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Super-resolution optical microscopy of nanosized pore dynamics in endothelial cells

Periodic Reporting for period 2 - DeLIVER (Super-resolution optical microscopy of nanosized pore dynamics in endothelial cells)

Reporting period: 2020-01-01 to 2022-06-30

DeLIVER is an Innovative Training Network (ITN) funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 766181. The main purpose of DeLIVER is the training of 14 early stage researchers in state of the art biomedical research and imaging methods to further our understanding of the structure and function of cells critical to liver function and healthy ageing. This network comprises a collaborative activity of 6 universities and 3 small and medium sized enterprises across Europe with additional partners from across the world.

The liver contains a large number of very fine capillaries (the sinusoids), which are lined by endothelial cells. In the liver, these endothelial cells are called liver sinousoidal endothelial cells (LSEC) and the contain thousands of nanosized pores that enable the clearance of molecules and small particles from the blood. The size of these nanopores is well below the optical diffraction limit and consequently, very little is known about the extremely important physiological function of these unique structures and their role in the transfer and/or clearance of metabolites and pharmaceuticals to vital organs. LSEC are also responsible for the removal and degradation of pharmaceuticals, virus and waste macromolecules, making them a highly relevant type of cell for the study of pharmacological drug uptake. Because of the issues mentioned above, however, most pharmaceutical companies currently cannot assess the effect of drugs on these cells. Novel optical microscopy tools have become available in last few years that now enable for the first time the microscopic study of living cells on the nanoscale and their function.

The key research objectives of DeLIVER are:
- To develop novel high-speed super-resolution optical technologies that transcend the 200nm optical diffraction barrier
- To develop open-access tools for super-resolution optical image reconstruction and blue-prints for high-speed, real-time image reconstruction.
- To extend optical nanoscopy methods to 3D cell culture and in situ tissue studies.
- To obtain mechanistic descriptions of small molecule/pharmaceutical interactions with living LSEC, with liver tissue, and the effect of ageing on this process.
The project consortium has successfully recruited all 14 early stage researchers and has begun to work on the objectives of the project.
A novel, compact concept for high-speed structured illumination microscopy was developed and a prototype constructed.
The effects of several drugs on the number and size of liver sinusoidal endothelial cell fenestrations were established and have been characterized carefully. These include
compounds, such as coffee, as well as anti-aging drug. Several scientific publications have already resulted from this work and 3 patent applications have been filed so far.
DeLIVER will, for the first time, enable the direct visualization of the interaction and effect of nanoparticles (virus, drug formulations, lipids) with living liver sinusoidal endothelial cells.

The DeLIVER project will enable us to identify novel drugs and their effect on the aging liver.

As part of this work, the DeLIVER consortium will have developed novel open access tools for image reconstruction of super-resolved optical microscopy data. It will have also developed novel approaches that enable the
cost-effective distribution of novel super-resolution optical microscopy methods to researchers in the life sciences around the world.

This will allow the consortium to provide a first mechanistic description of how small molecules, pharmaceuticals, toxins, blood flow/pressure/temperature interact with living LSEC.
We also expect to have demonstrated the full 3D imaging of LSECs in their natural environment, i.e. intact liver sinusoids.
Liver sinusoidal endothelial cells line the fine capillaries that cross the liver.