- •Hepatocytes engrafted in the kidney created an organ-sized and complex liver.
- •At least three types of liver-specific NPCs were recruited in the neo-liver.
- •Recruited NPCs originated from the host tissues including bone marrow.
- •The neo-liver in the kidney exhibited liver-specific functions and architectures.
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.
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.
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.
Our data clearly show that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment.
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).
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Hepatology
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes.Am J Pathol. 1997; 151: 1273-1280
- Liver regeneration: from myth to mechanism.Nat Rev Mol Cell Biol. 2004; 5: 836-847
- Liver regeneration.J Cell Physiol. 2007; 213: 286-300
- Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene.Cell. 1991; 66: 245-256
- Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.Nat Genet. 1996; 12: 266-273
- Near completely humanized liver in mice shows human-type metabolic responses to drugs.Am J Pathol. 2004; 165: 901-912
- Allogeneic hepatocyte transplantation in the rat spleen under cyclosporine immunosuppression.Transplantation. 1986; 42: 537-541
- Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases.Hepatology. 2005; 41: 132-140
- The mouse lymph node as an ectopic transplantation site for multiple tissues.Nat Biotechnol. 2012; 30: 976-983
- Cell and tissue engineering for liver disease.Sci Transl Med. 2014; 6: 245sr242
- Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets.Nat Med. 2007; 13: 880-885
- Monocrotaline, an alternative to retrorsine-based hepatocyte transplantation in rodents.Cell Transplant. 2005; 14: 41-47
- Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.Physiol Rev. 2008; 88: 125-172
- The mononuclear phagocyte system of the mouse defined by immunohistochemical localisation of antigen F4/80: macrophages associated with epithelia.Anat Rec. 1984; 210: 503-512
- Development of murine hepatic sinusoidal endothelial cells characterized by the expression of hyaluronan receptors.Dev Dyn. 2007; 236: 2258-2267
- Liver sinusoidal endothelial cells in hepatic fibrosis.Hepatology. 2015; 61: 1740-1746
- Characterization of sinusoidal endothelial cells of the liver and bone marrow using an intravital lectin injection method.J Mol Histol. 2008; 39: 471-479
- Imaging biliary lipid secretion in the rat: ultrastructural evidence for vesiculation of the hepatocyte canalicular membrane.J Lipid Res. 1995; 36: 2147-2163
- Liver regeneration.J Hepatol. 2000; 32: 19-31
- Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice.Science. 1996; 274: 1379-1383
- Hepatoprotection via the IL-6/Stat3 pathway.J Clin Invest. 2003; 112: 978-980
- Positional and developmental regulation of glutamine synthetase expression in mouse liver.Mol Cell Biol. 1988; 8: 4966-4971
- LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis.Cancer Res. 2001; 61: 8079-8084
- Development of complementary expression patterns of E- and N-cadherin in the mouse liver.Hepatol Res. 2007; 37: 230-237
- Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver.Nature. 2015; 524: 180-185
- A new lipophilic gadolinium chelate as a tissue-specific contrast medium for MRI.Magn Reson Med. 1991; 22: 233-237
- Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial-mesenchymal transition in liver injury.Proc Natl Acad Sci U S A. 2013; 110: 2324-2329
- Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury.Gastroenterology. 2009; 137: 704-712
- Liver sinusoidal endothelial cells and liver regeneration.J Clin Invest. 2013; 123: 1861-1866
- Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells.Gastroenterology. 2012; 143 (e1552): 1555-1563
- Tissue-resident macrophages.Nat Immunol. 2013; 14: 986-995
- Liver macrophages in tissue homeostasis and disease.Nat Rev Immunol. 2017; 17: 306-321
- Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells.Nat Commun. 2016; 7: 10321
- Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats.J Clin Invest. 2012; 122: 1567-1573
- Oxygen: modulator of metabolic zonation and disease of the liver.Hepatology. 2000; 31: 255-260
- Beta-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation!.Hepatology. 2014; 60: 964-976
Published online: December 26, 2017
Accepted: December 19, 2017
Received in revised form: December 18, 2017
Received: June 15, 2017
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.