3D aggregate culture improves metabolic maturation of human pluripotent stem cell derived cardiomyocytes

Cláudia Correia, Alexey Koshkin, Patrícia Duarte, Dongjian Hu, Madalena Carido, Maria J. Sebastião, Patrícia Gomes-Alves, David A. Elliott, Ibrahim J. Domian, Ana Palma Teixeira, Paula M. Alves, Margarida Serra

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Three-dimensional (3D) cultures of human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) hold great promise for drug discovery, providing a better approximation to the in vivo physiology over standard two-dimensional (2D) monolayer cultures. However, the transition of CM differentiation protocols from 2D to 3D cultures is not straightforward. In this work, we relied on the aggregation of hPSC-derived cardiac progenitors and their culture under agitated conditions to generate highly pure cardiomyocyte aggregates. Whole-transcriptome analysis and 13C-metabolic flux analysis allowed to demonstrate at both molecular and fluxome levels that such 3D culture environment enhances metabolic maturation of hiPSC-CMs. When compared to 2D, 3D cultures of hiPSC-CMs displayed down-regulation of genes involved in glycolysis and lipid biosynthesis and increased expression of genes involved in OXPHOS. Accordingly, 3D cultures of hiPSC-CMs had lower fluxes through glycolysis and fatty acid synthesis and increased TCA-cycle activity. Importantly, we demonstrated that the 3D culture environment reproducibly improved both CM purity and metabolic maturation across different hPSC lines, thereby providing a robust strategy to derive enriched hPSC-CMs with metabolic features closer to that of adult CMs.

Original languageEnglish
Pages (from-to)630-644
Number of pages15
JournalBiotechnology and Bioengineering
Volume115
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • 3D aggregates
  • fluxome
  • human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs)
  • metabolic maturation
  • transcriptome

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