Dr Matthias Zilbauer
Intestinal stem cell biology
Department of Paediatrics & Cambridge Stem Cell Institute
Email: mz304@cam.ac.uk
Research
The Zilbauer group's main research interest lies in the field of human intestinal epithelial stem cell biology during development, health and related diseases such as Inflammatory Bowel Diseases (IBD) and Necrotising Enterocolitis (NEC). A particular focus lies on the role of role of epigenetic mechanisms (i.e. DNA methylation) in regulating gene expression and cellular function of the human intestinal epithelium and the implication of epigenetic (re)programming on development and disease pathogenesis.
As one of the main experimental models, they use human mucosa derived intestinal epithelial organoids. Over the past 5 years, they have generated a large living biobank of organoids derived from a wide range of patients, including healthy controls, as well as children diagnosed with Inflammatory Bowel Diseases and other related conditions. Organoids were generated from different gut segments, patients form different age groups as well as human fetal gut. All organoid lines are accompanied by detailed clinical phenotype information of the donor and many have been subjected to multi-omic molecular profiling and genotyping. The biobank provides a unique resource for our own research as well as a range of collaborative projects.
In addition to organoids derived from intestinal mucosal samples, induced pluripotent stem cells (iPSCs) can be differentiated into intestinal epithelium, which is the subject of an ongoing collaboration with the Vallier group.
More recently, the group has been subjecting both primary human gut biopsy samples as well as patient derived organoids to single cell RNA sequencing and spatial transcriptomics (Figure 2, Elmentaite and Ross et al, Developmental Cell 2020). Computational analyses of data allow us to not only interrogate in-vivo cell transcription but also further validate human gut organoids by comparing cell identities on a single cell level.
Figure 1: Human Intestinal Epithelial Organoids (IEOs) derived from A) Small bowel biopsy and stained for Nuclei (blue), epithelial cell marker EpCAM (green) and actin (red), B) from the Terminal Ileum (TI) and Sigmoid Colon (SC) of children newly diagnosed with Crohn’s Disease (CD) and healthy controls (Ctrl).
Figure 2: Single-Cell Sequencing of Developing Human Gut Reveals Transcriptional Links to Childhood Crohn’s Disease, Elmentaite and Ross et al, Developmental Cell 2021.
Key publications
- Elmentaite, R. et al. Single-Cell Sequencing of Developing Human Gut Reveals Transcriptional Links to Childhood Crohn's Disease. Dev Cell 55, 771-783 e775, doi:10.1016/j.devcel.2020.11.010 (2020). PMCID: PMC7762816
- Kraiczy, J. et al. DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development. Gut 68, 49-61, doi:10.1136/gutjnl-2017-314817 (2019). PMCID: PMC6839835
- Howell, K. J. et al. DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome. Gastroenterology 154, 585-598, doi:10.1053/j.gastro.2017.10.007 (2018). PMCID: PMC6381389
- Rimland, C. A. et al. Regional Differences in Human Biliary Tissues and Corresponding In Vitro-Derived Organoids. Hepatology 73, 247-267, doi:10.1002/hep.31252 (2021).
- Kraiczy, J. et al. Genome-Wide Epigenetic and Transcriptomic Characterization of Human-Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids. Cell Mol Gastroenterol Hepatol 7, 285-288, doi:10.1016/j.jcmgh.2018.10.008 (2019). PMCID: PMC6354438
