Metabolic substrate shift in human induced pluripotent stem cells during cardiac differentiation: Functional assessment using in vitro radionuclide uptake assay

Naoko Nose, Rudolf A. Werner, Yuichiro Ueda, Katharina Günther, Constantin Lapa, Mehrbod S. Javadi, Kazuhito Fukushima, Frank Edenhofer, Takahiro Higuchi

Research output: Contribution to journalArticle

Abstract

Background: Recent developments in cellular reprogramming technology enable the production of virtually unlimited numbers of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Although hiPSC-CM share various characteristic hallmarks with endogenous cardiomyocytes, it remains a question as to what extent metabolic characteristics are equivalent to mature mammalian cardiomyocytes. Here we set out to functionally characterize the metabolic status of hiPSC-CM in vitro by employing a radionuclide tracer uptake assay. Material and methods: Cardiac differentiation of hiPSC was induced using a combination of well-orchestrated extrinsic stimuli such as WNT activation (by CHIR99021) and BMP signalling followed by WNT inhibition and lactate based cardiomyocyte enrichment. For characterization of metabolic substrates, dual tracer uptake studies were performed with 18 F‑2‑fluoro‑2‑deoxy‑D‑glucose ( 18 F-FDG) and 125 I‑β‑methyl‑iodophenyl‑pentadecanoic acid ( 125 I-BMIPP) as transport markers of glucose and fatty acids, respectively. Results: After cardiac differentiation of hiPSCs, in vitro tracer uptake assays confirmed metabolic substrate shift from glucose to fatty acids that was comparable to those observed in native isolated human cardiomyocytes. Immunostaining further confirmed expression of fatty acid transport and binding proteins on hiPSC-CM. Conclusions: During in vitro cardiac maturation, we observed a metabolic shift to fatty acids, which are known as a main energy source of mammalian hearts, suggesting hi-PSC-CM as a potential functional phenotype to investigate alteration of cardiac metabolism in cardiac diseases. Results also highlight the use of available clinical nuclear medicine tracers as functional assays in stem cell research for improved generation of autologous differentiated cells for numerous biomedical applications.

Original languageEnglish (US)
Pages (from-to)229-234
Number of pages6
JournalInternational Journal of Cardiology
Volume269
DOIs
StatePublished - Oct 15 2018

Keywords

  • Cardiomyocytes
  • Fatty acid
  • Induced pluripotent stem cells
  • Stem cell therapy
  • Tracer
  • hiPSC-CM

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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