More than 20 million Canadians suffer from digestive disorders every year. Such high numbers make it necessary to study and develop new drugs to combat these diseases. Recently, Principal investigator Jim Wells, Ph.D., director of the Pluripotent Stem Cell Facility at Cincinnati Children's and his team has generated gastric fundus organoids from human pluripotent stem cells (hPOCs)2, which will prove to be crucial to the testing of new drugs, designed to treat digestive problems.Drug testing is often carried out in mouse models, before they can be approved for clinical trials. This approach can be problematic as mice and humans differ physiologically and genetically and the drugs tested in mouse models might not always have the same effects in humans. Furthermore, once the drug is tested in an animal model then it has to go through human clinical trials, which can be limited by the number of participants. These issues can be avoided if we use organoids as models for drug testing. Organoids are miniaturized organs that show realistic microanatomy and are produced in vitro, usually from stem cells. These are genetically identical to humans and can be regenerated, hence making drug testing more convenient and reliable.
In a study published in nature, the authors generated gastric fundus organoids from hPOCs3. A key challenge the authors faced was the fact that there was no known protocol or pathway that was previously known to contribute to fundus differentiation. In this study, the authors determined that the Wnt/β-catenin pathway were essential for fundus development because knocking out β-catenin led to the expression of Pdx1, a marker found in antral epithelium of the stomach but not the fundus epithelium. Furthermore, fundus specific markers such as Irx2, Irx3, Irx5 were greatly reduced as well. Once the importance of Wnt/β-catenin was realized, the authors indirectly stimulated the Wnt/β-catenin by using CIHR. This drove the development of fundal organoids, which was then followed by the use of a variety of cytodifferentiation factors to stimulate the formation of fundal epithelium specific lineages.
This study has made key contributions to the development of a system on which drugs can be tested to determine their effects on the gastrointestinal system. Currently, our knowledge of the key pathways that regulate the differentiation of gastrointestinal progenitors into specific lineages is still incomplete. This system can shed some light onto those regulatory pathways and help us to develop even more robust models for drug testing and studying gastrointestinal diseases.
References
- http://www.cdhf.ca/en/statistics
- http://www.medicalnewstoday.com/articles/315043.php
- McCracken, K. W. et al. Wnt/β-catenin promotes gastric fundus specification in mice and humans. Nature 541, 182–187 (2017).
Article Summary Courtesy: Jennifer Lu and Waleed Khan