su min (violet) hong

read_status: annotated
type: paper
title: In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice
year: 2023
authors:
  - Bouffi, Carine
  - Wikenheiser-Brokamp, Kathryn A.
  - Chaturvedi, Praneet
  - Sundaram, Nambirajan
  - Goddard, Gillian R.
  - Wunderlich, Mark
  - Brown, Nicole E.
  - Staab, Janet F.
  - Latanich, Rachel
  - Zachos, Nicholas C.
  - Holloway, Emily M.
  - Mahe, Maxime M.
  - Poling, Holly M.
  - Vales, Simon
  - Fisher, Garrett W.
  - Spence, Jason R.
  - Mulloy, James C.
  - Zorn, Aaron M.
  - Wells, James M.
  - Helmrath, Michael A.
journal: Nature Biotechnology
doi: 10.1038/s41587-022-01558-x
url: https://www.nature.com/articles/s41587-022-01558-x
project:
  - Rotation_03
system:
  - intestinal_epithelium
  - lamina_propria
  - gut_associated_lymphoid_tissue
  - human_intestinal_organoids
  - humanized_mouse_model
disease:
  - intestinal_inflammatory_disease
  - food_allergy
  - enteric_infection
genes:
  - gp2
  - pigr
  - ccl19
  - ccl21
  - cxcl13
processes:
  - immune_cell_infiltration
  - lymphoid_follicle_formation
  - epithelial_immune_crosstalk
  - m_cell_differentiation
  - antigen_transcytosis
  - iga_secretion
methods:
  - organoid_transplantation
  - humanized_mouse_engraftment
  - mass_cytometry
  - immunohistochemistry
  - microbial_lysate_challenge
  - enteroid_monolayer_culture
key_findings:
  - immune_cell_recruitment_to_organoids
  - g_alt_like_structure_formation
  - microbiota_induced_m_cell_specification
  - functional_iga_response
limitations:
  - human_specific_gut_immunity_model
  - developmental_gi_immunology
  - translational_infection_and_allergy_model
relevance:
  - gi
  - organoids
  - mucosal_immunity
  - development
  - humanized_models
concepts:
  - epithelial_immune_crosstalk_in_gut_development
  - m_cell_dependent_mucosal_immunity
  - organoid_based_human_immune_models
tags:
  - gi
  - organoids
  - mucosal_immunity
  - development
  - humanized_models

Abstract

        Human intestinal organoids (HIOs) derived from pluripotent stem cells provide a valuable model for investigating human intestinal organogenesis and physiology, but they lack the immune components required to fully recapitulate the complexity of human intestinal biology and diseases. To address this issue and to begin to decipher human intestinal–immune crosstalk during development, we generated HIOs containing immune cells by transplanting HIOs under the kidney capsule of mice with a humanized immune system. We found that human immune cells temporally migrate to the mucosa and form cellular aggregates that resemble human intestinal lymphoid follicles. Moreover, after microbial exposure, epithelial microfold cells are increased in number, leading to immune cell activation determined by the secretion of IgA antibodies in the HIO lumen. This in vivo HIO system with human immune cells provides a framework for future studies on infection- or allergen-driven intestinal diseases.

Key Findings

• Human immune cells migrate into HIO mucosa and epithelium after in vivo transplantation

• T- and B-cell aggregates organize into lymphoid follicle–like structures over time

• Immune architecture recapitulates human fetal GALT development temporally and spatially

• Microbial exposure is required to induce epithelial M-cell differentiation

• GP2⁺ M cells are functionally competent, enabling IgA secretion into the lumen

Methods

• Transplantation of PSC-derived HIOs under the kidney capsule of humanized NSGS mice

• Mass cytometry (CyTOF) with UMAP clustering to define immune composition

• Immunohistochemistry and immunofluorescence for spatial immune mapping

• E. coli lysate luminal injection to model microbial antigen exposure

Notes

• Demonstrates that epithelium alone is insufficient; in vivo context drives immune tissue formation

• Positions HIOs as developmentally instructive niches for immune organization

• Separates immune recruitment from immune activation, requiring microbial cues

• Provides a human-specific alternative to mouse GALT studies

• Bridges organoid biology with functional mucosal immunity

Figures / Data

• Figure 1: Human immune cells infiltrate transplanted HIOs but not host intestine

• Figure 2: CyTOF profiling reveals diverse, GALT-like immune populations

• Figure 3: Spatially organized T- and B-cell aggregates emerge over time

• Figure 4: HIO immune development parallels human fetal gut lymphoid maturation

• Figure 5: Microbial challenge induces GP2⁺ M cells and IgA secretion

Limitations

• Immune responses modeled are acute, not chronic

• Lacks full microbiota diversity and dynamics

• Stromal organizer cell identities remain indirectly inferred

• Vascular and neural immune interactions are not resolved