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Dissolved oxygen concentration regulates human hepatic organoid formation from pluripotent stem cells in a fully controlled bioreactor.

Authors
  • Farzaneh, Zahra1
  • Abbasalizadeh, Saeed1, 2
  • Asghari-Vostikolaee, Mohammad-Hassan1
  • Alikhani, Mehdi1
  • Cabral, Joaquim M S2
  • Baharvand, Hossein1, 3
  • 1 Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. , (Iran)
  • 2 Department of Bioengineering and IBB - Institute for Bioengineering and Biosciences, Institute Superior Técnico, Universidade de Lisboa, Lisboa, Portugal. , (Portugal)
  • 3 Department of Developmental Biology, University of Science and Culture, Tehran, Iran. , (Iran)
Type
Published Article
Journal
Biotechnology and Bioengineering
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2020
Volume
117
Issue
12
Pages
3739–3756
Identifiers
DOI: 10.1002/bit.27521
PMID: 32725885
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Developing technologies for scalable production of human organoids has gained increased attention for "organoid medicine" and drug discovery. We developed a scalable and integrated differentiation process for generation of hepatic organoid from human pluripotent stem cells (hPSCs) in a fully controlled stirred tank bioreactor with 150 ml working volume by application of physiological oxygen concentrations in different liver tissue zones. We found that the 20-40% dissolved oxygen concentration [DO] (corresponded to 30-60 mmHg pO2 within the liver tissue) significantly influences the process outcome via regulating the differentiation fate of hPSC aggregates by enhancing mesoderm induction. Regulation of the [DO] at 30% DO resulted in efficient generation of human fetal-like hepatic organoids that had a uniform size distribution and were comprised of red blood cells and functional hepatocytes, which exhibited improved liver-specific marker gene expressions, key liver metabolic functions, and, more important, higher inducible cytochrome P450 activity compared to the other trials. These hepatic organoids were successfully engrafted in an acute liver injury mouse model and produced albumin after implantation. These results demonstrated the significant impact of the dissolved oxygen concentration on hPSC hepatic differentiation fate and differentiation efficacy that should be considered ascritical translational aspect of established scalable liver organoid generation protocols for potential clinical and drug discovery applications. © 2020 Wiley Periodicals LLC.

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