Homeostatic mini-intestines through scaffold-guided organoid morphogenesis

Mikhail Nikolaev, Olga Mitrofanova, Nicolas Broguiere, Sara Geraldo, Devanjali Dutta, Yoji Tabata, Bilge Elci, Nathalie Brandenberg, Irina Kolotuev, Nikolce Gjorevski, Hans Clevers, Matthias P Lutolf

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)574-578
Number of pages5
JournalNature
Volume585
Issue number7826
DOIs
Publication statusPublished - Sep 2020

Keywords

  • Animals
  • Body Patterning
  • Cell Differentiation
  • Cell Lineage
  • Cryptosporidium parvum/pathogenicity
  • Homeostasis
  • Human Embryonic Stem Cells/cytology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intestines/cytology
  • Mice
  • Models, Biological
  • Morphogenesis
  • Organoids/cytology
  • Regeneration
  • Regenerative Medicine
  • Stem Cells
  • Tissue Culture Techniques/methods
  • Tissue Engineering
  • Tissue Scaffolds

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