Organoids, Volume 4, Issue 4 (December 2025) – 4 articles

Obesity is an epidemic with myriad health effects, but little is understood regarding individual obese phenotypes and how they may respond to therapy. Epigenetic changes associated with obesity have been detected in blood, liver, pancreas, and adipose tissues. Previous work using human organoids found that dietary glucose hyperabsorption is a steadfast trait in cultures derived from some obese subjects, but detailed transcriptional or epigenomic features of the intestinal epithelia associated with this persistent phenotype are unknown. This study evaluated differentially expressed genes and relative chromatin accessibility in intestinal organoids established from donors classified as non-obese, obese, or obese hyperabsorptive by body mass index and glucose transport assays. Transcriptomic analysis indicated that obese hyperabsorptive subject organoids have significantly upregulated dietary nutrient absorption transcripts and downregulated type I interferon targets. Chromatin accessibility and transcription factor footprinting predicted that enhanced HNF4G binding may promote the obese hyperabsorption phenotype. Quantitative RT-PCR assessment in organoids representing a larger subject cohort suggested that intestinal epithelial expression of CUBN, GIP, SLC5A11, and SLC2A5 were highly correlated with hyperabsorption. Thus, the obese hyperabsorption phenotype was characterized by transcriptional changes that support increased nutrient uptake by intestinal epithelia, potentially driven by differentially accessible chromatin. Recognizing unique intestinal phenotypes in obesity provides a new perspective in considering therapeutic targets and options with which to manage the disease. Full article

First-trimester placental development comprises many critical yet understudied cellular events that determine pregnancy outcomes. Improper placentation leads to a host of health issues that not only impact the fetal period but also influence later-life offspring health. Thus, an experimental paradigm for studying early placental development is necessary and has spurred the development of new in vitro models. Organoid model systems are three-dimensional structures comprising multiple differentiated cell types that originate from a progenitor population. Trophoblasts are the progenitor cells that serve as the proliferative base for the differentiation and maintenance of the placenta. Due to research constraints, experimental studies on the causal mechanisms underlying pathological pregnancies cannot readily be performed in human subjects. The nonhuman primate (NHP) offers a solution to this problem as it circumvents the limitations of human pregnancy sampling. Importantly, NHPs share many developmental features of human pregnancy, including placenta type and a similar fetal growth trajectory, making longitudinal pregnancy studies feasible and relevant. Since perturbations made in vivo can be validated in vitro, an NHP model of early pregnancy would facilitate mechanistic studies of pregnancy disorders. Herein, we describe the methodology for the establishment of a first-trimester NHP placenta trophoblast organoid model system. Full article

Organoid technology has emerged as a revolutionary tool in cancer research, offering physiologically accurate, three-dimensional models that preserve the histoarchitecture, genetic stability, and phenotypic complexity of primary tumors. These self-organizing structures, derived from adult stem cells, induced pluripotent stem cells, or patient tumor biopsies, recapitulate critical aspects of tumor heterogeneity, clonal evolution, and microenvironmental interactions. Organoids serve as powerful systems for modeling tumor progression, assessing drug sensitivity and resistance, and guiding precision oncology strategies. Recent innovations have extended organoid capabilities beyond static culture systems. Integration with microfluidic organoid-on-chip platforms, high-throughput CRISPR-based functional genomics, and AI-driven phenotypic analytics has enhanced mechanistic insight and translational relevance. Co-culture systems incorporating immune, stromal, and endothelial components now permit dynamic modeling of tumor–host interactions, immunotherapeutic responses, and metastatic behavior. Comparative analyses with conventional platforms, 2D monolayers, spheroids, and patient-derived xenografts emphasize the superior fidelity and clinical potential of organoids. Despite these advances, several challenges remain, such as protocol variability, incomplete recapitulation of systemic physiology, and limitations in scalability, standardization, and regulatory alignment. Addressing these gaps with unified workflows, synthetic matrices, vascularized and innervated co-cultures, and GMP-compliant manufacturing will be crucial for clinical integration. Proactive engagement with regulatory frameworks and ethical guidelines will be pivotal to ensuring safe, responsible, and equitable clinical translation. With the convergence of bioengineering, multi-omics, and computational modeling, organoids are poised to become indispensable tools in next-generation oncology, driving mechanistic discovery, predictive diagnostics, and personalized therapy optimization. Full article

In many cancers, tumorigenesis is determined in part by the cell type in the tissue that transforms, which has been called the cell of origin. In intestinal cancer, previous observations suggested that transformation can occur from both stem cells and more differentiated cells; in the latter case, this is provided that NF-kB is activated and apoptosis is blocked. However, whether these distinct transformation trajectories yield similar types of cancer remains unresolved. In this study the effect of APC loss within different cellular backgrounds was analyzed. Transformation of either stem-like cells or secretory-like cells, as defined by CD24 or c-KIT expression, by deleting the APC function in organoids in vitro, led to WNT-independent growth of organoids in both cellular populations. Importantly, transformed cultures derived from secretory-like cells had significantly distinct gene expression profiles as compared to the more stem cell-derived (CD44^high cells) APC mutant cultures and in fact preserved a level of gene expression that relates back to their original cell lineage. Our data highlights the influence of different cellular backgrounds on the initiation of intestinal cancer and suggests that the cell of origin could be a defining factor in colorectal cancer heterogeneity. Full article