Journal
BIOMATERIALS
Volume 163, Issue -, Pages 116-127Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.02.024
Keywords
Cardiac tissue engineering; Human pluripotent stem cells; Ventricular pump function; Contractility; Electrophysiology
Funding
- US National Institutes of Health NHLBI [F30 HL118923]
- NIGMS [T32GM008553]
- NIDCR-Interdisciplinary Training in Systems and Developmental Biology and Birth Defects [T32HD075735]
- NIH/NHLBI Program of Excellence in Nanotechnology (PEN) [HHSN268201000045C]
- Research Grants Council [TRS 113-706/11]
- Innovation and Technology Commission and Novoheart Limited [ITS/131/131FX]
- Sarnoff Cardiovascular Research Foundation
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [T32HD075735] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [F30HL118923] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008553] Funding Source: NIH RePORTER
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Tissue engineers and stem cell biologists have made exciting progress toward creating simplified models of human heart muscles or aligned monolayers to help bridge a longstanding gap between experimental animals and clinical trials. However, no existing human in vitro systems provide the direct measures of cardiac performance as a pump. Here, we developed a next-generation in vitro biomimetic model of pumping human heart chamber, and demonstrated its capability for pharmaceutical testing. From human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCM) embedded in collagen based extracellular matrix hydrogel, we engineered a three-dimensional (3D) electro-mechanically coupled, fluid-ejecting miniature human ventricle-like cardiac organoid chamber (hvCOC). Structural characterization showed organized sarcomeres with myofibrillar microstructures. Transcript and RNA-seq analyses revealed upregulation of key Ca2+-handling, ion channel, and cardiac-specific proteins in hvCOC compared to lower-order 2D and 3D cultures of the same constituent cells. Clinically-important, physiologically complex contractile parameters such as ejection fraction, developed pressure, and stroke work, as well as electrophysiological properties including action potential and conduction velocity were measured: hvCOC displayed key molecular and physiological characteristics of the native ventricle, and showed expected mechanical and electrophysiological responses to a range of pharmacological interventions (including positive and negative inotropes). We conclude that such human-heart-in-a-jar technology could facilitate the drug discovery process by providing human-specific preclinical data during early stage drug development. (C) 2018 Published by Elsevier Ltd.
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