Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Author Info

Ahsley H. Fong, University of California, Irvine
Mónica Romero-López, University of California, Irvine
Christopher M. Heylman, University of California, IrvineFollow
Mark Keating, University of California, Irvine
David Tran, University of California, Irvine
Agua Sobrino, University of California, Irvine
Anh Q. Tran, University of California, Irvine
Hiep H. Pham, University of California, Irvine
Cristhian Fimbres, University of California, Irvine
Paul D. Gershon, University of California, Irvine
Elliot L. Botvinick, University of California, Irvine
Steven C. George, Washington University in St. Louis
Christopher C.W. Hughes, University of California, Irvine

Recommended Citation

Postprint version. Published in Tissue Engineering Part A, Volume 22, Issue 15-16, Summer August 1, 2016, pages 1016-1025.

At the time of publication, the author, Christopher Heylman, was not yet affiliated with Cal Poly.

The definitive version is available at https://doi.org/10.1089/ten.tea.2016.0027.

Abstract

Pluripotent stem cell-derived cardiomyocytes (CMs) have great potential in the development of new therapies for cardiovascular disease. In particular, human induced pluripotent stem cells (iPSCs) may prove especially advantageous due to their pluripotency, their self-renewal potential, and their ability to create patient-specific cell lines. Unfortunately, pluripotent stem cell-derived CMs are immature, with characteristics more closely resembling fetal CMs than adult CMs, and this immaturity has limited their use in drug screening and cell-based therapies. Extracellular matrix (ECM) influences cellular behavior and maturation, as does the geometry of the environment—twodimensional (2D) versus three-dimensional (3D). We therefore tested the hypothesis that native cardiac ECM and 3D cultures might enhance the maturation of iPSC-derived CMs in vitro. We demonstrate that maturation of iPSCderived CMs was enhanced when cells were seeded into a 3D cardiac ECM scaffold, compared with 2D culture. 3D cardiac ECMpromoted increased expression of calcium-handling genes, Junctin, CaV1.2, NCX1, HCN4, SERCA2a, Triadin, and CASQ2. Consistent with this, we find that iPSC-derived CMs in 3D adult cardiac ECM show increased calcium signaling (amplitude) and kinetics (maximum upstroke and downstroke) compared with cells in 2D. Cells in 3D culture were also more responsive to caffeine, likely reflecting an increased availability of calcium in the sarcoplasmic reticulum. Taken together, these studies provide novel strategies for maturing iPSC-derived CMs that may have applications in drug screening and transplantation therapies to treat heart disease.

Disciplines

Biomedical Engineering and Bioengineering

Copyright

2016 Tissue Engineering Part A