Study for pathophysiological analysis of Hirschsprung's Disease using iPSC derived mini-gut

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K18167
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Uchida Hajime 国立研究開発法人国立成育医療研究センター, 小児外科系専門診療部, 医師 (30648697)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: ヒルシュスプルング病 / オルガノイド / iPS細胞

Outline of Final Research Achievements

Our aim is to construct a system that can recapitulate human intestinal plexus as well as intestinal development, and elucidate the development and dysfunction of intestinal ganglions. Our group succeeded for the first time in the world in creating intestinal organoids (mini-guts), and have human intestinal functions such as peristalsis, absorption, and secretory capacity. In order to evaluate the slow peristalsis as much as possible, we found that the video evaluation by adding histamine is applicable as a method to select mini-intestines capable of peristalsis (mini-intestine-histamine challenge test). In the process of induction of mini-intestine differentiation, PAX3, ZIC1 and SOX10 early markers of crest cells were already expressed on day 7 from the start of differentiation induction, and their expression was observed until day 14 in the mini-gut development. We will develop the creation of loss-of-function models by genome editing of disease-related genes such as the RET gene.

Free Research Field

移植医療

Academic Significance and Societal Importance of the Research Achievements

消化管の希少疾患バイオモデルの構築から初期発生、消化管神経分化を模倣する分子プログラム追跡が可能となった。小児希少疾患の疾患機序解明とともに、創薬開発では革新的なin vitro試験系開発を促進させる。今後は、ミニ腸モデルでの検証でヒトin vitro臨床試験モデルの構築を目指す。