Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem CellsSummary
Background & Aims: Organs of the gastrointestinal tract contain tissue-resident immune cells that function during tissue development, homeostasis, and disease. However, most published human organoid model systems lack resident immune cells, thus limiting their potential as disease avatars. F...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X24001991 |
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| author | Kentaro Tominaga Daniel O. Kechele J. Guillermo Sanchez Simon Vales Ingrid Jurickova Lizza Roman Akihiro Asai Jacob R. Enriquez Heather A. McCauley Keishi Kishimoto Kentaro Iwasawa Akaljot Singh Yuko Horio Jorge O. Múnera Takanori Takebe Aaron M. Zorn Michael A. Helmrath Lee A. Denson James M. Wells |
| author_facet | Kentaro Tominaga Daniel O. Kechele J. Guillermo Sanchez Simon Vales Ingrid Jurickova Lizza Roman Akihiro Asai Jacob R. Enriquez Heather A. McCauley Keishi Kishimoto Kentaro Iwasawa Akaljot Singh Yuko Horio Jorge O. Múnera Takanori Takebe Aaron M. Zorn Michael A. Helmrath Lee A. Denson James M. Wells |
| author_sort | Kentaro Tominaga |
| collection | DOAJ |
| description | Background & Aims: Organs of the gastrointestinal tract contain tissue-resident immune cells that function during tissue development, homeostasis, and disease. However, most published human organoid model systems lack resident immune cells, thus limiting their potential as disease avatars. For example, human intestinal organoids (HIOs) derived from pluripotent stem cells contain epithelial and various mesenchymal cell types but lack immune cells. In this study, we aimed to develop an HIO model with functional tissue-resident macrophages. Methods: HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined in vitro. Following 2 weeks of coculture, the organoids were used for transcriptional profiling, functional analysis of macrophages, or transplanted into immunocompromised mice and matured in vivo for an additional 10–12 weeks. Results: Macrophages were incorporated into developing HIOs and persisted for 2 weeks in vitro HIOs and for at least 12 weeks in HIOs in vivo. These cocultured macrophages had a transcriptional signature that resembled those in the human fetal intestine, indicating that they were acquiring the features of tissue-resident macrophages. HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals, such as lipopolysaccharide, which could be reversed with interleukin-10. Conclusions: We generated an HIO system containing functional tissue-resident macrophages for an extended period. This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease. |
| format | Article |
| id | doaj-art-d102c6f7447d4691a96f3fab730e28da |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-d102c6f7447d4691a96f3fab730e28da2025-02-05T04:32:11ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01194101444Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem CellsSummaryKentaro Tominaga0Daniel O. Kechele1J. Guillermo Sanchez2Simon Vales3Ingrid Jurickova4Lizza Roman5Akihiro Asai6Jacob R. Enriquez7Heather A. McCauley8Keishi Kishimoto9Kentaro Iwasawa10Akaljot Singh11Yuko Horio12Jorge O. Múnera13Takanori Takebe14Aaron M. Zorn15Michael A. Helmrath16Lee A. Denson17James M. Wells18Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, JapanDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioCenter for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioCenter for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioCenter for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioCenter for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioTranslational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South CarolinaDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioCenter for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioCenter for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OhioDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Correspondence Address correspondence to: James M. Wells, PhD, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7007, Cincinnati, Ohio 45229.Background & Aims: Organs of the gastrointestinal tract contain tissue-resident immune cells that function during tissue development, homeostasis, and disease. However, most published human organoid model systems lack resident immune cells, thus limiting their potential as disease avatars. For example, human intestinal organoids (HIOs) derived from pluripotent stem cells contain epithelial and various mesenchymal cell types but lack immune cells. In this study, we aimed to develop an HIO model with functional tissue-resident macrophages. Methods: HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined in vitro. Following 2 weeks of coculture, the organoids were used for transcriptional profiling, functional analysis of macrophages, or transplanted into immunocompromised mice and matured in vivo for an additional 10–12 weeks. Results: Macrophages were incorporated into developing HIOs and persisted for 2 weeks in vitro HIOs and for at least 12 weeks in HIOs in vivo. These cocultured macrophages had a transcriptional signature that resembled those in the human fetal intestine, indicating that they were acquiring the features of tissue-resident macrophages. HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals, such as lipopolysaccharide, which could be reversed with interleukin-10. Conclusions: We generated an HIO system containing functional tissue-resident macrophages for an extended period. This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease.http://www.sciencedirect.com/science/article/pii/S2352345X24001991Human Intestinal OrganoidsTissue-Resident MacrophagesImmune CellsInflammatory Bowel Disease |
| spellingShingle | Kentaro Tominaga Daniel O. Kechele J. Guillermo Sanchez Simon Vales Ingrid Jurickova Lizza Roman Akihiro Asai Jacob R. Enriquez Heather A. McCauley Keishi Kishimoto Kentaro Iwasawa Akaljot Singh Yuko Horio Jorge O. Múnera Takanori Takebe Aaron M. Zorn Michael A. Helmrath Lee A. Denson James M. Wells Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem CellsSummary Cellular and Molecular Gastroenterology and Hepatology Human Intestinal Organoids Tissue-Resident Macrophages Immune Cells Inflammatory Bowel Disease |
| title | Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem CellsSummary |
| title_full | Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem CellsSummary |
| title_fullStr | Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem CellsSummary |
| title_full_unstemmed | Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem CellsSummary |
| title_short | Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem CellsSummary |
| title_sort | deriving human intestinal organoids with functional tissue resident macrophages all from pluripotent stem cellssummary |
| topic | Human Intestinal Organoids Tissue-Resident Macrophages Immune Cells Inflammatory Bowel Disease |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X24001991 |
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