Induced Endothelial Cell-Integrated Liver Assembloids Promote Hepatic Maturation and Therapeutic Effect on Cholestatic Liver Fibrosis
Donggyu Nam,
Myung Rae Park,
Hyunah Lee,
Sung Chul Bae,
Daniela Gerovska,
Marcos J. Araúzo-Bravo,
Holm Zaehres,
Hans R. Schöler,
Jeong Beom Kim
Affiliations
Donggyu Nam
Hans Schöler Stem Cell Research Center (HSSCRC), Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea
Myung Rae Park
Hans Schöler Stem Cell Research Center (HSSCRC), Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea
Hyunah Lee
Hans Schöler Stem Cell Research Center (HSSCRC), Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea
Sung Chul Bae
Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea
Daniela Gerovska
Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastian, Spain
Marcos J. Araúzo-Bravo
Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastian, Spain
Holm Zaehres
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany
Hans R. Schöler
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany
Jeong Beom Kim
Hans Schöler Stem Cell Research Center (HSSCRC), Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea
The transplantation of pluripotent stem cell (PSC)-derived liver organoids has been studied to solve the current donor shortage. However, the differentiation of unintended cell populations, difficulty in generating multi-lineage organoids, and tumorigenicity of PSC-derived organoids are challenges. However, direct conversion technology has allowed for the generation lineage-restricted induced stem cells from somatic cells bypassing the pluripotent state, thereby eliminating tumorigenic risks. Here, liver assembloids (iHEAs) were generated by integrating induced endothelial cells (iECs) into the liver organoids (iHLOs) generated with induced hepatic stem cells (iHepSCs). Liver assembloids showed enhanced functional maturity compared to iHLOs in vitro and improved therapeutic effects on cholestatic liver fibrosis animals in vivo. Mechanistically, FN1 expressed from iECs led to the upregulation of Itgα5/β1 and Hnf4α in iHEAs and were correlated to the decreased expression of genes related to hepatic stellate cell activation such as Lox and Spp1 in the cholestatic liver fibrosis animals. In conclusion, our study demonstrates the possibility of generating transplantable iHEAs with directly converted cells, and our results evidence that integrating iECs allows iHEAs to have enhanced hepatic maturation compared to iHLOs.
