Three-dimensional bioprinted hepatorganoids prolong survival of mice with liver failure
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Open Access
- 20 May 2020
- Vol. 70 (3), 567-574
- https://doi.org/10.1136/gutjnl-2019-319960
Abstract
Objective Shortage of organ donors, a critical challenge for treatment of end-stage organ failure, has motivated the development of alternative strategies to generate organs in vitro. Here, we aim to describe the hepatorganoids, which is a liver tissue model generated by three-dimensional (3D) bioprinting of HepaRG cells and investigate its liver functions in vitro and in vivo. Design 3D bioprinted hepatorganoids (3DP-HOs) were constructed using HepaRG cells and bioink, according to specific 3D printing procedures. Liver functions of 3DP-HOs were detected after 7 days of differentiation in vitro, which were later transplanted into Fah-deficient mice. The in vivo liver functions of 3DP-HOs were evaluated by survival time and liver damage of mice, human liver function markers and human-specific debrisoquine metabolite production. Results 3DP-HOs broadly acquired liver functions, such as ALBUMIN secretion, drug metabolism and glycogen storage after 7 days of differentiation. After transplantation into abdominal cavity of Fah-/-Rag2-/- mouse model of liver injury, 3DP-HOs further matured and displayed increased synthesis of liver-specific proteins. Particularly, the mice acquired human-specific drug metabolism activities. Functional vascular systems were also formed in transplanted 3DP-HOs, further enhancing the material transport and liver functions of 3DP-HOs. Most importantly, transplantation of 3DP-HOs significantly improved the survival of mice. Conclusions Our results demonstrated a comprehensive proof of principle, which indicated that 3DP-HO model of liver tissues possessed in vivo hepatic functions and alleviated liver failure after transplantation, suggesting that 3D bioprinting could be used to generate human liver tissues as the alternative transplantation donors for treatment of liver diseases.Keywords
This publication has 32 references indexed in Scilit:
- In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation CapacityCell Stem Cell, 2018
- Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogensCell Research, 2018
- 3D bioprinting of tissues and organs for regenerative medicineAdvanced Drug Delivery Reviews, 2018
- Resection versus transplantation for hepatocellular carcinoma exceeding Milan criteria within increasing donor shortageHepatoBiliary Surgery and Nutrition, 2017
- Living donor liver transplantation: eliminating the wait for death in end-stage liver disease?Nature Reviews Gastroenterology & Hepatology, 2017
- Acute-on-chronic liver failureThe Lancet, 2015
- Direct Reprogramming of Human Fibroblasts to Functional and Expandable HepatocytesCell Stem Cell, 2014
- In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regenerationNature, 2013
- Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cellsHepatology, 2009
- Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytesHepatology, 2007