Pioneers in Modeling Cardiovascular Disease


Development of a mouse model for investigating the cardiopulmonary remodeling after the Glenn Procedure

Tai Yi, MD, Microsurgery Center Director, Nationwide Children’s Hospital

Abstract: The Glenn shunt is a surgical procedure in which the superior vena cava is anastomosed to the pulmonary artery. The Glenn procedure is the second in a series of operations resulting in the creation of the Fontan circulation in which the venous circulation is directly connected to the pulmonary artery bypassing the right ventricle. This series of staged operations represent the current standard of care for patients born with single ventricle anomalies. While life saving, the Fontan procedure is associated with decreased longevity and significant life-long morbidity. The etiology underlying the multi-organ failure associated with Fontan circulation is poorly understood but is thought to be multifactorial arising from both the genetic factors associated with the underlying single ventricle disease in addition to the pathophysiological effects of Fontan hemodynamics. Mouse models provide a powerful tool for investigating the cellular and molecular mechanisms underlying disease. Herein we describe our initial results developing a mouse model for investigating the pathophysiological mechanisms underlying the Fontan circulation beginning with cardiopulmonary remodeling after the Glenn shunt.

Modeling collateral blood flow in regenerating and failing hearts

Kristy Red-Horse, PhD, Associate Professor of Biology at Stanford University and Howard Hughes Medical Institute Investigator

Abstract: Developing organisms create tissues de novo, and the underlying instructions could inform organ regeneration. With this mindset, we study coronary arteries—which bring blood flow to heart muscle—in hopes of eventually treating coronary artery disease, the number one killer worldwide. We have discovered how mouse coronary arteries are built, and reinstated developmental pathways in adults to aid recovery following cardiac injury.  

Generating the diversity of cardiovascular cell types from human pluripotent stem cells

Nicole Dubois, PhD, Associate Professor of Cell, Developmental and Regenerative Biology at the Icahn School of Medicine at Mount Sinai

Abstract: Many excellent strategies have been developed over the past years to generate the diversity of cardiovascular cell types in vitro from human pluripotent stem cells (hPSCs). However, there remain multiple open questions, including how to best mature in vitro-derived cells, how to generate complex tissue models or how to derive cells of the ventricular conduction system, for example. We show that transient Notch activation in ventricular cardiomyocytes results in stable induction of a Purkinje Fiber-like fate, including expression of conduction system markers, increased conduction velocity and adoption of Purkinje Fiber-like cell morphology. We further interrogated the role of metabolism for cardiac maturation, and have found that activation of PPAR signaling, in an isoform-specific manner, results in metabolic maturation of hPSC-derived cardiomyocytes, including enhanced fatty acid oxidation (FAO), expression of the FAO machinery, maturation of the mitochondrial network and enhanced sarcomere organization. Integrating these new strategies with existing approaches will enable the generation of relevant in vitro human models to study human heart development and disease.

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