Tindle Courtney, Katkar Gajanan D, Fonseca Ayden G, Taheri Sahar, Lee Jasper, Maity Priti, Sayed Ibrahim M, Ibeawuchi Stella-Rita, Vidales Eleadah, Pranadinata Rama F, Fuller Mackenzie, Stec Dominik L, Anandachar Mahitha Shree, Perry Kevin, Le Helen N, Ear Jason, Boland Brigid S, Sandborn William J, Sahoo Debashis, Das Soumita, Ghosh Pradipta
bioRxiv. 2023 Mar 13:2023.03.11.532245. doi: 10.1101/2023.03.11.532245.
Crohn's disease (CD) is a complex, clinically heterogeneous disease of multifactorial origin; there is no perfect pre-clinical model, little insight into the basis for such heterogeneity, and still no cure. To address these unmet needs, we sought to explore the translational potential of adult stem cell-derived organoids that not only retain their tissue identity, but also their genetic and epigenetic disease-driving traits. We prospectively created a biobank of CD patient-derived organoid cultures (PDOs) using biopsied tissues from colons of 34 consecutive subjects representing all clinical subtypes (Montreal Classification B1-B3 and perianal disease). PDOs were generated also from healthy subjects. Comparative gene expression analyses enabled benchmarking of PDOs as tools for modeling the colonic epithelium in active disease and revealed that despite the clinical heterogeneity there are two major molecular subtypes: immune-deficient infectious-CD [IDICD] and stress and senescence-induced fibrostenotic-CD [S2FCD]. The transcriptome, genome and phenome show a surprising degree of internal consistency within each molecular subtype. The spectrum of morphometric, phenotypic, and functional changes within the "living biobank" reveals distinct differences between the molecular subtypes. These insights enabled drug screens that reversed subtype-specific phenotypes, e.g., impaired microbial clearance in IDICD was reversed using agonists for nuclear receptors, and senescence in S2FCD was rectified using senotherapeutics, but not . Phenotyped-genotyped CD-PDOs may fill the gap between basic biology and patient trials by enabling pre-clinical Phase '0' human trials for personalized therapeutics.
This work creates a prospectively biobanked phenotyped-genotyped Crohn's disease patient-derived organoids (CD-PDOs) as platforms for molecular subtyping of disease and for ushering personalized therapeutics.
Prospectively biobanked CD-organoids recapitulate the disease epithelium in patientsThe phenome-transcriptome-genome of CD-organoids converge on two molecular subtypesOne subtype shows impaired microbial clearance, another increased cellular senescencePhenotyped-genotyped PDOs are then used for integrative and personalized therapeutics.
克罗恩病（CD）是一种起源多因素的复杂临床异质性疾病；目前尚无完美的临床前模型，对这种异质性的基础了解甚少，且仍无法治愈。为满足这些未被满足的需求，我们试图探索源自成体干细胞的类器官的转化潜力，这些类器官不仅保留其组织特性，还保留其遗传和表观遗传疾病驱动特征。我们前瞻性地利用来自34例连续受试者结肠活检组织创建了一个克罗恩病患者来源类器官培养物（PDO）生物样本库，这些受试者代表了所有临床亚型（蒙特利尔分类B1 - B3和肛周疾病）。也从健康受试者中生成了PDO。比较基因表达分析能够将PDO作为在活动性疾病中模拟结肠上皮的工具进行基准测试，并揭示尽管存在临床异质性，但有两种主要分子亚型：免疫缺陷感染性克罗恩病[IDICD]和应激与衰老诱导的纤维狭窄性克罗恩病[S2FCD]。转录组、基因组和表型组在每个分子亚型内显示出惊人程度的内部一致性。“活体生物样本库”内形态计量、表型和功能变化的谱揭示了分子亚型之间的明显差异。这些见解使得能够进行药物筛选，逆转亚型特异性表型，例如，使用核受体激动剂逆转IDICD中受损的微生物清除，使用衰老治疗剂纠正S2FCD中的衰老，但并非……通过启用针对个性化治疗的临床前“0期”人体试验，表型分型 - 基因分型的CD - PDO可能填补基础生物学与患者试验之间的差距。
这项工作创建了一个前瞻性生物样本库，其中包含表型分型 - 基因分型的克罗恩病患者来源类器官（CD - PDO），作为疾病分子亚型分类和引入个性化治疗的平台。
前瞻性生物样本库中的CD类器官概括了患者的疾病上皮细胞
CD类器官的表型组 - 转录组 - 基因组汇聚为两种分子亚型
一种亚型显示微生物清除受损，另一种显示细胞衰老增加
然后将表型分型 - 基因分型的PDO用于综合和个性化治疗。
