title: Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes.
abstract: Therapeutic delivery of cardiomyocytes derived from human pluripotent stem cells (hPSC-CMs) represents a novel clinical approach to regenerate the injured myocardium. However, poor survival and contractility of these cells are a significant bottleneck to their clinical use. To better understand the role of cell-cell communication in enhancing the phenotype and contractile properties of hPSC-CMs, we developed a three-dimensional (3D) hydrogel composed of hPSC-CMs, human pluripotent stem cell-derived endothelial cells (hPSC-ECs), and/or human amniotic mesenchymal stem cells (hAMSCs). The objective of this study was to examine the role of multi-cellular interactions among hPSC-ECs and hAMSCs on the survival and long-term contractile phenotype of hPSC-CMs in a 3D hydrogel. Quantification of spontaneous contractility of hPSC-CMs in tri-culture demonstrated a 6-fold increase in the area of contractile motion after 6 weeks with characteristic rhythmic contraction frequency, when compared to hPSC-CMs alone (P < 0.05). This finding was supported by a statistically significant increase in cardiac troponin T protein expression in the tri-culture hydrogel construct at 6 weeks, when compared to hPSC-CMs alone (P < 0.001). The sustained hPSC-CM survival and contractility in tri-culture was associated with a significant upregulation in the gene expression of L-type Ca(2+) ion channel, Cav1.2, and the inward-rectifier potassium channel, Kir2.1 (P < 0.05), suggesting a role of ion channels in mediating these processes. These findings demonstrate that multi-cellular interactions modulate hPSC-CM phenotype, function, and survival, and they will have important implications in engineering cardiac tissues for treatment of cardiovascular diseases.
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Medicine, Division of Cardiovascular Medicine Palo Alto, CA ; Institute for Stem Cell Biology and Regenerative Medicine Palo Alto, CA.
authors: Paul W
authors: PW
authors: Burridge
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Medicine, Division of Pediatric Cardiology Palo Alto, CA.
authors: Scott A
authors: SA
authors: Metzler
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Cardiothoracic Surgery Palo Alto, CA ; Veterans Affairs Palo Alto Health Care System Palo Alto, CA.
authors: Karina H
authors: KH
authors: Nakayama
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Medicine, Division of Cardiovascular Medicine Palo Alto, CA.
authors: Oscar J
authors: OJ
authors: Abilez
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Mechanical Engineering, Stanford University School of Engineering Stanford, CA ; Department of Mechanical and Aerospace Engineering, University of Florida College of Engineering Gainesville, FL.
authors: Chelsey S
authors: CS
authors: Simmons
authors: Department of Pediatrics (Immunology), Stanford University School of Medicine Stanford, California, USA.
authors: Marc A
authors: MA
authors: Bruce
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Medicine, Division of Cardiovascular Medicine Palo Alto, CA.
authors: Yuka
authors: Y
authors: Matsuura
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Medicine, Division of Cardiovascular Medicine Palo Alto, CA.
authors: Paul
authors: P
authors: Kim
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Medicine, Division of Cardiovascular Medicine Palo Alto, CA ; Institute for Stem Cell Biology and Regenerative Medicine Palo Alto, CA.
authors: Joseph C
authors: JC
authors: Wu
authors: Department of Pediatrics (Immunology), Stanford University School of Medicine Stanford, California, USA.
authors: Manish
authors: M
authors: Butte
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Cardiothoracic Surgery Palo Alto, CA ; Veterans Affairs Palo Alto Health Care System Palo Alto, CA.
authors: Ngan F
authors: NF
authors: Huang
authors: Stanford Cardiovascular Institute Palo Alto, CA ; Department of Medicine, Division of Cardiovascular Medicine Palo Alto, CA ; Institute for Stem Cell Biology and Regenerative Medicine Palo Alto, CA.
authors: Phillip C
authors: PC
authors: Yang
keywords: Induced pluripotent stem cell; cardiac patch; cardiomyocyte; differentiation; endothelial cell; mesenchymal stem cell
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