Biology subjects

Huelsken, J.

Publications and source records attributed to Huelsken, J..

3 recordsLinked to original sources

bioRxiv2026

Deciphering spatial heterogeneity of patient-derived organoids of colorectal tumors for drug discovery

The spatial organization of tumors is critical for drug development, as spatial heterogeneity in cancer cells and the tumor microenvironment can present a significant barrier to effective therapies. Patient-derived tumor organoids (PDOs) offer promising platforms to study tumor biology and for drug development. Previous studies have demonstrated that PDOs can maintain the genomic/clonal heterogeneity of tumors, as well as expression heterogeneity. However, the spatial heterogeneity of PDOs and its correlation with the original tumors remains unclear. We propose an integrated pipeline combining spatial transcriptomics and phenotypic analyses of PDOs to capture and track spatial heterogeneity. This platform integrates multiplexed organoid cultures with imaging-based spatial transcriptomics and analysis at single organoid resolution. We validate the platform by comparing results with non-spatial single-cell transcriptomic data and spatial transcriptomic analysis of donor tumors. The combination of ex vivo PDOs and spatial transcriptomics could open novel avenues for developing drugs.

cancer biology↗

bioRxiv2025

Intestinal Stem and Progenitor Cells Exhibit Distinct Adaptive Responses to Inflammatory Stress in IBD

BackgroundIntestinal epithelial stem cells (SCs) and their transit-amplifying (TA) progeny are critical for mucosal repair and regeneration. However, their behaviour under chronic inflammatory conditions, such as those observed in Inflammatory Bowel Disease (IBD), remains incompletely understood. MethodsWe investigated the impact of chronic inflammation on intestinal stem/progenitor cells by integrating bulk RNA sequencing from the largest IBD biopsy cohort to date with single-cell transcriptomic analysis and experimental assays using patient-derived intestinal organoids. ResultsActive inflammation was associated with a reduction in canonical LGR5 intestinal stem cells and a concurrent expansion of OLFM4 populations, consistent with an inflammation-induced epithelial repair program. Notably, SC/TA cells from both inflamed and non-inflamed IBD tissues exhibited persistent transcriptional changes that were distinct from those in healthy controls. Single-cell analysis identified transcriptionally heterogeneous SC/TA subpopulations, including a previously uncharacterized inflammation-associated cluster enriched in immune signalling pathways. Pseudotime trajectory analysis demonstrated a shift in differentiation toward deep crypt secretory (Paneth-like) cell lineages under inflammatory conditions. ConclusionsChronic intestinal inflammation reshapes the epithelial stem and progenitor cell compartment, promoting altered differentiation and the emergence of immune-responsive epithelial states. These findings highlight the plasticity of the human intestinal epithelium in IBD and point to new avenues for therapeutic strategies aimed at maintaining epithelial integrity during chronic inflammation.

molecular biology↗

bioRxiv2020

Interruption in POSTN-ITGAV axis affects lympho-hematopoiesis in mouse spleen

Outside-in integrin signaling regulates cell fate decisions in a variety of cell types, including hematopoietic stem cells (HSCs). Our earlier published studies showed that interruption of Periostin (POSTN) and Integrin-v (ITGAV) interaction induces faster proliferation in HSCs with developmental stage dependent functional effects. Here, we examined the role of POSTN-ITGAV axis in lympho-hematopoietic activity in spleen that hosts rare population of HSCs, the functional regulation of which is not clearly known. Vav-iCre mediated deletion of Itgav in hematopoietic system led to higher proliferation rates, resulting in increased frequency of primitive HSCs in adult spleen. However, in vitro CFU-C assays demonstrated a poorer differentiation potential following Itgav deletion. This also led to a decrease in the white pulp area with a significant decline in the B-cell numbers. Systemic deletion of its ligand, POSTN, phenocopied the effects noted in Vav-Itgav-/- mice. Histological examination of Postn deficient spleen also showed increase in the spleen trabecular areas. Surprisingly, these were the myofibroblasts of the trabecular and capsular areas that expressed high levels of POSTN within the spleen tissue. In addition, vascular smooth muscle cells also expressed POSTN. Through CFU-S12 assays, we showed that hematopoietic support potential of stroma in Postn deficient splenic hematopoietic niche was defective. Overall, we demonstrate that POSTN-ITGAV interaction plays important role in spleen lympho-hematopoiesis.

immunology↗