QiutanYang

Institute of Zoology, Chinese Academy of Sciences, China

The construction of organoid systems from  human  pluripotent  stem  cells (PSCs) has significantly advanced disease modeling, personalized medicine, and the study of human biology. However, achieving sufficient maturity in PSC-derived  intestinal organoids  remains  a substantial challenge, as they often fail to match the maturity of their adult stem cell-derived counterparts. Additionally,  human  embryonic  tissue-derived  intestinal  organoids,  which represent the early developmental stages of the intestinal epithelium, cannot be fully matured to adult tissue status under conventional in vitro Matrigel culture conditions.

In this study, we introduce a strategy of multi-germ-layer co-culture, initiated at the onset of human PSC differentiation. This approach yields intestinal organoids that exhibit morphology, cellular composition, and physiological functions  resembling those of adult tissue-derived organoids. Single-cell transcriptomic analysis  and  in  vivo  transplantation  studies  reveal  that  the  induced  organoids  mimic the fetal  gut epithelium towards the end of the first trimester of pregnancy, which is more mature than intestinal organoids   in   currently   reported   PSC-induced   in  vitro  systems.   Moreover,   long-term   passaging demonstrates that these organoids can continue to develop further in vitro without the need for in vivo transplantation.

Our  findings  highlight  the  potential  of  applying  developmental  principles through  multi-germ-layer co-culture to  enhance  the  maturation  of  intestinal  organoids,  thereby  providing  a  valuable  tool  for advancing organoid engineering and disease modeling.