The latest study from the Jill Roberts Institute, "CX3CR1+ mononuclear phagocytes control immunity to intestinal fungi," was published on January 11 in Science. To read more, click here.  Dr. Gregory Sonnenberg wins inaugural award from the Society for Mucosal Immunology. To read more, click here.  The Kenneth Rainin Foundation awarded Dr. Iliyan Iliev and colleagues from Mount Sinai a $250,000 Synergy Award to examine the composition of the fungal community in babies born to mothers with inflammatory bowel disease. To read more, click here. Dr. Randy Longman received the Irma T. Hirschl Career Scientist Award and the New York Crohn’s Foundation Award.    

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Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing.

TitleColonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing.
Publication TypeJournal Article
Year of Publication2017
AuthorsCrespo, M, Vilar, E, Tsai, S-Y, Chang, K, Amin, S, Srinivasan, T, Zhang, T, Pipalia, NH, Chen, HJoyce, Witherspoon, M, Gordillo, M, Xiang, JZhaoying, Maxfield, FR, Lipkin, S, Evans, T, Chen, S
JournalNat Med
Volume23
Issue7
Pagination878-884
Date Published2017 Jul
ISSN1546-170X
KeywordsAdenoma, Adenomatous Polyposis Coli, Adenomatous Polyposis Coli Protein, Antibiotics, Antineoplastic, Blotting, Western, Cell Differentiation, Cell Proliferation, Colon, Colorectal Neoplasms, Drug Screening Assays, Antitumor, Enteroendocrine Cells, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Profiling, Gentamicins, Germ-Line Mutation, Goblet Cells, Heterocyclic Compounds, 3-Ring, Human Embryonic Stem Cells, Humans, Immunohistochemistry, Induced Pluripotent Stem Cells, Microscopy, Confocal, Mutation, Organoids, Real-Time Polymerase Chain Reaction, Sirolimus, Wnt Signaling Pathway
Abstract

With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. Two potential compounds, XAV939 and rapamycin, decreased proliferation in FAP-COs, but also affected cell proliferation in wild-type COs, which thus limits their therapeutic application. By contrast, we found that geneticin, a ribosome-binding antibiotic with translational 'read-through' activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease.

DOI10.1038/nm.4355
Alternate JournalNat. Med.
PubMed ID28628110
Grant ListDP2 DK098093 / DK / NIDDK NIH HHS / United States
DP3 DK111907 / DK / NIDDK NIH HHS / United States