Generation Of Human Intestinal Organoids From Cronkhite Canada Syndrome Patients Reveals Serotonin As A Link To Intestinal Proliferation

Cronkhite Canada Syndrome (CCS) is a rare, non-inherited polyposis syndrome affecting 1 in a million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To investigate and better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from two CCS patients. We discovered that CCS HIOs have unique growth characteristics and have increased serotonin (5-hydroxytryptamine, 5HT) positive cells. Further investigation revealed that 5HT can induce HIO proliferation, and inhibition of 5HT results in decreased proliferation in the CCS HIOs. Our findings indicate that dysregulation of 5HT may explain polyposis observed in CCS and provide new insight into regulation of the intestinal stem cell. This work illustrates the important contribution organoids can make to understanding disease etiology and identifying novel therapies. Biopsies from 2 CCS patients and controls were obtained and the stem cells were isolated to generate the organoids. Organoids were differentiated for 3 days prior to RNA extraction and sequencing.