Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips

Nathaniel Huebsch; Berenice Charrez; Gabriel Neiman; Brian Siemons; Steven C Boggess; Samuel Wall; Verena Charwat; Karoline H Jæger; David Cleres; Åshild Telle; Felipe T Lee-Montiel; Nicholas C Jeffreys; Nikhil Deveshwar; Andrew G Edwards; Jonathan Serrano; Matija Snuderl; Andreas Stahl; Aslak Tveito; Evan W Miller; Kevin E Healy

doi:10.1038/s41551-022-00884-4

Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips

Nat Biomed Eng. 2022 Apr;6(4):372-388. doi: 10.1038/s41551-022-00884-4. Epub 2022 Apr 27.

Authors

Nathaniel Huebsch^#^{1

2}, Berenice Charrez^#¹, Gabriel Neiman¹, Brian Siemons¹, Steven C Boggess³, Samuel Wall⁴, Verena Charwat¹, Karoline H Jæger⁴, David Cleres¹, Åshild Telle⁴, Felipe T Lee-Montiel¹, Nicholas C Jeffreys¹, Nikhil Deveshwar¹, Andrew G Edwards⁵, Jonathan Serrano⁶, Matija Snuderl⁶, Andreas Stahl⁷, Aslak Tveito⁴, Evan W Miller^{3

8

9}, Kevin E Healy^{10

11}

Affiliations

¹ Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA, USA.
² Department of Biomedical Engineering, The Washington University in Saint Louis, Saint Louis, MO, USA.
³ Department of Chemistry, University of California at Berkeley, Berkeley, CA, USA.
⁴ Simula Research Laboratory, Oslo, Norway.
⁵ Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA.
⁶ Department of Pathology, New York University Langone Health and Medical School, New York, NY, USA.
⁷ Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA, USA.
⁸ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA.
⁹ Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
¹⁰ Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA, USA. kehealy@berkeley.edu.
¹¹ Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, CA, USA. kehealy@berkeley.edu.

^# Contributed equally.

Abstract

The immature physiology of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) limits their utility for drug screening and disease modelling. Here we show that suitable combinations of mechanical stimuli and metabolic cues can enhance the maturation of hiPSC-derived cardiomyocytes, and that the maturation-inducing cues have phenotype-dependent effects on the cells' action-potential morphology and calcium handling. By using microfluidic chips that enhanced the alignment and extracellular-matrix production of cardiac microtissues derived from genetically distinct sources of hiPSC-derived cardiomyocytes, we identified fatty-acid-enriched maturation media that improved the cells' mitochondrial structure and calcium handling, and observed divergent cell-source-dependent effects on action-potential duration (APD). Specifically, in the presence of maturation media, tissues with abnormally prolonged APDs exhibited shorter APDs, and tissues with aberrantly short APDs displayed prolonged APDs. Regardless of cell source, tissue maturation reduced variabilities in spontaneous beat rate and in APD, and led to converging cell phenotypes (with APDs within the 300-450 ms range characteristic of human left ventricular cardiomyocytes) that improved the modelling of the effects of pro-arrhythmic drugs on cardiac tissue.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Calcium / metabolism
Cell Differentiation
Humans
Induced Pluripotent Stem Cells*
Microfluidics
Myocytes, Cardiac

Substances

Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding