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Stem Cell Res Ther. 2018 Jan 10;9(1):5. doi: 10.1186/s13287-017-0749-1.

Human liver organoids generated with single donor-derived multiple cells rescue mice from acute liver failure.

Author information

1
Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 236-0004, Japan.
2
Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 236-0004, Japan. ywzheng@md.tsukuba.ac.jp.
3
Department of Advanced Gastroenterological Surgical Science and Technology, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, 305-8575, Japan. ywzheng@md.tsukuba.ac.jp.
4
Research Center of Stem Cells and Regenerative Medicine, Jiangsu University Hospital, Zhenjiang, Jiangsu, 212001, China. ywzheng@md.tsukuba.ac.jp.
5
Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 236-0004, Japan.
6
Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 236-0004, Japan. rtanigu@med.yokohama-cu.ac.jp.
7
Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 236-0004, Japan. rtanigu@med.yokohama-cu.ac.jp.

Abstract

BACKGROUND:

Acute liver failure (ALF) is a life-threatening disease with a high mortality rate. However, there are limited treatments or devices available for ALF therapy. Here, we aimed to develop a new strategy for ALF treatment by transplanting functional liver organoids (LOs) generated from single donor-derived human induced pluripotent stem cell (hiPSC) endoderm, endothelial cells (ECs), and mesenchymal cells (MCs).

METHODS:

First, we isolated ECs and MCs from a single donor umbilical cord (UC) through enzyme digestion and characterized the UC-ECs and UC-MCs by flow cytometry. Second, using a nonviral reprogramming method, we generated same donor-derived hiPSCs from the UC-ECs and investigated their hepatic differentiation abilities. Finally, we simultaneously plated EC-hiPSC endoderm, UC-ECs, and UC-MCs in a three-dimensional (3D) microwell culture system, and generated single donor cell-derived differentiated LOs for ALF mouse treatment.

RESULTS:

We obtained ECs and MCs from a single donor UC with high purity, and these cells provided a multicellular microenvironment that promoted LO differentiation. hiPSCs from the same donor were generated from UC-ECs, and the resultant EC-hiPSCs could be differentiated efficiently into pure definitive endoderm and further into hepatic lineages. Simultaneous plating of EC-hiPSC endoderm, UC-ECs, and UC-MCs in the 3D microwell system generated single donor cell-derived LOs (SDC-LOs) that could be differentiated into functional LOs with enhanced hepatic capacity as compared to that of EC-hiPSC-derived hepatic-like cells. When these functional SDC-LOs were transplanted into the renal subcapsules of ALF mice, they rapidly assumed hepatic functions and improved the survival rate of ALF mice.

CONCLUSION:

These results demonstrate that functional LOs generated from single donor cells can improve the condition of ALF mice. Functional SDC-LO transplantation provides a promising novel approach for ALF therapy.

KEYWORDS:

Acute liver failure; Human induced pluripotent stem cells; Liver organoids; Liver regeneration; Single donor

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