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

Ashley H. Fong, Mónica Romero-López, Christopher M. Heylman, Mark Keating, David Tran, Agua Sobrino, Anh Q. Tran, Hiep H. Pham, Cristhian Fimbres, Paul D. Gershon, Elliot L. Botvinick, Steven George, Christopher C.W. Hughes

Research output: Contribution to journalArticle

45 Citations (Scopus)

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 - two-dimensional (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 iPSC-derived CMs was enhanced when cells were seeded into a 3D cardiac ECM scaffold, compared with 2D culture. 3D cardiac ECM promoted 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.

Original languageEnglish (US)
Pages (from-to)1016-1025
Number of pages10
JournalTissue Engineering - Part A
Volume22
Issue number15-16
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

Fingerprint

Induced Pluripotent Stem Cells
Stem cells
Cardiac Myocytes
Extracellular Matrix
Calcium
Pluripotent Stem Cells
Preclinical Drug Evaluations
Screening
Caffeine
Calcium Signaling
Cell culture
Scaffolds
Pharmaceutical Preparations
Sarcoplasmic Reticulum
Cell- and Tissue-Based Therapy
Genes
Heart Diseases
Cells
Availability
Cardiovascular Diseases

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Biomaterials
  • Biomedical Engineering

Cite this

Fong, A. H., Romero-López, M., Heylman, C. M., Keating, M., Tran, D., Sobrino, A., ... Hughes, C. C. W. (2016). Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Tissue Engineering - Part A, 22(15-16), 1016-1025. https://doi.org/10.1089/ten.tea.2016.0027

Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. / Fong, Ashley H.; Romero-López, Mónica; Heylman, Christopher M.; Keating, Mark; Tran, David; Sobrino, Agua; Tran, Anh Q.; Pham, Hiep H.; Fimbres, Cristhian; Gershon, Paul D.; Botvinick, Elliot L.; George, Steven; Hughes, Christopher C.W.

In: Tissue Engineering - Part A, Vol. 22, No. 15-16, 01.08.2016, p. 1016-1025.

Research output: Contribution to journalArticle

Fong, AH, Romero-López, M, Heylman, CM, Keating, M, Tran, D, Sobrino, A, Tran, AQ, Pham, HH, Fimbres, C, Gershon, PD, Botvinick, EL, George, S & Hughes, CCW 2016, 'Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes', Tissue Engineering - Part A, vol. 22, no. 15-16, pp. 1016-1025. https://doi.org/10.1089/ten.tea.2016.0027
Fong, Ashley H. ; Romero-López, Mónica ; Heylman, Christopher M. ; Keating, Mark ; Tran, David ; Sobrino, Agua ; Tran, Anh Q. ; Pham, Hiep H. ; Fimbres, Cristhian ; Gershon, Paul D. ; Botvinick, Elliot L. ; George, Steven ; Hughes, Christopher C.W. / Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. In: Tissue Engineering - Part A. 2016 ; Vol. 22, No. 15-16. pp. 1016-1025.
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