Ileal Derived Organoids From Crohn’s Disease Patients Show Unique Transcriptomic and Secretomic SignaturesSummary
Background & Aims: We used patient-derived organoids (PDOs) to study the epithelial-specific transcriptional and secretome signatures of the ileum during Crohn’s disease (CD) with varying phenotypes to screen for disease profiles and potential druggable targets. Methods: RNA sequencing was p...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21001338 |
| _version_ | 1818675353221070848 |
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| author | Barbara Joanna Niklinska-Schirtz Suresh Venkateswaran Murugadas Anbazhagan Vasantha L. Kolachala Jarod Prince Anne Dodd Raghavan Chinnadurai Gregory Gibson Lee A. Denson David J. Cutler Anil G. Jegga Jason D. Matthews Subra Kugathasan |
| author_facet | Barbara Joanna Niklinska-Schirtz Suresh Venkateswaran Murugadas Anbazhagan Vasantha L. Kolachala Jarod Prince Anne Dodd Raghavan Chinnadurai Gregory Gibson Lee A. Denson David J. Cutler Anil G. Jegga Jason D. Matthews Subra Kugathasan |
| author_sort | Barbara Joanna Niklinska-Schirtz |
| collection | DOAJ |
| description | Background & Aims: We used patient-derived organoids (PDOs) to study the epithelial-specific transcriptional and secretome signatures of the ileum during Crohn’s disease (CD) with varying phenotypes to screen for disease profiles and potential druggable targets. Methods: RNA sequencing was performed on isolated intestinal crypts and 3-week-old PDOs derived from ileal biopsies of CD patients (n = 8 B1, inflammatory; n = 8 B2, stricturing disease) and non-inflammatory bowel disease (IBD) controls (n = 13). Differentially expressed (DE) genes were identified by comparing CD vs control, B1 vs B2, and inflamed vs non-inflamed. DE genes were used for computational screening to find candidate small molecules that could potentially reverse B1and B2 gene signatures. The secretome of a second cohort (n = 6 non-IBD controls, n = 7 CD, 5 non-inflamed, 2 inflamed) was tested by Luminex using cultured organoid conditioned medium. Results: We found 90% similarity in both the identity and abundance of protein coding genes between PDOs and intestinal crypts (15,554 transcripts of 19,900 genes). DE analysis identified 814 genes among disease group (CD vs non-IBD control), 470 genes different between the CD phenotypes, and 5 false discovery rate correction significant genes between inflamed and non-inflamed CD. The PDOs showed both similarity and diversity in the levels and types of soluble cytokines and growth factors they released. Perturbagen analysis revealed potential candidate compounds to reverse B2 disease phenotype to B1 in PDOs. Conclusions: PDOs are similar at the transcriptome level with the in vivo epithelium and retain disease-specific gene expression for which we have identified secretome products, druggable targets, and corresponding pharmacologic agents. Targeting the epithelium could reverse a stricturing phenotype and improve outcomes. |
| first_indexed | 2024-12-17T08:26:14Z |
| format | Article |
| id | doaj.art-138e1bb610ec4c1a92016aaad7d4e59a |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-17T08:26:14Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-138e1bb610ec4c1a92016aaad7d4e59a2022-12-21T21:56:46ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-0112412671280Ileal Derived Organoids From Crohn’s Disease Patients Show Unique Transcriptomic and Secretomic SignaturesSummaryBarbara Joanna Niklinska-Schirtz0Suresh Venkateswaran1Murugadas Anbazhagan2Vasantha L. Kolachala3Jarod Prince4Anne Dodd5Raghavan Chinnadurai6Gregory Gibson7Lee A. Denson8David J. Cutler9Anil G. Jegga10Jason D. Matthews11Subra Kugathasan12Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Atlanta, GeorgiaDivision of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Atlanta, GeorgiaDivision of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Atlanta, GeorgiaDivision of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Atlanta, GeorgiaDivision of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Atlanta, GeorgiaDivision of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Atlanta, GeorgiaDepartment of Biomedical Sciences, Mercer University School of Medicine, Savannah, GeorgiaDepartment of Biology, Georgia Institute of Technology, Atlanta, GeorgiaDivision of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OhioDepartment of Human Genetics, Emory University, Atlanta, GeorgiaDivision of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OhioDivision of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Atlanta, GeorgiaDivision of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children’s Healthcare of Atlanta, Atlanta, Georgia; Correspondence Address correspondence to: Subra Kugathasan, MD, Division of Pediatric Gastroenterology, Emory University School of Medicine & Children’s Healthcare of Atlanta, 1760 Haygood Drive, W-427, Atlanta, Georgia 30322. fax: (404) 727-4069.Background & Aims: We used patient-derived organoids (PDOs) to study the epithelial-specific transcriptional and secretome signatures of the ileum during Crohn’s disease (CD) with varying phenotypes to screen for disease profiles and potential druggable targets. Methods: RNA sequencing was performed on isolated intestinal crypts and 3-week-old PDOs derived from ileal biopsies of CD patients (n = 8 B1, inflammatory; n = 8 B2, stricturing disease) and non-inflammatory bowel disease (IBD) controls (n = 13). Differentially expressed (DE) genes were identified by comparing CD vs control, B1 vs B2, and inflamed vs non-inflamed. DE genes were used for computational screening to find candidate small molecules that could potentially reverse B1and B2 gene signatures. The secretome of a second cohort (n = 6 non-IBD controls, n = 7 CD, 5 non-inflamed, 2 inflamed) was tested by Luminex using cultured organoid conditioned medium. Results: We found 90% similarity in both the identity and abundance of protein coding genes between PDOs and intestinal crypts (15,554 transcripts of 19,900 genes). DE analysis identified 814 genes among disease group (CD vs non-IBD control), 470 genes different between the CD phenotypes, and 5 false discovery rate correction significant genes between inflamed and non-inflamed CD. The PDOs showed both similarity and diversity in the levels and types of soluble cytokines and growth factors they released. Perturbagen analysis revealed potential candidate compounds to reverse B2 disease phenotype to B1 in PDOs. Conclusions: PDOs are similar at the transcriptome level with the in vivo epithelium and retain disease-specific gene expression for which we have identified secretome products, druggable targets, and corresponding pharmacologic agents. Targeting the epithelium could reverse a stricturing phenotype and improve outcomes.http://www.sciencedirect.com/science/article/pii/S2352345X21001338Inflammatory Bowel DiseaseHuman Intestinal OrganoidsChildrenEpigeneticsIntestinal EpitheliumSecretome |
| spellingShingle | Barbara Joanna Niklinska-Schirtz Suresh Venkateswaran Murugadas Anbazhagan Vasantha L. Kolachala Jarod Prince Anne Dodd Raghavan Chinnadurai Gregory Gibson Lee A. Denson David J. Cutler Anil G. Jegga Jason D. Matthews Subra Kugathasan Ileal Derived Organoids From Crohn’s Disease Patients Show Unique Transcriptomic and Secretomic SignaturesSummary Cellular and Molecular Gastroenterology and Hepatology Inflammatory Bowel Disease Human Intestinal Organoids Children Epigenetics Intestinal Epithelium Secretome |
| title | Ileal Derived Organoids From Crohn’s Disease Patients Show Unique Transcriptomic and Secretomic SignaturesSummary |
| title_full | Ileal Derived Organoids From Crohn’s Disease Patients Show Unique Transcriptomic and Secretomic SignaturesSummary |
| title_fullStr | Ileal Derived Organoids From Crohn’s Disease Patients Show Unique Transcriptomic and Secretomic SignaturesSummary |
| title_full_unstemmed | Ileal Derived Organoids From Crohn’s Disease Patients Show Unique Transcriptomic and Secretomic SignaturesSummary |
| title_short | Ileal Derived Organoids From Crohn’s Disease Patients Show Unique Transcriptomic and Secretomic SignaturesSummary |
| title_sort | ileal derived organoids from crohn s disease patients show unique transcriptomic and secretomic signaturessummary |
| topic | Inflammatory Bowel Disease Human Intestinal Organoids Children Epigenetics Intestinal Epithelium Secretome |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21001338 |
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