Disease Modeling and Gene Therapy of Copper Storage Disease in Canine Hepatic Organoids

作者：Nantasanti Sathidpak; Spee Bart; Kruitwagen Hedwig S; Chen Chen; Geijsen Niels; Oosterhoff Loes A; van Wolferen Monique E; Pelaez Nicolas; Fieten Hille; Wubbolts Richard W; Grinwis Guy C; Chan Jefferson; Huch Meritxell; Vries Robert R G; Clevers Hans; de Bruin Alain; Rothuizen Jan; Penning Louis C; Schotanus Baukje A^*

来源：Stem Cell Reports, 2015, 5(5): 895-907.

DOI：10.1016/j.stemcr.2015.09.002

The recent development of 3D-liver stem cell cultures (hepatic organoids) opens up new avenues for gene and/or stem cell therapy to treat liver disease. To test safety and efficacy, a relevant large animal model is essential but not yet established. Because of its shared pathologies and disease pathways, the dog is considered the best model for human liver disease. Here we report the establishment of a long-term canine hepatic organoid culture allowing undifferentiated expansion of progenitor cells that can be differentiated toward functional hepatocytes. We show that cultures can be initiated from fresh and frozen liver tissues using Tru-Cut or fine-needle biopsies. The use of Wnt agonists proved important for canine organoid proliferation and inhibition of differentiation. Finally, we demonstrate that successful gene supplementation in hepatic organoids of COMMD1-deficient dogs restores function and can be an effective means to cure copper storage disease.

• 出版日期2015-11-10