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Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes
Author(s) -
Unzu Carmen,
Planet Evarist,
Brandenberg Nathalie,
Fusil Floriane,
Cassano Marco,
PerezVargas Jimena,
Friedli Marc,
Cosset FrançoisLoïc,
Lutolf Matthias P.,
Wildhaber Barbara E.,
Trono Didier
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30425
Subject(s) - progenitor cell , induced pluripotent stem cell , biology , ex vivo , epigenetics , microbiology and biotechnology , liver regeneration , hepatocyte , transcriptome , regenerative medicine , regeneration (biology) , hepatic stellate cell , in vivo , cancer research , stem cell , in vitro , embryonic stem cell , genetics , gene expression , endocrinology , gene
The liver is an organ with strong regenerative capacity, yet primary hepatocytes have a low amplification potential in vitro , a major limitation for the cell‐based therapy of liver disorders and for ex vivo biological screens. Induced pluripotent stem cells (iPSCs) may help to circumvent this obstacle but often harbor genetic and epigenetic abnormalities, limiting their potential. Here, we describe the pharmacological induction of proliferative human hepatic progenitor cells (HPCs) through a cocktail of growth factors and small molecules mimicking the signaling events involved in liver regeneration. Human HPCs from healthy donors and pediatric patients proliferated vigorously while maintaining their genomic stability and could be redifferentiated in vitro into metabolically competent cells that supported the replication of hepatitis B and delta viruses. Redifferentiation efficiency was boosted by three‐dimensional culture. Finally, transcriptome analysis showed that HPCs were more closely related to mature hepatocytes than iPSC‐derived hepatocyte‐like cells were. Conclusion: HPC induction holds promise for a variety of applications such as ex vivo disease modeling, personalized drug testing or metabolic studies, and development of a bioartificial liver.