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Deriving functional human enteroendocrine cells from pluripotent stem cells.

Katie L Sinagoga1, Heather A McCauley1, Jorge O Múnera1

  • 1Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA.

Development (Cambridge, England)
|August 26, 2018
PubMed
Summary

Researchers used a gene pulse to significantly increase enteroendocrine cells (EECs) in human organoids, enabling better study of digestion and nutrient balance. This advance aids research into gut hormones and related diseases.

Keywords:
HormonesIncretinNeurogenin 3OrganoidsSatietyStem cell

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Area of Science:

  • Gastroenterology
  • Developmental Biology
  • Stem Cell Biology

Background:

  • Enteroendocrine cells (EECs) are crucial for digestion, satiety, and nutrient homeostasis.
  • Human intestinal organoid models contain EECs, but their low numbers hinder functional studies.

Purpose of the Study:

  • To enhance enteroendocrine cell (EEC) development in human intestinal organoids in vitro using the transcription factor NEUROG3.
  • To investigate the function and hormone secretion of EECs generated in organoid models.

Main Methods:

  • Utilized a transient 8-hour pulse of NEUROG3 expression in human pluripotent stem cell-derived intestinal and colonic organoids.
  • Analyzed EEC differentiation, hormone expression (mRNA/protein), and secretion using molecular and cellular techniques.
  • Stimulated organoids with glucose and assessed hormone secretion and cell responses.
  • Transplanted engineered organoids into mice to evaluate EEC subtype formation in vivo.

Main Results:

  • An 8-hour NEUROG3 pulse significantly increased EECs, comprising up to 25% of the epithelium after 7 days.
  • Generated EECs expressed a wide range of gut hormones (e.g., GLP-1, serotonin, GIP) at mRNA and protein levels.
  • EEC cultures demonstrated hormone secretion (e.g., GIP, GLP-1) and responded to glucose stimulation with increased GIP secretion.
  • Transplantation studies confirmed the formation of all known small intestinal EEC subtypes.

Conclusions:

  • Transient NEUROG3 expression is an effective method to generate substantial numbers of functional EECs in human organoid models.
  • These enhanced organoid models provide a powerful platform for studying EEC development, hormone regulation, and gut-related diseases.
  • The findings pave the way for improved disease modeling and therapeutic strategies targeting EEC function.