Volker Martin Lauschke

Primary human hepatocytes rapidly lose their functionality in conventional 2D cultures, which significantly limits their usefulness as an in vitro model to study hepatotoxicity, particularly of biological and nanoparticle therapeutics, which commonly accumulate and exert their effects over prolonged periods of time. Thus, in the absence of relevant in vitro systems, animal models constitute a cornerstone to predict the toxicity of newly developed biologics. The liver is however an organ with pronounced species differences with regards to expression and catalytic activities of factors involved in drug absorption, distribution, metabolism and excretion. This is further amplified for nucleotide- and antibody-based therapeutics where sequence and epitope differences between species are common problems during preclinical development.We have previously developed a 3D human liver model that accurately predicts the hepatotoxicity of small molecules, which is by now widely used in industry. Here, we aim to extend this work and develop and benchmark a platform that can predict hepatotoxicity and liver biodistribution of biologics (antisense oligonucleotides, siRNAs, therapeutic antibodies) and different nanoparticles (lipid-based, polymeric and inorganic). This system aspires to improve the predictability and translatability of findings as well as to mitigate the need for animal models, thus reducing the number of animals needed in pre-clinical discovery and development.

Non-alcoholic steatohepatitis (NASH) is a prevalent liver disease that affects up to 2-6% of the general population and 15-40% of obese persons. NASH is characterized by steatosis, chronic inflammation and hepatocyte injury and is prone to progress into liver cirrhosis and liver cancer. However, despite tremendous efforts, there are currently no approved treatments for NASH. NASH is closely linked to obesity, sarcopenia, dyslipidemia and insulin resistance and it has become clear that multiple extrahepatic tissues, including pancreas, skeletal muscle and adipose tissue produce signals that orchestrate hepatic metabolism, inflammation and fibrosis. However, the underlying mechanisms in humans remain poorly understood.Here, we will integrate patient-derived ex vivo tissue models of liver, pancreas, skeletal muscle and fat to comprehensively map human metabolic crosstalk. By analyzing the secretome from healthy and diseased individuals, we will identify novel endocrine signals that contribute to NASH etiology and progression. Moreover, we will use the established platform to screen chemogenomic libraries to identify compounds that activate “healthy” signals or inhibit “disease” cues. This project thus provides a conceptually novel perspective that considers NASH as a complex pathology caused by dysregulated tissue interactions and targets these disease mechanisms, which are neglected by current drug development programs, to finally develop effective treatments.

The availability of relevant in vitro models of tissue units would be highly valuable for our struggles to understand human biology and physiology to obtain better health solutions. In the native tissue, cells are organized by a supporting extracellular matrix (ECM) in various types of microenvironments. ECM proteins build up the frameworks of these different environments, e.g. interstitial fiber networks in connective tissue and basement membranes in biological barriers. It has lately become clear that cells in culture are largely affected by their microenvironment, and especially mechanotransduction and the availability of cell-cell and cell-matrix connections. We will herein use a functionalised recombinant spider silk protein to construct relevant ECM-mimics, both networks for parenchymal and support cells in tissue compartments, and membranes for their biological barriers. These we will use to survey the effect of different parameters of the environment for cells in culture. For investigations of biological processes, it is essential to include a combination of cellular compartments and biological barriers. We will use our obtained knowledge to construct physiologically relevant tissue units of 1) tumours in stroma with blood vessels, for investigations of the interplay between cancer cells and vasculature, as well as 2) tumours behind blood brain barrier (BBB), for investigation of treatment strategies of brain tumours.