Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids

Ouchi, Rie; Togo, Shodai; Kimura, Masaki; Shinozawa, Tadahiro; Koido, Masaru; Koike, Hiroyuki; Thompson, Wendy L.; Karns, Rebekah; Mayhew, Christopher N.; McGrath, Patrick S.; McCauley, Heather A.; Zhang, Ranran; Lewis, Kyle; Hakozaki, Shoyo; Ferguson, Autumn; Saiki, Norikazu; Yoneyama, Yoshimasa; Takeuchi, Ichiro; Mabuchi, Yo; Akazawa, Chihiro; Yoshikawa, Hiroshi; Wells, James M.; Takebe, Takanori

doi:10.1016/j.cmet.2019.05.007

Cited by 316 publications

(406 citation statements)

References 63 publications

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“…Foregut spheroids were then incubated with retinoic acid and subsequently cultured in in hepatocyte differentiation media containing HGF, Dex, and OSM . The protocol results in the formation of human HLOs containing major liver cell types including hepatocytes, HSCs, Kupffer cells, and cholangiocytes . Analysis of HLO cell identity by means of single‐cell transcriptomics analysis confirmed the presence of hepatocytes expressing the signature genes HNF4A , CEBPA , RBP4 , and ASGR1 ; HSCs expressing VIM , CYGB , DES , and COL1A1 ; and Kupffer cells expressing CD14, FLT1, ATLR4 , and GPBAR1 .…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

“…This is a condition caused by to excessive accumulation of free fatty acids (FFAs) by the hepatocytes, causing hepatocyte stress and an inflammatory response that is partly driven by liver‐resident monocytic cells called Kupffer cells . A protocol has been recently developed for the generation of human liver organoids (HLOs) containing Kupffer‐like cells with inflammatory activity inducible by FFAs . This protocol results in the generation of human liver tissues through an initial step of endoderm specification followed by generation of foregut spheroids by sequential incubations with Activin A and BMP4, Activin A alone, FGF4, and CHIR99201, as previously shown .…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

“…A protocol has been recently developed for the generation of human liver organoids (HLOs) containing Kupffer‐like cells with inflammatory activity inducible by FFAs . This protocol results in the generation of human liver tissues through an initial step of endoderm specification followed by generation of foregut spheroids by sequential incubations with Activin A and BMP4, Activin A alone, FGF4, and CHIR99201, as previously shown . Foregut spheroids were then incubated with retinoic acid and subsequently cultured in in hepatocyte differentiation media containing HGF, Dex, and OSM .…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

“…This protocol results in the generation of human liver tissues through an initial step of endoderm specification followed by generation of foregut spheroids by sequential incubations with Activin A and BMP4, Activin A alone, FGF4, and CHIR99201, as previously shown . Foregut spheroids were then incubated with retinoic acid and subsequently cultured in in hepatocyte differentiation media containing HGF, Dex, and OSM . The protocol results in the formation of human HLOs containing major liver cell types including hepatocytes, HSCs, Kupffer cells, and cholangiocytes .…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

“…Persistent activation of Kupffer cells is observed in pathological conditions such as viral liver infection, alcoholic liver disease, and nonalcoholic fatty liver disease also known as steatohepatitis . Re‐creation of steatohepatitis conditions in HLO cultures by addition of FFAs in the culture media resulted in the accumulation of lipids and triglycerides, and the buildup of an inflammatory response evidenced by increased secretion of interleukin 6 (IL6), and expression of TNFΑ and IL8 mRNAs, after 3 days of exposure to FFAs . After 5 days of exposure, HLOs developed fibrosis, as indicated by an increased number of VIM + HSCs‐expressing ACTA2, indicating that under these culture conditions HSCs adopt a myofibroblast phenotype .…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

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Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

Sobral-Reyes

Lemos

2019

Stem Cells

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As new applications for human pluripotent stem cell‐derived organoids in drug screenings and tissue replacement therapies emerge, there is a need to examine the mechanisms of tissue injury and repair recently reported for various organoid models. In most cases, organoids contain the main cell types and tissues present in human organs, spatially arranged in a manner that largely resembles the architecture of the organ. Depending on the differentiation protocol used, variations may exist in cell type ratios relative to the organ of reference, and certain tissues, including some parenchymal components and the endothelium, might be poorly represented, or lacking altogether. Despite those caveats, recent studies have shown that organoid tissue injury recapitulates major events and histopathological features of damaged human tissues. In particular, major mechanisms of parenchyma cell damage and interstitial fibrosis can be reproduced with remarkable faithfulness. Although further validation remains to be done in order to establish the relevance of using organoid for either mechanistic studies or drug assays, this technology is becoming a promising tool for the study of human tissue homeostasis, injury, and repair.

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Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

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Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

Sobral-Reyes

Lemos

2019

Stem Cells

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Engineering Liver Microtissues for Disease Modeling and Regenerative Medicine

Huang

Gibeley

et al. 2020

Adv Funct Materials

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The burden of liver diseases is increasing worldwide, accounting for two million deaths annually. In the past decade, tremendous progress has been made in the basic and translational research of liver tissue engineering. Liver microtissues are small, 3D hepatocyte cultures that recapitulate liver physiology and have been used in biomedical research and regenerative medicine. This review summarizes the recent advances, challenges, and future directions in liver microtissue research. Cellular engineering approaches are used to sustain primary hepatocytes or produce hepatocytes derived from pluripotent stem cells and other adult tissues. 3D microtissues are generated using scaffoldfree assembly or scaffold-assisted methods such as macroencapsulation, droplet microfluidics, and bioprinting. Optimization of the hepatic microenvironment entails incorporating the appropriate cell composition for enhanced cell-cell interactions and niche-specific signals, and creating scaffolds with desired chemical, mechanical, and physical properties. Perfusion-based culture systems such as bioreactors and microfluidic systems are used to achieve efficient exchange of nutrients and soluble factors. Taken together, systematic optimization of liver microtissues is a multidisciplinary effort focused on creating liver cultures and on-chip models with greater structural complexity and physiological relevance for use in liver disease research, therapeutic development, and regenerative medicine.

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Engineered Biomaterial Platforms to Study Fibrosis

Davidson

Burdick

Wells

2020

Adv Healthcare Materials

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Many pathologic conditions lead to the development of tissue scarring and fibrosis, which are characterized by the accumulation of abnormal extracellular matrix (ECM) and changes in tissue mechanical properties. Cells within fibrotic tissues are exposed to dynamic microenvironments that may promote or prolong fibrosis, which makes it difficult to treat. Biomaterials have proved indispensable to better understand how cells sense their extracellular environment and are now being employed to study fibrosis in many tissues. As mechanical testing of tissues becomes more routine and biomaterial tools become more advanced, the impact of biophysical factors in fibrosis are beginning to be understood. Herein, fibrosis from a materials perspective is reviewed, including the role and mechanical properties of ECM components, the spatiotemporal mechanical changes that occur during fibrosis, current biomaterial systems to study fibrosis, and emerging biomaterial systems and tools that can further the understanding of fibrosis initiation and progression. This review concludes by highlighting considerations in promoting wide‐spread use of biomaterials for fibrosis investigations and by suggesting future in vivo studies that it is hoped will inspire the development of even more advanced biomaterial systems.

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Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids

Cited by 316 publications

References 63 publications

Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

Engineering Liver Microtissues for Disease Modeling and Regenerative Medicine

Engineered Biomaterial Platforms to Study Fibrosis

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