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Publications

Journal Article Research Support, Non-U.S. Gov't Epublish 14 citations

PubMed: 35159346 DOI: 10.3390/cells11030537

Evidence of Adult Features and Functions of Hepatocytes Differentiated from Human Induced Pluripotent Stem Cells and Self-Organized as Organoids.

Cells 11(3)

Authors: Antonietta Messina, Eléanor Luce, Nassima Benzoubir, Mattia Pasqua, Ulysse Pereira, Lydie Humbert, Thibaut Eguether, Dominique Rainteau, Jean-Charles Duclos-Vallée, Cécile Legallais, Anne Dubart-Kupperschmitt

Affiliations

  • UMR_S 1193, INSERM/Université Paris-Saclay, F-94800 Villejuif, France.
  • Centre Hépatobiliaire, Fédération Hospitalo-Universitaire (FHU) Hépatinov, AP-HP, Hôpital Paul Brousse, F-94800 Villejuif, France.
  • UMR CNRS 7338 Biomechanics & Bioengineering, Université de Technologie de Compiègne, Sorbonne Universités, 60203 Compiegne, France.
  • Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM, CRSA, AP-HP, Hôpital Saint Antoine, Metomics, 75012 Paris, France.

Abstract

BACKGROUND

Human-induced pluripotent stem cell-derived hepatocytes (iHeps) have been shown to have considerable potential in liver diseases, toxicity, and pharmacological studies. However, there is a growing need to obtain iHeps that are truly similar to primary adult hepatocytes in terms of morphological features and functions. We generated such human iHeps, self-assembled as organoids (iHep-Orgs).

METHODS

iPSC-derived hepatoblasts were self-assembled into spheroids and differentiated into mature hepatocytes modulating final step of differentiation.

RESULTS

In about four weeks of culture, the albumin secretion levels and the complete disappearance of α-fetoprotein from iHep-Orgs suggested the acquisition of a greater degree of maturation than those previously reported. The expression of apical transporters and bile acid secretion evidenced the acquisition of complex hepatocyte polarity as well as the development of a functional and well-defined bile canalicular network confirmed by computational analysis. Activities recorded for CYP450, UGT1A1, and alcohol dehydrogenase, response to hormonal stimulation, and glucose metabolism were also remarkable. Finally, iHep-Orgs displayed a considerable ability to detoxify pathological concentrations of lactate and ammonia.

CONCLUSIONS

With features similar to those of primary adult hepatocytes, the iHep-Orgs thus produced could be considered as a valuable tool for the development and optimization of preclinical and clinical applications.

MeSH

Bile, Microscopy, Electron, Scanning Transmission, Induced Pluripotent Stem Cells, Hepatocytes, Organoids

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