Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism
Collin de l'Hortet,Alexandra1; Takeishi,Kazuki1,2; Guzman-Lepe,J.1; Morita,Kazutoyo1; Achreja,Abhinav3,4; Popovic,Branimir1; Wang,Yang1,5; Handa,Kan1; Mittal,Anjali4,6; Meurs,Noah3,4; Zhu,Z.3,4; Weinberg,F.8; Salomon,Michael9; Fox,I. J.10; Deng,Chu Xia11; Nagrath,Deepak3,4,6,7; Soto-Gutierrez,Alejandro1
Source PublicationCell Metabolism
AbstractThe mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis and end-stage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 play a role in the development of fatty liver in inbred animals. The ability to perform similar studies using human tissue has been limited by the genetic variability in man. We generated human induced pluripotent stem cells (iPSCs) with controllable expression of SIRT1. By differentiating edited iPSCs into hepatocytes and knocking down SIRT1, we found increased fatty acid biosynthesis that exacerbates fat accumulation. To model human fatty livers, we repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1 knockdown iPSC-derived hepatocytes and found that the human iPSC-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype, and shared a similar lipid and metabolic profiling to human fatty livers. Biofabrication of genetically edited human liver tissue may become an important tool for investigating human liver biology and disease. Collin de l'Hortet et al. biofabricated human fatty livers using genetically modified human hepatocytes differentiated from induced pluripotent stem cells, mesenchymal cells, fibroblasts, and macrophages. This methodology uncovered the molecular mechanisms of downregulated SIRT1 in human liver tissue. The biofabricated tissue reflected many aspects of human livers with non-alcoholic fatty liver disease.
Keywordcellular engineering hepatic differentiation human fatty liver human iPSCs liver metabolism NAFLD NASH SIRT1
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Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorSoto-Gutierrez,Alejandro
Affiliation1.Department of Pathology,University of Pittsburgh,Pittsburgh,United States
2.Department of Surgery and Science,Graduate School of Medical Sciences,Kyushu University,Fukuoka,Japan
3.Department of Biomedical Engineering,University of Michigan Biomedical Engineering,Ann Arbor,United States
4.Biointerfaces Institute,University of Michigan,Ann Arbor,United States
5.Department of Hepatobiliary Surgery,Peking University People's Hospital,Beijing,China
6.Department of Chemical Engineering,University of Michigan,Ann Arbor,United States
7.Rogel Cancer Center,University of Michigan,Ann Arbor,United States
8.Division of Hematology/Oncology,Department of Internal Medicine,University of Michigan Rogel Cancer Center,Ann Arbor,United States
9.Sirion Biotech,Planegg,Am Klopferspitz 19,82152,Germany
10.Department of Surgery,Children's Hospital of Pittsburgh of UPMC,University of Pittsburgh,Pittsburgh,United States
11.Faculty of Health Sciences,University of Macau,Avenida da Universidade,Taipa,China
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GB/T 7714
Collin de l'Hortet,Alexandra,Takeishi,Kazuki,Guzman-Lepe,J.,et al. Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism[J]. Cell Metabolism,2019,30(2):385-401.e9.
APA Collin de l'Hortet,Alexandra.,Takeishi,Kazuki.,Guzman-Lepe,J..,Morita,Kazutoyo.,Achreja,Abhinav.,...&Soto-Gutierrez,Alejandro.(2019).Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism.Cell Metabolism,30(2),385-401.e9.
MLA Collin de l'Hortet,Alexandra,et al."Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism".Cell Metabolism 30.2(2019):385-401.e9.
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