Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes

• Published in: American journal of translational research Vol. 6; no. 6; pp. 724 - 735
• Main Authors: Burridge, Paul W, Metzler, Scott A, Nakayama, Karina H, Abilez, Oscar J, Simmons, Chelsey S, Bruce, Marc A, Matsuura, Yuka, Kim, Paul, Wu, Joseph C, Butte, Manish, Huang, Ngan F, Yang, Phillip C
• Format: Journal Article
• Language: English
• Published: United States e-Century Publishing Corporation 01-01-2014
• Subjects: Original; Induced pluripotent stem cell; cardiac patch; mesenchymal stem cell; differentiation; endothelial cell; cardiomyocyte
• ISSN: 1943-8141; 1943-8141

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.