Abstract

Colonoids From Patients With Pediatric Inflammatory Bowel Disease Exhibit Decreased Growth Associated With Inflammation Severity and Durable Upregulation of Antigen Presentation Genes

Judith R Kelsen 1, Noor Dawany 2, Maire A Conrad 1, Tatiana A Karakasheva 1, Kelly Maurer 3, Jane M Wei 1, Selen Uman 4, Maiah H Dent 1, Rithika Behera 1, Laura M Bryant 1, Xianghui Ma 1, Leticia Moreira 5, Priya Chatterji 6, Rawan Shraim 1, Audrey Merz 1, Rei Mizuno 7, Lauren A Simon 1, Amanda B Muir 1, Claudio Giraudo 8, Edward M Behrens 9, Kelly A Whelan 10, Marcella Devoto 11 12, Pierre A Russo 13, Sarah F Andres 14, Kathleen E Sullivan 3, Kathryn E Hamilton 1

 
     

Author information

  • 1Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
  • 2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
  • 3Division of Allergy Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
  • 4Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States.
  • 5Department of Gastroenterology, Hospital Clinic, Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Catalonia, Spain.
  • 6Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States.
  • 7Department of Medicine, Gastroenterology Division, University of Pennsylvania, Philadelphia, PA, United States.
  • 8Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States.
  • 9Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
  • 10Fels Institute for Cancer Research & Molecular Biology, Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.
  • 11Division of Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
  • 12Division of Anatomic Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
  • 13Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States.
  • 14Department of Translational and Precision Medicine, University of Rome Sapienza, Rome, Italy.

Abstract

Background: Defining epithelial cell contributions to inflammatory bowel disease (IBD) is essential for the development of much needed therapies for barrier repair. Children with very early onset (VEO)-IBD have more extensive, severe, and refractory disease than older children and adults with IBD and, in some cases, have defective barrier function. We therefore evaluated functional and transcriptomic differences between pediatric IBD (VEO and older onset) and non-IBD epithelium using 3-dimensional, biopsy-derived organoids.

Methods: We measured growth efficiency relative to histopathological and clinical parameters in patient enteroid (ileum) and colonoid (colon) lines. We performed RNA-sequencing on patient colonoids and subsequent flow cytometry after multiple passages to evaluate changes that persisted in culture.

Results: Enteroids and colonoids from pediatric patients with IBD exhibited decreased growth associated with histological inflammation compared with non-IBD controls. We observed increased LYZ expression in colonoids from pediatric IBD patients, which has been reported previously in adult patients with IBD. We also observed upregulation of antigen presentation genes HLA-DRB1 and HLA-DRA, which persisted after prolonged passaging in patients with pediatric IBD.

Conclusions: We present the first functional evaluation of enteroids and colonoids from patients with VEO-IBD and older onset pediatric IBD, a subset of which exhibits poor growth. Enhanced, persistent epithelial antigen presentation gene expression in patient colonoids supports the notion that epithelial cell-intrinsic differences may contribute to IBD pathogenesis.

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