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Organoid Analysis Highlights the Intercellular Signaling Processes controlling Hepatogenesis



Review of “Multilineage communication regulates human liver bud development from pluripotency” from Nature by Stuart P. Atkinson

The development of three-dimensional (3D) organ-like multicellular tissues from human pluripotent stem cells (hPSCs) represents one of the most exciting technological advances in recent times. The potential for these “organoids” encompasses drug screening, developmental studies, and even the generation of transplantable cells and tissues. However, at present, we do not fully appreciate the spatial and temporal processes that transpire in these self-organizing tissues.

Previous studies from the labs of Keisuke Sekine, Takanori Takebe, and Barbara Treutlein have described how human induced pluripotent stem cells (iPSC)-derivatives can form 3D liver bud (LB) organoids with the capacity to graft into mouse recipients [1]. In their new Nature study, Camp et al. analyze LB organoid cells by single-cell RNA sequencing (scRNA-seq)-based techniques [2, 3] to understand the intercellular signaling processes that drive hepatogenesis [4].

As a first step, the authors assessed transcriptional states during hepatic cell differentiation of hiPSCs in conventional two-dimensional culture and discovered that this recapitulated many aspects of in vivo hepatogenesis. Comparisons to transcriptional data collected during the development of 3D LB organoids containing human hepatic endoderm (HE) and endothelial and mesenchymal support cells [5] indicated many similarities but underscored important transcriptional differences indicating differential hepatic development in LB organoids. Indeed, hepatic cells from LB organoids transcriptionally resembled fetal liver cells more closely than 2D hepatocytes.

The authors surmised that the transcriptional differences might arise due to signaling from the endothelial and mesenchymal support cells present during LB organoid development. To discover critical pathways, the team combined an in silico receptor–ligand pairing screen, RNAi-based knockdowns, and high-throughput imaging employing miniaturized LBs and specific inhibitors to highlight a crucial role for VEGFA-VEGFR2 interactions in the LB-specific hepatic differentiation.

Overall, this exciting new study has begun to highlight the molecular underpinnings of multicellular interlineage interactions that control 3D differentiation, which may help us to understand organ development and tissue regeneration.

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  1. Takebe T, Sekine K, Enomura M, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 2013;499:481-484.
  2. Treutlein B, Brownfield DG, Wu AR, et al. Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature 2014;509:371-375.
  3. Camp JG, Badsha F, Florio M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A 2015;112:15672-15677.
  4. Camp JG, Sekine K, Gerber T, et al. Multilineage communication regulates human liver bud development from pluripotency. Nature 2017;546:533-538.
  5. Takebe T, Enomura M, Yoshizawa E, et al. Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation. Cell Stem Cell 2015;16:556-565.