Liver organoids: Current advances and future applications for hepatology
Authors: Yohan Kim, Minseok Kang, Michael Girma Mamo, Michael Adisasmita, Dongho Choi
Journal: Clinical and Molecular Hepatology (2024)

The creation of self-organizing liver organoids represents a significant, although modest, step toward addressing the ongoing organ shortage crisis in allogeneic liver transplantation.However, researchers have recognized that achieving a fully functional whole liver remains a distant goal, and the original ambition of organoid-based liver generation has been temporarily put on hold.Instead, liver organoids have revolutionized the field of hepatology, extending their influence into various domains of precision and molecular medicine.These 3D cultures, capable of replicating key features of human liver function and pathology, have opened new avenues for human-relevant disease modeling, CRISPR gene editing, and high-throughput drug screening that animal models cannot accomplish.Moreover, advancements in creating more complex systems have led to the development of multicellular assembloids, dynamic organoid-on-chip systems, and 3D bioprinting technologies.These innovations enable detailed modeling of liver microenvironments and complex tissue interactions.Progress in regenerative medicine and transplantation applications continues to evolve and strives to overcome the obstacles of biocompatibility and tumorigenecity.In this review, we examine the current state of liver organoid research by offering insights into where the field currently stands, and the pivotal developments that are driving its shaping its future.and difficulties in high-throughput screening, which is one of the advantages of 2D cell culture systems 15 .Given the limitations of 2D culture systems and animal models, 3D culture systems, such as organoids, spheroids, and 3D bioprinting, have recently emerged as promising technologies to address these challenges.Spheroids represent the simplest form of 3D culture, allowing the formation of spherical 3D structures through cell aggregation without the need for extracellular matrix (ECM) components such as Matrigel 16- 20 .Their simplicity enables easy culturing, and they have been widely studied in cell types that aggregate well, such as cancer cells, embryoid bodies, and hepatocytes.However, most types of spheroids form solid spherical structures, which limits their ability to replicate the specific structural characteristics of various organs.Additionally, the delivery of nutrients and oxygen to cells at the center of the spheroid is challenging, often resulting in cell necrosis and other limitations 17,20,21 .In this manuscript, we aim to focus on organoids, one of the various 3D culture systems.In 2008, when self-organized apico-basally polarized cortical tissue were reported from embryonic stem cells (ESCs) 22 , and Lgr5-positive stem cells isolated from adult intestinal tissue were shown to form cryptvillus structure through self-organization 23 , studies on the generation and expansion methods of organoids from various organ have been published.Organoids are 3D structures formed by the self-organization of adult stem cells (ASCs), pluripotent stem cells (PSCs) or progenitor cells, which recapitulate the target organ structures and functions 24 .Organoids have recently been actively utilized and studied across various fields because of their ability to incorporate the advantages of traditional experimental models, such as high-throughput screening, genetic manipulation, and replication of physiological features 25 .ASC-derived organoids are formed by isolating primary cells from adult tissues and culturing them under the key signaling conditions of the respective organ, allowing them to maintain the structural, physiological, and functional characteristics of the organ 23,[26][27][28] .These ASC-organoid have shown genetic stability even after long-term expansion 26 and, as they can be generated from patient-derived cells, hold potential for applications in personalized medicine, such as toxicity assessments and gene therapy.However, the requirement for invasive procedures to obtain patient tissues is considered a drawback.On the other hand, PSC-derived organoids can be generated using relatively less invasive methods and offer the advantage of generating organoids for organs, such as the brain, where tissue samples are difficult to obtain [29][30][31][32] .Brain organoid research is predominantly conducted using PSC-derived organoids, and induced-pluripotent stem cells (iPSC)-derived organoids are particularly promising in regenerative medicine, as they enable the generation of patient-specific organoids.However, the complex differentiation processes required to generate PSC-derived organoids are considered a major source of high variability among organoids 33,34 .Additionally, differences in characteristics between PSC lines are another concern.Despite these challenges, both ASC-derived and PSC-derived organoids effectively recapitulate in vivo organs in vitro and are utilized across various applications.By leveraging the strengths and addressing the limitations of each cell source, effective research tailored to specific applications can be conducted.