Mapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth

Delilah Hendriks (), Benedetta Artegiani (), Thanasis Margaritis, Iris Zoutendijk, Susana Chuva de Sousa Lopes and Hans Clevers ()
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Delilah Hendriks: Royal Netherlands Academy of Arts and Sciences
Benedetta Artegiani: The Princess Maxima Center for Pediatric Oncology
Thanasis Margaritis: The Princess Maxima Center for Pediatric Oncology
Iris Zoutendijk: The Princess Maxima Center for Pediatric Oncology
Susana Chuva de Sousa Lopes: Leiden University Medical Center
Hans Clevers: Royal Netherlands Academy of Arts and Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Mechanisms underlying human hepatocyte growth in development and regeneration are incompletely understood. In vitro, human fetal hepatocytes (FH) can be robustly grown as organoids, while adult primary human hepatocyte (PHH) organoids remain difficult to expand, suggesting different growth requirements between fetal and adult hepatocytes. Here, we characterize hepatocyte organoid outgrowth using temporal transcriptomic and phenotypic approaches. FHs initiate reciprocal transcriptional programs involving increased proliferation and repressed lipid metabolism upon initiation of organoid growth. We exploit these insights to design maturation conditions for FH organoids, resulting in acquisition of mature hepatocyte morphological traits and increased expression of functional markers. During PHH organoid outgrowth in the same culture condition as for FHs, the adult transcriptomes initially mimic the fetal transcriptomic signatures, but PHHs rapidly acquire disbalanced proliferation-lipid metabolism dynamics, resulting in steatosis and halted organoid growth. IL6 supplementation, as emerged from the fetal dataset, and simultaneous activation of the metabolic regulator FXR, prevents steatosis and promotes PHH proliferation, resulting in improved expansion of the derived organoids. Single-cell RNA sequencing analyses reveal preservation of their fetal and adult hepatocyte identities in the respective organoid cultures. Our findings uncover mitogen requirements and metabolic differences determining proliferation of hepatocytes changing from development to adulthood.

Date: 2024
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DOI: 10.1038/s41467-024-48550-4

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