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

Paul W. Burridge, Scott A. Metzler, Karina H. Nakayama, Oscar J. Abilez, Chelsey S. Simmons, Marc A. Bruce, Yuka Matsuura, Paul Kim, Joseph C. Wu, Manish Butte, Ngan F. Huang, Phillip C. Yang

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 signifcant 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. Quantifcation 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 fnding was supported by a statistically signifcant 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 signifcant upregulation in the gene expression of L-type Ca2+ ion channel, Cav1.2, and the inward-rectifer potassium channel, Kir2.1 (P < 0.05), suggesting a role of ion channels in mediating these processes. These fndings 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.

Original languageEnglish (US)
Pages (from-to)724-735
Number of pages12
JournalAmerican Journal of Translational Research
Volume6
Issue number6
StatePublished - 2014
Externally publishedYes

Fingerprint

Pluripotent Stem Cells
Stem cells
Cardiac Myocytes
Hydrogel
Endothelial cells
Mesenchymal Stromal Cells
Phenotype
Ion Channels
Cell Survival
Endothelial Cells
Troponin T
Survival
Potassium Channels
Tissue Engineering
Gene expression
Cell Communication
Myocardium
Cardiovascular Diseases
Up-Regulation
Tissue

Keywords

  • Cardiac patch
  • Cardiomyocyte
  • Differentiation
  • Endothelial cell
  • Induced pluripotent stem cell
  • Mesenchymal stem cell

ASJC Scopus subject areas

  • Medicine(all)
  • Cancer Research
  • Clinical Biochemistry
  • Molecular Medicine

Cite this

Burridge, P. W., Metzler, S. A., Nakayama, K. H., Abilez, O. J., Simmons, C. S., Bruce, M. A., ... Yang, P. C. (2014). Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes. American Journal of Translational Research, 6(6), 724-735.

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

In: American Journal of Translational Research, Vol. 6, No. 6, 2014, p. 724-735.

Research output: Contribution to journalArticle

Burridge, PW, Metzler, SA, Nakayama, KH, Abilez, OJ, Simmons, CS, Bruce, MA, Matsuura, Y, Kim, P, Wu, JC, Butte, M, Huang, NF & Yang, PC 2014, 'Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes', American Journal of Translational Research, vol. 6, no. 6, pp. 724-735.
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. / Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes. In: American Journal of Translational Research. 2014 ; Vol. 6, No. 6. pp. 724-735.
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