Integration of multimodal imaging for insight into the BTBR obob model of diabetic nephropathy
- Abstract number
- 254
- Presentation Form
- Submitted Talk
- Corresponding Email
- [email protected]
- Session
- Stream 5: Imaging in Development and Disease
- Authors
- Dr Stephanie Ling (1), Dr Alan Race (2), Dr Daniel Sutton (1), Mr Harris Vince (1), Ms Sophie Peacock (1), Dr Magnus Soderberg (1), Dr Anna Björnson Granqvist (1), Dr Pernilla Tonelius (1), Dr Julie Williams (1), Dr Arthur Lewis (1), Dr Stewart Jones (1)
- Affiliations
-
1. AstraZeneca
2. University of Marburg
- Keywords
Multimodal, Integration, Mass Spectrometry Imaging, Imaging Mass Cytometry, Diabetes, Chronic Kidney Disease, Histology, Immunometabolism
- Abstract text
Summary
We demonstrate the power of leveraging the strengths of multiple imaging modalities from standard histological analysis, multiplexed biomarker analysis and small molecule mass spectrometry imaging to understand the interplay between metabolism and the immune response in diabetic nephropathy. Effective integration across multiple approaches enables systems-level understanding of tissue for metabolically driven disease characterisation and translation.
Introduction
All tissues, both normal and diseased, are made up of several different cell types, all of which are in constant flux of signalling and metabolism both within each cell and in interactions between multiple populations. The function of immune cells are in turn closely modulated by their metabolic environment, and the metabolism of many immune cells is altered upon their activation. Improved understanding of the interplay that exists between the host immune response and key metabolic tissues, such as the kidney, will provide critical insights into the mechanisms that govern ‘metabolic-immune’ crosstalk.
Methods
In order to understand these complex interactions and the cellular and molecular level, several distinct techniques must be used in concert, each specialised for their ability to detect aspects of these biological processes, with the amalgamation of the diverse datasets generated being critical to drive novel insight into the underlying biology.
Hyperplex detection of proteins, their post-translational modifications in techniques such as Imaging Mass Cytometry of >35 biomarkers are revolutionizing our understanding of the complex ‘multisurface’ microenvironment, particularly in the deconvolution of the immune landscape. Combining these with histology and Mass Spectrometry Imaging (MSI) – based spatially resolved metabolomics analysis can provide unmatched information about how regional tissue metabolic profiles in disease and enable detection of greater heterogeneity than previously possible by traditional pathology methods.
Each one of these technologies provides us with a piece of the puzzle, and the development of novel data integration strategies have been crucial to convert this wealth of disparate information into new insight. By combining several of these modalities together that we can have a holistic systems level view of what is happening in tissues.
Results and Discussion
We demonstrate that the combination of targeted analysis strategies such as pathologist annotation-trained AI-driven segmentation of the kidney with untargeted analyses, including for detection of discriminative or colocalised cell types, phenotypes and tissue metabolic profiles, can be used for statistical identification of de novo endogenous metabolite biomarkers & cellular phenotypes for mechanistic understanding of diabetic nephropathy.
The ability to link local metabolic changes with differences in immune infiltration, activation and polarisation provides insight into the mechanism of immunometabolic targeting. In particular, in metabolic diseases such as diabetic nephropathy, we demonstrate the value in integrating these data types for disease and model characterisation. Use of this integrative approach allows us to investigate how initial metabolic deregulation feeds the inflammatory response, pathological fibrosis and leads to eventual tissue damage.
Conclusion
One of the key areas that the use of these novel approaches are driving advances is in immunometabolism. By integrating these innovative, information-rich techniques, linking histological signatures, gene expression profiles, cell signalling and metabolic states, we aim to generate insight into the critical mechanism and relative contribution and interplay between the metabolic microenvironment and immune response in early metabolic dysregulation and inflammation.