02119nas a2200337   4500000000100000008004100001260001500042653001900057653001000076653001500086653003500101653001900136653001000155653001800165653001300183653002000196100002100216700002100237700001200258700002200270700001900292700001700311700002200328700002300350245009200373856007200465300001700537490000700554520120600561022001401767       2024                            d  c2024-08-0110aBioengineering10aColon10acolonocyte10agastrointestinal drug toxicity10agut physiology10amucus10aorgan-on-chip10aorganoid10asmall intestine1 aOlga Mitrofanova1 aMikhail Nikolaev1 aQuan Xu1 aNicolas Broguiere1 aIrineja Cubela1 aJ. Gray Camp1 aMichael Bscheider1 aMatthias P. Lutolf00aBioengineered human colon organoids with in vivo-like cellular complexity and function  uhttps://www.sciencedirect.com/science/article/pii/S193459092400184X  a1175-1186.e70 v313 aOrganoids and organs-on-a-chip have emerged as powerful tools for modeling human gut physiology and disease in vitro. Although physiologically relevant, these systems often lack the environmental milieu, spatial organization, cell type diversity, and maturity necessary for mimicking human intestinal mucosa. To instead generate models closely resembling in vivo tissue, we herein integrated organoid and organ-on-a-chip technology to develop an advanced human organoid model, called “mini-colons.” By employing an asymmetric stimulation with growth factors, we greatly enhanced tissue longevity and replicated in vivo-like diversity and patterning of proliferative and differentiated cell types. Mini-colons contain abundant mucus-producing goblet cells and, signifying mini-colon maturation, single-cell RNA sequencing reveals emerging mature and functional colonocytes. This methodology is expanded to generate microtissues from the small intestine and incorporate additional microenvironmental components. Finally, our bioengineered organoids provide a precise platform to systematically study human gut physiology and pathology, and a reliable preclinical model for drug safety assessment.  a1934-5909