Biology subjects

Modderman, R.

Publications and source records attributed to Modderman, R..

3 recordsLinked to original sources

bioRxiv2026

Autologous biopsy-derived co-culture platform for interrogation of intestinal epithelial-T cell crosstalk

Interactions between intraepithelial lymphocytes (IELs) and the intestinal epithelium are central to mucosal homeostasis and disease. However, mechanistic in vitro studies describing their crosstalk in humans are limited by scarceness of primary material and insufficient knowledge about co-culture requirements. Here, we establish an autologous human duodenal IEL-organoid co-culture system encompassing expandable and bankable IEL and organoid protocols, with co-culture conditions that allow viability of both cell types. This system enables successive interrogation of lympho-epithelial interactions starting from minimal biopsy material. Under baseline conditions, CD45CD8CD103TCR{beta} IELs retain tissue-residency and effector features and induce an epithelial interferon response and chemokine production, without overt epithelial apoptosis. IL-15 and IL-21, essential cytokines involved in IEL-activation in intestinal enteropathies like celiac disease, increases granzyme B expression and interferon-{gamma} secretion but do not trigger epithelial cell death. However, enforcing IEL-epithelial contact using an anti-CD3-anti-Ep-CAM bispecific antibody induces epithelial apoptosis accompanied by increased tumor necrosis factor (TNF) and FAS-ligand (FASLG) secretion. These findings validate the platforms ability to resolve non-destructive and cytotoxic lympho-epithelial interaction and provide a tractable system for studying intestinal inflammation and immune-mediated epithelial cell death.

immunology↗

bioRxiv2025

Butyrate blocks specific histone acetylation by preventing recruitment of p300 to acetylated histones

Butyrate, a short-chain fatty acid (SCFA) produced by microbial fermentation of dietary fiber, exerts beneficial metabolic and immunomodulatory functions through hyperactivation of the histone acetylase (HAT) p300 and inhibition of histone deacetylases (HDAC). These effects are widely believed to result in the acetylation of distinct histones that regulate specific genes, including at transcription starting sites (TSS) and enhancers. However, we show that this is not the case, as butyrate dose-dependently increases the acetylation of histones throughout the entire genome. Molecular dynamics simulations suggest that the RING-loop prevents the recruitment of p300 to acetylated histones through its bromodomain, and thereby cannot maintain the acetylation of specific histones through positive feedback. This was confirmed by showing that only catalytically inactive p300 stably binds to acetylated histones. Thus, the epigenetic regulation of specific genes by butyrate is limited, but butyrate instead increases histone acetylation globally resulting in opening of the entire chromatin structure.

molecular biology↗

bioRxiv2024

Intestine-on-chip enhances nutrient and drug metabolism and maturation of iPSC-derived intestinal epithelial cells relative to organoids and Transwells

The human intestinal epithelial barrier is shaped by various biological and biomechanical influences such as growth factor gradients and the flow of intestinal contents. Exposure to these cues in vitro impacts the cell type composition and function of adult stem cell (ASC)-derived intestinal epithelial cells, but their effect on human induced pluripotent stem cell (hiPSC)-derived cells is largely unexplored. Here, we characterize and compare the cellular composition and gene expression profiles of hiPSC-derived intestinal epithelial cells exposed to various medium compositions and cultured as organoids, in Transwell and in microfluidic intestine-on-chip systems. We demonstrate that inhibition and activation of the WNT, BMP, NOTCH and MAPK pathways regulates the presence of dividing, absorptive and secretory epithelial lineages within these systems, as has been described for ASC-based systems. Upon differentiation, intestinal epithelial organoids and monolayers in Transwell systems expressed genes involved in important intestinal functions, including digestive enzymes, nutrient transporters and members of the Cytochrome P450 family implicated in drug metabolism. However, the dynamic microenvironment of the intestine-on-chip system induced the strongest upregulation of these genes, with an expression profile that suggests a more mature developmental state. Overall, these results underscore the value of hiPSC-derived intestinal epithelial cells for modeling important functions of the human intestinal epithelial barrier and facilitates the selection of relevant culture conditions for specific applications.

cell biology↗