Periodic Reporting for period 1 - GUTMAPS (Cellular cartography of the intestine in health and inflammation)
Reporting period: 2021-05-01 to 2023-04-30
Ulcerative colitis (UC) and Crohn’s disease (CD) are the two major forms of inflammatory bowel disease (IBD). They affect an estimated 4 million people in the United States and Europe and have a rising incidence in the developing world. Both conditions are incurable, often diagnosed at a young age and are associated with significant morbidity and socio-economic costs. Considerable progress in understanding the pathogenesis of IBD has been achieved within the last decade, with notable advances in the contribution of genetic susceptibility, epithelial barrier dysfunction, microbial flora and environmental factors. Currently, around 40% of patients fail to respond to or lose response to currently available immunotherapies. To make progress in developing novel drugs and therapies to treat IBD, it is crucial to first understand the composition and architecture of the intestine in greater detail. Considerable progress has been made in understanding the composition of this organ with the advent of recent single cell RNA sequencing (scRNA-seq) technologies. Although scRNA-seq is a very powerful technique, important spatial information is lost as soon as tissues are dissociated. So even if we now know more about the composition of the intestine, we still lack considerable information about its architecture, especially the localisation of various cell types and niches within it.
A recent study from the lamina propria of CD patients using scRNA-seq and multiplexed imaging, identified a unique cellular signature (comprising of immune and stromal cells) associated with resistance to anti-TNF therapy. Patients presenting with this signature/module showed a unique cellular organisation in their inflamed tissues as compared to patients who did not present this module. Such data confirm that understanding the cellular architecture of any organ is as important as understanding its composition. This knowledge is currently lacking and thus the objective of this this MSC action, “ Cellular Cartography of the intestine in health and inflammation” was to map the architecture of the intestine in health and inflammation.
Work was conducted via 5 work packages (WPs). Work packages 1 and 2 comprised research tasks where the fellow along with the students he supervised generated single cell multi-omic tissue maps from colonic biopsies of actively inflamed tissue from Ulcerative Colitis patients and compared them to non-involved tissue from UC patients and also Healthy controls. In WP2, many of the observations from WP1 were validated using techniques such as multi-colour immunohistochemistry, imaging mass cytometry, and carrying out in-vitro assays using patient derived colonic organoids.
WP3 comprised of tasks that are associated with training for all of the techniques that are utilised in WP1 & 2. In WP3, the fellow also sought to hone his skills on academic leadership, grant writing and presentations skills. He also regularly supervised two Ph.D. students and one masters student.
WP4 comprised of tasks associated with communication and outreach. The fellow’s work was presented as a poster at the European Crohn’s and Colitis Organisation conference in 2021 and a talk at the MRC Human Immunology Unit research day 2021 in Oxford, UK. He gave an invited talk at the International Symposium on Biomedicine and Biomaterials (ISBB 2022) organised by the Biomedical Research Center, Northwest Minzu University, China. He also gave two annual research seminars at the Gastroenterology Department of the host institute. Outreach was done to University Masters in Nanobiology students at TU Delft where the fellow presented his work as an invited speaker for their course on single cell RNA sequencing. He also took part in a live webinar organized by Abbvie, and presented a talk titled, “Etiology of post-operative recurrence in Crohn’s Disease” held on 31st May 2023. Lastly, he also invited a high school student to spend 20 weeks in the lab. Results of the MSCA will be reported in two publications, one of which, related to UC is already under review at an open access journal, while the second manuscript (related to CD) is under preparation.
In WP5, the fellow’s progress was tracked via regular meetings with his host supervisor with weekly meetings and quarterly progress evaluations. Furthermore, he also had 5 meetings which were specifically focussed on the fellow’s career development. During this project, the fellow has developed new collaborations and successfully co-applied to various grants, such as the ECCO Pioneer grant (300K) and the NWO-KWO grant (750k) to carry out similar work in IBD and cancer.
WP3 comprised of tasks that are associated with training for all of the techniques that are utilised in WP1 & 2. In WP3, the fellow also sought to hone his skills on academic leadership, grant writing and presentations skills. He also regularly supervised two Ph.D. students and one masters student.
WP4 comprised of tasks associated with communication and outreach. The fellow’s work was presented as a poster at the European Crohn’s and Colitis Organisation conference in 2021 and a talk at the MRC Human Immunology Unit research day 2021 in Oxford, UK. He gave an invited talk at the International Symposium on Biomedicine and Biomaterials (ISBB 2022) organised by the Biomedical Research Center, Northwest Minzu University, China. He also gave two annual research seminars at the Gastroenterology Department of the host institute. Outreach was done to University Masters in Nanobiology students at TU Delft where the fellow presented his work as an invited speaker for their course on single cell RNA sequencing. He also took part in a live webinar organized by Abbvie, and presented a talk titled, “Etiology of post-operative recurrence in Crohn’s Disease” held on 31st May 2023. Lastly, he also invited a high school student to spend 20 weeks in the lab. Results of the MSCA will be reported in two publications, one of which, related to UC is already under review at an open access journal, while the second manuscript (related to CD) is under preparation.
In WP5, the fellow’s progress was tracked via regular meetings with his host supervisor with weekly meetings and quarterly progress evaluations. Furthermore, he also had 5 meetings which were specifically focussed on the fellow’s career development. During this project, the fellow has developed new collaborations and successfully co-applied to various grants, such as the ECCO Pioneer grant (300K) and the NWO-KWO grant (750k) to carry out similar work in IBD and cancer.
The MSCA has contributed greatly towards the overall scientific endeavour of the research community to map every cell in our body. This project has contributed to this goal by developing tissue maps of diseased intestines. The results from our integrative analysis of multi-modal single cell profiling and spatial transcriptomics in IBD patients have identified key transcriptomic perturbations that delineate these conditions and how these converge into discrete micro-domains within the intestinal tissue architecture.
Such maps are urgently required to understand how tissues change during disease and which interactions are crucial for maintaining tissue homeostasis. Furthermore, such maps can be useful for biomarker identification and identifying novel drug targets. Finally, I expect this project to act as as template for larger studies where generation of such multi-modal data becomes an important tool in developing personalised medicine.
Such maps are urgently required to understand how tissues change during disease and which interactions are crucial for maintaining tissue homeostasis. Furthermore, such maps can be useful for biomarker identification and identifying novel drug targets. Finally, I expect this project to act as as template for larger studies where generation of such multi-modal data becomes an important tool in developing personalised medicine.