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Review
. 2021 Aug 3;10(1):27.
doi: 10.1186/s13619-021-00089-1.

Emerging liver organoid platforms and technologies

Do Thuy Uyen Ha Lam  1   2 , Yock Young Dan  2   3 , Yun-Shen Chan  4   5 , Huck-Hui Ng  6   7   8   9
Affiliations
Review

Emerging liver organoid platforms and technologies

Do Thuy Uyen Ha Lam et al. Cell Regen. .

Abstract

Building human organs in a dish has been a long term goal of researchers in pursue of physiologically relevant models of human disease and for replacement of worn out and diseased organs. The liver has been an organ of interest for its central role in regulating body homeostasis as well as drug metabolism. An accurate liver replica should contain the multiple cell types found in the organ and these cells should be spatially organized to resemble tissue structures. More importantly, the in vitro model should recapitulate cellular and tissue level functions. Progress in cell culture techniques and bioengineering approaches have greatly accelerated the development of advance 3-dimensional (3D) cellular models commonly referred to as liver organoids. These 3D models described range from single to multiple cell type containing cultures with diverse applications from establishing patient-specific liver cells to modeling of chronic liver diseases and regenerative therapy. Each organoid platform is advantageous for specific applications and presents its own limitations. This review aims to provide a comprehensive summary of major liver organoid platforms and technologies developed for diverse applications.

Keywords: Disease models; Liver; Organoids; Regenerative therapy; Stem cells.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Stem cell and progenitor liver organoids. Top panel: Proliferating bipotent biliary organoids isolated from patient liver tissue can be maintained in culture as an expandable cell source and differentiated into functional cholangiocytes or hepatocytes. This approach has been employed to derived tumoroids from the three major liver cancer subtypes. Middle panel: Using similar approach with additional hepatocyte supporting signaling factors, proliferating hepatocytes can also be derived from liver tissues. These proliferating hepatocytes can be further matured into highly functional hepatocytes. (Bottom panel): Transdifferentiation of fibroblast to liver organoids. Fibroblast over-expressing (OE) SV40 large T antigen (SV40LT) is transdifferentiated into human-induced hepatocyte organoids (HiHeps), using a combination of FOXA3, HNF1A and HNF4A. Introduction of various HCC oncogenes transform the HiHeps into liver cancer organoids
Fig. 2
Fig. 2
Pluripotent stem cell (PSC) derived liver organoids. PSCs are provided with signalling cues to differentiate along the endoderm lineage into cells resembling the definitive endoderm (DE), posterior foregut (PFG) and hepatic endoderm (HE). These intermediate endoderm lineage progenitors are utilized to generate various liver organoids. The DE can use to generate the midgut (MG) and foregut (FG) spheroids. The MG and FG co-culture induces hepato-biliary-pancreatic (HBP) organogenesis at the boundary to generate the HBP organoids containing cell and structure resembling the duodenum (Duo), pancreas (Pan) and liver that are interconnected by the biliary (Bil) structure. PFG can be employed to generate multi-cellular liver organoids containing both parenchymal (hepatocytes) and non-parenchymal (HSCs and Kupffer cells) cells. The HE can be co-culture with mesenchymal stem cells and HUVEC to produce liver buds that further mature into vascularized tissues when transplanted in mice. Multiple groups have also further differentiated the HE to generate liver organoids that contain only cholangiocytes or hepatocytes, or hepatobiliary organoids containing both liver parenchymal cell types in different configurations
Fig. 3
Fig. 3
Engineering approaches to create liver organoids. Different parenchymal and non-parenchymal liver cell types have been employed with a variety of engineering tools to create bio-engineered liver organoids. Cell sources range from primary cells derived from tissues to immortalized cell lines and cells differentiated from expandable stem cells. Non-parenchymal endothelial, mesenchymal and Kupffer cells are the common stroma and immune liver cell types employed to recapitulate the niche environment of the liver tissue. Cells are seeded with precision in controlled environment using one or more common bio-engineering platforms and approaches such as patterned ECM, microwell arrays, matrix overlays, microfluidics platform and 3D bio-printing. Common bioengineered organoids generated using the various cell types with different engineering approaches are depicted
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References

    1. Achberger K, Probst C, Haderspeck J, Bolz S, Rogal J, Chuchuy J, Nikolova M, Cora V, Antkowiak L, Haq W, Shen N, Schenke-Layland K, Ueffing M, Liebau S, Loskill P. Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform. eLife. 2019;8:e46188. doi: 10.7554/eLife.46188. - DOI - PMC - PubMed
    1. Ahmed HMM, Salerno S, Morelli S, Giorno L, De Bartolo L. 3D liver membrane system by co-culturing human hepatocytes, sinusoidal endothelial and stellate cells. Biofabrication. 2017;9(2):025022. doi: 10.1088/1758-5090/aa70c7. - DOI - PubMed
    1. Aizarani N, Saviano A, Sagar, Mailly L, Durand S, Herman JS, Pessaux P, Baumert TF, Grün D. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature. 2019;572(7768):199–204. doi: 10.1038/s41586-019-1373-2. - DOI - PMC - PubMed
    1. Akbari S, Sevinç GG, Ersoy N, Basak O, Kaplan K, Sevinç K, Ozel E, Sengun B, Enustun E, Ozcimen B, Bagriyanik A, Arslan N, Önder TT, Erdal E. Robust, Long-term culture of endoderm-derived hepatic organoids for disease modeling. Stem Cell Rep. 2019;13(4):627–641. doi: 10.1016/j.stemcr.2019.08.007. - DOI - PMC - PubMed
    1. Almeda-Valdés P, Aguilar-Olivos NE, Uribe M, Méndez-Sánchez N. Chapter 25 - the metabolic syndrome, oxidative stress, and the liver. In: Muriel P, editor. Liver pathophysiology. Boston: Academic; 2017. pp. 323–329.

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