from ventricular and atrial human induced pluripotent stem cell-derived cardiomyocytes. Nature Communications. 11:75, 2020.
ˆ Wexler Y, Ghiringhelli M, Shaheen N, Gladstein S, Huber I, Edri O, Abboud Y, Landsberg M, Shiff D, Arbel G, Gepstein L. Chemogenetics for gene therapy based targeted cardiac electrophysiological modulation. Circ Res. 132:645-647, 2023.
Grants and Awards
2011 – 2016 European Research Council (ERC). “Induced pluripotent stem cells: A novel strategy to study inherited cardiac disorders (Cardio-iPS)”
2018 – 2024 European Research Council (ERC). “Combining induced pluripotent stem cells, tissue engineering, optogenetic and chemogenetic concepts for the study and treatment of atrial fibrillation (iPS-ChOp-AF)”
2019 – 2025 Fondation Leducq Transatlantic Network of Excellence in Cardiovascular Research. “Towards precision medicine with human iPSCs for cardiac channelopathies”
Network investigators: Joseph Wu (Stanford, USA), Peter Schwartz (Milano, Italy), Shinya Yamanaka (Kyoto, Japan), Lior Gepstein (Haifa, Israel), Jean-Sébastien Hulot (Paris, France), Björn C. Knollmann (Nashville, USA)
mdlior@tx.technion.ac.il
Lior Gepstein Lab
Human heart cell generated from induced pluripotent stem cells