Human Pluripotent Stem Cell-derived Hepatic Organoids: A Promising Novel Model of Liver Diseases

We read with great interest the article by Bin et al,1Bin Ramli M.N. et al.Gastroenterology. 2020; 159: 1471-1486Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar in which they generated hepatic organoids derived from human pluripotent stem cells (hPSCs). We congratulate the authors who contributed to this work because they have developed a promising and novel model that can be used to study liver diseases. The hepatic organoids produced according to their protocol include two parenchymal liver cell types—hepatocytes and cholangiocytes—both of which are functional. The organoids could organize a functional bile canaliculi system that can be used as a novel model to study liver diseases, including nonalcoholic steatohepatitis (NASH). Because of the lack of a microenvironment and the interactions between different cell types, the applications of organoids have many restrictions.2Park S.E. et al.Science. 2019; 364: 960-965Crossref PubMed Scopus (199) Google Scholar It is undoubtedly major progress to generate hepatic organoids with hepatocytes and cholangiocytes that form functional biliary structures. However, it has been reported that hepatic stellate cells (HSCs) and Kupffer cells play major roles in the progression of NASH.3Schwabe R.F. et al.Gastroenterology. 2020; 158: 1913-1928Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar,4Tomita K. et al.Hepatology. 2014; 59: 154-169Crossref PubMed Scopus (174) Google Scholar Bin et al1Bin Ramli M.N. et al.Gastroenterology. 2020; 159: 1471-1486Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar believe that their organoids enable modeling of molecular and cellular events in parenchymal cell types, but we doubt that the presence or absence of non-parenchymal cells, such as HSCs and Kupffer cells, may lead to different situations. The interaction between hepatocytes, macrophagocytes, and HSCs is an important mechanism leading to the progression of NASH.3Schwabe R.F. et al.Gastroenterology. 2020; 158: 1913-1928Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The hepatic organoids derived from hPSCs established by Ouchi et al5Ouchi R. et al.Cell Metab. 2019; 30: 374-384 e6Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar consisted of parenchymal cells, such as hepatocytes and cholangiocytes, and nonparenchymal cells such as HSCs and Kupffer cells. They found increases in the expression of IL-6, IL-8, and tumor necrosis factor-α in organoids exposed to free fatty acids, and the inflammatory cytokine induction was likely driven by Kupffer-like cells rather than hepatocyte-like cells. They also found an increase in the percentage of VIM and α-smooth muscle actin–positive stellate-like cells.5Ouchi R. et al.Cell Metab. 2019; 30: 374-384 e6Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar These data all directly suggest the pathological features of inflammation and fibrosis in NASH. Therefore, we believe that the presence of HSCs and Kupffer cells is essential to establish a model to study NASH in vitro. Additionally, Bin et al1Bin Ramli M.N. et al.Gastroenterology. 2020; 159: 1471-1486Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar found that the majority of organoids contained a high ratio of hepatocytes to cholangiocytes. We look forward to understanding the specific ratio of hepatocytes to cholangiocytes and whether it can reflect the actual condition of the liver. We believe it is inappropriate for the authors to declare that they are the first to prove that hepatic and biliary cells assemble to form a functional bile duct system; our understanding is that Wu et al6Wu F. et al.J Hepatol. 2019; 70: 1145-1158Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar have previously developed functional hepatobiliary organoids generated from hPSCs. Organoids have great variability in size, structural organization, functional capacity, and gene expression. This variability has been identified as a major obstacle that limits the potential of organoid technology, especially for applications in disease modeling, drug screening, and transplantation.2Park S.E. et al.Science. 2019; 364: 960-965Crossref PubMed Scopus (199) Google Scholar Unlike previously reported organoid systems, Bin et al reported that their protocol allows for the generation of organoids that are consistent in shape, size, and structure. However, we did not find enough data in the article to illustrate this point. We believe that the brightfield images of 48 individual organoids at day 50 of differentiation shown by the authors cannot prove this conclusion very well. Accurately measuring the size of more organoids may strengthen this finding. Additionally, the authors should emphasize how they reduced the variability in organoid production compared with other protocols. In summary, the work by Bin et al revealed the possible use of organoids as liver disease models. However, more research is needed to determine whether the organoids can be an accurate model of human liver diseases, as stated by the authors. B. Jin and X.-A. Wu contributed equally to this work. Human Pluripotent Stem Cell-Derived Organoids as Models of Liver DiseaseGastroenterologyVol. 159Issue 4PreviewThere are few in vitro models for studying the 3-dimensional interactions among different liver cell types during organogenesis or disease development. We aimed to generate hepatic organoids that comprise different parenchymal liver cell types and have structural features of the liver, using human pluripotent stem cells. Full-Text PDF Open AccessReplyGastroenterologyVol. 160Issue 6PreviewWe appreciate the interest in our study from Jin et al and would like to take the opportunity to further emphasize the highlights and challenges in creating liver organoids. Jin et al highlighted the need for multiple cell types in modeling complex diseases such as nonalcoholic steatohepatitis during nonalcoholic fatty liver disease (NAFLD) progression, and this underscores the value of creating multicellular organoids models.1 NAFLD is a progressive and complex metabolic disease with various phenotypes developed in the parenchymal and stromal cell types, that requires the interplay between these cells. Full-Text PDF