A living organoid biobank of patients with Crohn’s disease reveals molecular subtypes for personalized therapeutics
Crohn's disease (CD) is a complex and heterogeneous condition with no perfect preclinical model or cure. To address this, we explore adult stem cell-derived organoids that retain their tissue identity and disease-driving traits. We prospectively create a biobank of CD patient-derived organoid cultures (PDOs) from colonic biopsies of 53 subjects across all clinical subtypes and healthy subjects. Gene expression analyses enabled benchmarking of PDOs as tools for modeling the colonic epithelium in active disease and identified two major molecular subtypes: immune-deficient infectious CD (IDICD) and stress and senescence-induced fibrostenotic CD (S2FCD). Each subtype shows internal consistency in the transcriptome, genome, and phenome. The spectrum of morphometric, phenotypic, and functional changes within the "living biobank" reveals distinct differences between the molecular subtypes. Drug screens reverse subtype-specific phenotypes, suggesting phenotyped-genotyped CD PDOs can bridge basic biology and patient trials by enabling preclinical phase "0" human trials for personalized therapeutics.
Authors
- Courtney Tindle (ORCID: https://orcid.org/0000-0002-8356-9707)
- Pradipta Ghosh (ORCID: https://orcid.org/0000-0002-8917-3201)
- Ibrahim M. Sayed (ORCID: https://orcid.org/0000-0001-8207-6401)
- Brigid S. Boland (ORCID: https://orcid.org/0000-0002-5360-8816)
- Priti Maity
- Sahar Taheri (ORCID: https://orcid.org/0000-0001-6716-7356)
- William J. Sandborn (ORCID: https://orcid.org/0000-0002-3314-7960)
- Mackenzie Fuller (ORCID: https://orcid.org/0000-0001-6781-8710)
- Jasper Lee
- Gajanan D. Katkar (ORCID: https://orcid.org/0000-0002-9982-8582)
- Jason Ear (ORCID: https://orcid.org/0000-0002-8580-7748)
- Soumita Das (ORCID: https://orcid.org/0000-0003-3895-3643)
- Helen Le
- Dominik L. Stec
- Ayden G. Fonseca (ORCID: https://orcid.org/0000-0003-0174-897X)
- Kevin I. Perry (ORCID: https://orcid.org/0000-0003-1457-442X)
- Mahitha Shree Anandachar (ORCID: https://orcid.org/0000-0002-5362-3055)
- Rama F. Pranadinata
- Debashis Sahoo (ORCID: https://orcid.org/0000-0003-2329-8228)
- Eleadah Vidales
- Stella-Rita Ibeawuchi
Institutions
- UC San Diego Health System (US)
- University of California San Diego (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-09-26
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101748
- Citations
- 19
- Primary Topic
- Inflammatory Bowel Disease
- Type
- article
- Field-Weighted Citation Impact
- 10.46
Funders
- American Association of Immunologists
- Leona M. and Harry B. Helmsley Charitable Trust
- National Institutes of Health
- University of California, San Diego
- National Cancer Institute