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FRIMED2-FRIPRO forskerprosjekt, medisin og helse

Dissecting differentiation and diversification of gut macrophages

Alternative title: Hvilke mekanismer er ansvarlig for differensiering og mangfold av makrofager i tarmen

Awarded: NOK 12.0 mill.

Macrophages reside in virtually all organs and play a key role in host defense and tissue homeostasis. Tissue macrophages have a unique capacity to phagocytose (eat) and eliminate pathogens and toxic substances and are particularly important in the gut which is constantly bombarded by harmful bacteria, viruses and toxic material. However, gut macrophages also contribute to pathology in diseases of the gut such as inflammatory bowel disease. Studies have shown that macrophages infiltrating cancer tissue promote cancer growth. Blood monocytes (a type of white blood cells) constantly migrate into tissues and differentiate into macrophages. Little is known about this differentiation process. To understand this process we are using new advanced technologies to analyze every single cell isolated from the tissue independently. We find that gut macrophages are much more heterogeneous that previously anticipated. Moreover, macrophages in the mucosa are very different from macrophages in the muscle layer. This strongly suggests that monocyte-macrophage differentiation depends on signals they receive from other cells in the local microenvironment. The aim of this project is firstly to identify the nature of these signals, and secondly whether it is possible to interfere with this signaling process to "reprogram" macrophages. The latter could be an attractive approach to treat inflammatory diseases and cancer. Here we will perform advanced single-cell technologies and imaging techniques to reconstruct how gut macrophages differentiate and diversify in the tissue. Based on these experiments our aim is to identify the signals that are important for macrophage differentiation. Next we will establish 3-dimentional organ cultures of gut tissue to test whether we can block/manipulate these signals to "reprogam" macrophages. If successful, this experimental approach may pave the way for new therapeutic drugs.

Macrophages reside in virtually all organs and play a key role in host defense and tissue homeostasis. Tissue macrophages are particularly important in the gut where they defend the body against a wide variety of pathogens and toxic substances. However, gut macrophages also contribute to pathology such as inflammatory bowel disease. Moreover, paradoxically, studies have shown that tumor-associated macrophages in colorectal cancer promote cancer growth. Although gut macrophages are instrumental in both host defense and pathology, knowledge about their origin, heterogeneity and functional properties is scarce. We have recently analyzed macrophages derived from the mucosa and the muscle layer of the gut by single cell RNA sequencing, as well as by phenotypic and functional profiling. We found that macrophages in both compartments consist of many populations, which are transcriptionally and functionally distinct. Moreover, mucosal and muscularis macrophages are very different, indicating that microenvironmental signals imprint macrophages identity. Here our aim is to identify which environmental factors that imprint macrophage identity and whether it is possible to reprogram macrophages in vivo. We will apply an integrated approach combining high throughput single-cell technologies with a unique clinical material and 3D organ cultures. Computational integration of the data will provide spatiotemporal reconstruction of how macrophage differentiation and diversification in the human gut is regulated and reveal functional properties. This project will provide the necessary information to identity molecular targets to reprogram tissue macrophages in various pathologies (inflammation and cancer) and test the applicability of such targets in 3D colonic organoids.

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FRIMED2-FRIPRO forskerprosjekt, medisin og helse