Liver organoids are three-dimensional cellular tissue models in which cells interact to form unique structures in culture. During the past 10 years, liver organoids with various cellular compositions, structural features, and functional properties have been described. Methods to create these advanced human cell models range from simple tissue culture techniques to complex bioengineering approaches. Liver organoid culture platforms have been used in various research fields, from modeling liver diseases to regenerative therapy. This review discusses how liver organoids are used to model disease, including hereditary liver diseases, primary liver cancer, viral hepatitis, and nonalcoholic fatty liver disease. Specifically, we focus on studies that used either of two widely adopted approaches: differentiation from pluripotent stem cells or epithelial organoids cultured from patient tissues. These approaches have enabled the generation of advanced human liver models and, more importantly, the establishment of patient-tailored models for evaluating disease phenotypes and therapeutic responses at the individual level.
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Cirrhosis is a chronic condition that can lead to liver failure. Currently, the viable option for decreasing mortality is liver transplantation. However, transplant surgery is highly invasive. Therefore, cell-based therapy has been developed as an alternative. Based on promising findings from preclinical research, some new trials have been registered. One of them was autologous bone marrow cell infusion therapy and found that ameliorating liver fibrosis activated liver regeneration. Now, majority of trials focus on low-immunogenicity mesenchymal stem cells (MSCs) appropriate for allogeneic administration. However, despite about 20 years of research, only a limited number of cell-based therapies have entered routine practice. Furthermore, potential shortcomings of cell-based therapy include a limit on the number of cells, which may be administered, as well as their failure to infiltrate target organs. On the other hand, these research show that MSCs act as “conducting cells” and regulate host cells including macrophages via extracellular vesicles (EVs) or exosome signals, leading to ameliorate liver fibrosis and promote regeneration. Therefore, the concept of cell-free therapy, which makes use of cell-derived EVs or exosomes, is attracting attention. Cell-free therapies may be safely administered in large doses and are able to infiltrate target organs. However, development of cell-free therapy exhibits its own set of challenges and such therapy may not be completely curative in the context of liver disease. This review describes the history of cell-based therapy research and recent advances in cell-free therapy, as well as discussing the need for more effective therapies.
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End-stage liver disease is one of the leading causes of death around the world. Since insufficient sources of transplantable liver and possible immune rejection severely hinder the wide application of conventional liver transplantation therapy, artificial three-dimensional (3D) liver culture and assembly from stem cells have become a new hope for patients with end-stage liver diseases, such as cirrhosis and liver cancer. However, the induced differentiation of single-layer or 3D-structured hepatocytes from stem cells cannot physiologically support essential liver functions due to the lack of formation of blood vessels, immune regulation, storage of vitamins, and other vital hepatic activities. Thus, there is emerging evidence showing that 3D organogenesis of artificial vascularized liver tissue from combined hepatic cell types derived from differentiated stem cells is practical for the treatment of end-stage liver diseases. The optimization of novel biomaterials, such as decellularized matrices and natural macromolecules, also strongly supports the organogenesis of 3D tissue with the desired complex structure. This review summarizes new research updates on novel differentiation protocols of stem cell-derived major hepatic cell types and the application of new supportive biomaterials. Future biological and clinical challenges of this concept are also discussed.
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Most liver diseases lead to hepatic dysfunction with organ failure. Liver transplantation is the best curative
therapy, but it has some limitations such as donor shortage, possibility of rejection, and maintenance of
immunosuppressant. New therapies have been actively searched for over several decades, primarily in the form
of artificial liver support devices and hepatocyte transplantation, but both of these modalities remain
experimental. Stem cells have recently shown promise in cell therapy because they have the capacity for
self-renewal and multilineage differentiation, and are applicable to human diseases.
Very recent reports of unexpected plasticity in adult bone marrow have raised hopes of stem cell therapy
offering exciting therapeutic possibilities for patients with chronic liver disease. Both rodent and human
embryonic stem cells, bone marrow hematopoietic stem cells, mesenchymal stem cells, umbilical cord blood
cells, fetal liver progenitor cells, adult liver progenitor cells, and mature hepatocytes have been reported to be
capable of self-renewal, giving rise to daughter hepatocytes both in vivo and in vitro. These cells can
repopulate livers in animal models of liver injury and appear to be able to improve liver function. However,
significant challenges still exist before these cells can be used in humans, such as the lack of consensus about
the immunophenotype of liver progenitor cells, uncertainty of the physiological role of reported candidate
stem/progenitor cells, practicality of obtaining sufficient quantity of cells for clinical use, and concerns over
ethics, long-term efficacy, and safety. There have been reports of phase 1 trials using stem cell transplantation
in humans for liver diseases, but more effective trials are needed. We review the use of stem cells (focusing
on adult ones) and the reported human clinical trials, and highlight the challenges facing clinicians in their
quest to use liver stem cells to save lives. (Korean J Hepatol 2008;14:309-317)
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