Homeostatic mini-intestines through scaffold-guided organoid morphogenesis

TY - JOUR

T1 - Homeostatic mini-intestines through scaffold-guided organoid morphogenesis

AU - Nikolaev, Mikhail

AU - Mitrofanova, Olga

AU - Broguiere, Nicolas

AU - Geraldo, Sara

AU - Dutta, Devanjali

AU - Tabata, Yoji

AU - Elci, Bilge

AU - Brandenberg, Nathalie

AU - Kolotuev, Irina

AU - Gjorevski, Nikolce

AU - Clevers, Hans

AU - Lutolf, Matthias P

PY - 2020/9

Y1 - 2020/9

N2 - Epithelial organoids, such as those derived from stem cells of the intestine, have great potential for modelling tissue and disease biology1-4. However, the approaches that are used at present to derive these organoids in three-dimensional matrices5,6 result in stochastically developing tissues with a closed, cystic architecture that restricts lifespan and size, limits experimental manipulation and prohibits homeostasis. Here, by using tissue engineering and the intrinsic self-organization properties of cells, we induce intestinal stem cells to form tube-shaped epithelia with an accessible lumen and a similar spatial arrangement of crypt- and villus-like domains to that in vivo. When connected to an external pumping system, the mini-gut tubes are perfusable; this allows the continuous removal of dead cells to prolong tissue lifespan by several weeks, and also enables the tubes to be colonized with microorganisms for modelling host-microorganism interactions. The mini-intestines include rare, specialized cell types that are seldom found in conventional organoids. They retain key physiological hallmarks of the intestine and have a notable capacity to regenerate. Our concept for extrinsically guiding the self-organization of stem cells into functional organoids-on-a-chip is broadly applicable and will enable the attainment of more physiologically relevant organoid shapes, sizes and functions.

AB - Epithelial organoids, such as those derived from stem cells of the intestine, have great potential for modelling tissue and disease biology1-4. However, the approaches that are used at present to derive these organoids in three-dimensional matrices5,6 result in stochastically developing tissues with a closed, cystic architecture that restricts lifespan and size, limits experimental manipulation and prohibits homeostasis. Here, by using tissue engineering and the intrinsic self-organization properties of cells, we induce intestinal stem cells to form tube-shaped epithelia with an accessible lumen and a similar spatial arrangement of crypt- and villus-like domains to that in vivo. When connected to an external pumping system, the mini-gut tubes are perfusable; this allows the continuous removal of dead cells to prolong tissue lifespan by several weeks, and also enables the tubes to be colonized with microorganisms for modelling host-microorganism interactions. The mini-intestines include rare, specialized cell types that are seldom found in conventional organoids. They retain key physiological hallmarks of the intestine and have a notable capacity to regenerate. Our concept for extrinsically guiding the self-organization of stem cells into functional organoids-on-a-chip is broadly applicable and will enable the attainment of more physiologically relevant organoid shapes, sizes and functions.

KW - Animals

KW - Body Patterning

KW - Cell Differentiation

KW - Cell Lineage

KW - Cryptosporidium parvum/pathogenicity

KW - Homeostasis

KW - Human Embryonic Stem Cells/cytology

KW - Human Umbilical Vein Endothelial Cells

KW - Humans

KW - Intestines/cytology

KW - Mice

KW - Models, Biological

KW - Morphogenesis

KW - Organoids/cytology

KW - Regeneration

KW - Regenerative Medicine

KW - Stem Cells

KW - Tissue Culture Techniques/methods

KW - Tissue Engineering

KW - Tissue Scaffolds

U2 - 10.1038/s41586-020-2724-8

DO - 10.1038/s41586-020-2724-8

M3 - Article

C2 - 32939089

SN - 0028-0836

VL - 585

SP - 574

EP - 578

JO - Nature

JF - Nature

IS - 7826

ER -