A living organoid biobank of patients with Crohn's disease reveals molecular subtypes for personalized therapeutics

Courtney Tindle; Ayden G Fonseca; Sahar Taheri; Gajanan D Katkar; Jasper Lee; Priti Maity; Ibrahim M Sayed; Stella-Rita Ibeawuchi; Eleadah Vidales; Rama F Pranadinata; Mackenzie Fuller; Dominik L Stec; Mahitha Shree Anandachar; Kevin Perry; Helen N Le; Jason Ear; Brigid S Boland; William J Sandborn; Debashis Sahoo; Soumita Das; Pradipta Ghosh

doi:10.1016/j.xcrm.2024.101748

A living organoid biobank of patients with Crohn's disease reveals molecular subtypes for personalized therapeutics

Cell Rep Med. 2024 Oct 15;5(10):101748. doi: 10.1016/j.xcrm.2024.101748. Epub 2024 Sep 26.

Authors

Courtney Tindle¹, Ayden G Fonseca¹, Sahar Taheri², Gajanan D Katkar³, Jasper Lee⁴, Priti Maity¹, Ibrahim M Sayed⁴, Stella-Rita Ibeawuchi⁴, Eleadah Vidales¹, Rama F Pranadinata¹, Mackenzie Fuller¹, Dominik L Stec¹, Mahitha Shree Anandachar⁴, Kevin Perry¹, Helen N Le⁵, Jason Ear³, Brigid S Boland⁶, William J Sandborn⁷, Debashis Sahoo⁸, Soumita Das⁹, Pradipta Ghosh¹⁰

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; HUMANOID™ Center of Research Excellence (CoRE), University of California, San Diego, La Jolla, CA 92093, USA.
² Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
³ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: bboland@health.ucsd.edu.
⁷ Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: wsandborn@health.ucsd.edu.
⁸ Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: dsahoo@ucsd.edu.
⁹ HUMANOID™ Center of Research Excellence (CoRE), University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: soumita_das@uml.edu.
¹⁰ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; HUMANOID™ Center of Research Excellence (CoRE), University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: prghosh@ucsd.edu.

Abstract

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.

Keywords: barrier integrity; host-microbe interaction; inflammatory bowel disease; patient-derived organoids; therapeutics.

MeSH terms

Adult
Adult Stem Cells / metabolism
Biological Specimen Banks*
Colon / metabolism
Colon / pathology
Crohn Disease* / genetics
Crohn Disease* / pathology
Female
Humans
Male
Middle Aged
Organoids* / metabolism
Organoids* / pathology
Phenotype
Precision Medicine* / methods
Transcriptome / genetics