Colonic organoids: no longer be-hind in modelling disease

Crespo M, Vilar E, Tsai SY, et al. Colonic organoids derived from human induced pluripotent stem cells for modelling colorectal cancer and drug testing. Nat Med 2017. doi: 10.1038/nm.4355. (Epub ahead of print)

The ability to grow gastric and small intestinal organoids from human-induced pluripotent stem cells (hiPSCs) has allowed us to model intestinal biology adeptly. To date, although colonic organoids (COs) can be grown from adult tissue, they have not been obtained from hiPSCs as the hindgut has proved more challenging a source. The authors have accomplished this from both human embryonic stem cells and hiPSCs. They first cultured heSCs with GSK3β inhibitor; modulating the Wnt pathway in this way gave rise to cells positive for CDX2, a hindgut marker. When hindgut cells were treated with a small molecule inhibitor of BMP, they gave rise to COs, confirmed immunohistochemically by colonic markers CA2, LY6A/8 and CA4. Crypt-like structures formed with proliferating Ki67⁺ cells at the base and transcription profiling established these organoids to closely resemble human colon. Next hiPSCs were used to model FAP (familial adenomatous polyposis). Skin fibroblasts were obtained from two FAP patients and COs were derived. Mutated adenomatous polyposis coli (APC) was confirmed in the iPSCs and reduced APC expression in COs. The Wnt pathway was strongly upregulated and there was an increased proportion of proliferating cells, consistent with the FAP phenotype. Several drugs were then tested: rapamycin reduced proliferation in FAP as well as wild-type organoids, suggesting that this would harm healthy colon. In contrast, Geneticin, a ribosome-binding compound, restored APC expression in COs and reduced proliferation without affecting wild-type organoids. The ability to grow COs from a disease model allows accurate study of morphogen pathways as well as providing a unique platform for drug testing.

Biliary cells can form functional hepatocytes in the injured liver

Raven A, Lu WY, Man TY, …