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Nat Med. 2017 Jul;23(7):878-884. doi: 10.1038/nm.4355. Epub 2017 Jun 19.

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

Author information

1
Department of Surgery, Weill Cornell Medical College, New York, New York, USA.
2
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
3
Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
5
Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA.
6
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
7
Genomic Core, Weill Cornell Medical College, New York, New York, USA.
8
Department of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
9
Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA.

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.

PMID:
28628110
PMCID:
PMC6055224
DOI:
10.1038/nm.4355
[Indexed for MEDLINE]
Free PMC Article

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