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 Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Rep Med. 2024 Oct 15;5(10):101748. doi: 10.1016/j.xcrm.2024.101748. Epub 2024 Sep 26.
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.
克罗恩病（CD）是一种复杂且异质的疾病，目前尚无完美的临床前模型或治愈方法。为了解决这一问题，我们探索了源自成人干细胞的类器官，这些类器官保留了其组织特征和疾病驱动特征。我们前瞻性地从 53 名不同临床亚型的 CD 患者和健康受试者的结肠活检中创建了一个 CD 患者衍生的类器官培养物（PDO）生物库。基因表达分析使 PDO 成为在活动性疾病中模拟结肠上皮的工具，并确定了两种主要的分子亚型：免疫缺陷性感染性 CD（IDICD）和应激与衰老诱导的纤维狭窄性 CD（S2FCD）。每个亚型在转录组、基因组和表型上都具有内在一致性。“活体生物库”内形态计量、表型和功能变化的范围揭示了分子亚型之间的明显差异。药物筛选可逆转特定亚型的表型，这表明表型-基因型 CD PDO 可以通过为个性化治疗提供临床前阶段“0”期人体试验，在基础生物学和患者试验之间架起桥梁。
