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J Hepatol. 2018 Apr;68(4):744-753. doi: 10.1016/j.jhep.2017.12.016. Epub 2017 Dec 26.

Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney.

Author information

1
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan; Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, Chiba, Japan.
2
Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Surgery, Takamatsu Red Cross Hospital, Kagawa, Japan.
3
Department of Surgery, Nara Medical University, Nara, Japan.
4
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan; Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka, Japan.
5
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, Chiba, Japan.
6
Department of Radiology, Nara Medical University, Nara, Japan.
7
Department of Pathology, Saiseikai Chuwa Hospital, Nara, Japan.
8
Research Center, Nihon Nohyaku Co., Ltd., Osaka, Japan.
9
Nara Medical University, Nara, Japan.
10
Department of Surgery, Takamatsu Red Cross Hospital, Kagawa, Japan.
11
Liver Research Unit, Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan.
12
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
13
Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
14
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan; Department of Surgery, Nara Medical University, Nara, Japan; Laboratory of Drug Development and Science, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan. Electronic address: ohashikazuo@hotmail.com.

Abstract

BACKGROUND & AIMS:

Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers because of its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through complex intercellular signaling. However, the mechanism of liver organogenesis, especially the role of adult hepatocytes at ectopic sites, remains unknown. In this study, we demonstrate that hepatocytes alone spurred liver organogenesis to form an organ-sized complex 3D liver that exhibited native liver architecture and functions in the kidneys of mice.

METHODS:

Isolated hepatocytes were transplanted under the kidney capsule of monocrotaline (MCT) and partial hepatectomy (PHx)-treated mice. To determine the origin of NPCs in neo-livers, hepatocytes were transplanted into MCT/PHx-treated green fluorescent protein transgenic mice or wild-type mice transplanted with bone marrow cells isolated from green fluorescent protein-mice.

RESULTS:

Hepatocytes engrafted at the subrenal space of mice underwent continuous growth in response to a chronic hepatic injury in the native liver. More than 1.5 years later, whole organ-sized liver tissues with greater mass than those of the injured native liver had formed. Most remarkably, we revealed that at least three types of NPCs with similar phenotypic features to the liver NPCs were recruited from the host tissues including bone marrow. The neo-livers in the kidney exhibited liver-specific functions and architectures, including sinusoidal vascular systems, zonal heterogeneity, and emergence of bile duct cells. Furthermore, the neo-livers successfully rescued the mice with lethal liver injury.

CONCLUSION:

Our data clearly show that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment.

LAY SUMMARY:

The role of adult hepatocytes at ectopic locations has not been clarified. In this study, we demonstrated that engrafted hepatocytes in the kidney proliferated, recruited non-parenchymal cells from host tissues including bone marrow, and finally created an organ-sized, complex liver system that exhibited liver-specific architectures and functions. Our results revealed previously undescribed functions of hepatocytes to direct liver organogenesis through non-parenchymal cell recruitment and organize multiple cell types into a complex 3D liver at ectopic sites. Transcript profiling: Microarray data are deposited in GEO (GEO accession: GSE99141).

KEYWORDS:

Ectopic site; Hepatocytes; Liver injury; Neo-liver; Non-parenchymal cells; Organogenesis

PMID:
29288124
PMCID:
PMC6019609
DOI:
10.1016/j.jhep.2017.12.016
[Indexed for MEDLINE]
Free PMC Article

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