Lauschke-lab: Personalized Medicine and Drug Development
The research is focused on liver metabolism and function as well as the role of the liver in complex pathologies, such as type 2 diabetes mellitus.
|Magnus Ingelman-Sundberg||Professor, senior|
|Julianna Kele Olovsson||Forskare|
|Reza Zandi Shafagh||Forskningsassistent|
At the Section of Pharmacogenetics an integrated 3D spheroid cell culture system for primary human hepatocytes (PHH) in which cells remain viable and functionally stable for multiple weeks was developed (Bell et al., SciRep, 2016). Importantly, we showed that PHH in this model exhibited superior sensitivity to hepatotoxic agents compared to other emerging cell models, such as HepG2 and HepaRG cells, and were faithfully reproducing in vivo drug toxicity mechanisms in man. Furthermore, using a combination of untargeted and targeted metabolomics, we showed that the endogenous and xenobiotic metabolic signatures of PHH were maintained in 3D spheroids, thus allowing to comprehensively study drug-induced molecular effects on cellular metabolism and to investigate mechanisms of drug action (Vorrink et al., FASEB J, 2017).
The results indicate that the 3D PHH spheroid system faithfully mimics hepatic phenotypes in vivo and can be utilized for long-term analyses of drug metabolism, liver function and regulation.
In Vitro toxicity models
We aim to establish the spheroid model as a platform for the prediction of drug-induced liver injury (DILI) using a large panel of compounds that are hepatotoxic in man.
Integration of histological, transcriptomic and metabolomic signatures during different stages of DILI will allow in-depth analyses of toxicity mechanisms. Matching these toxicity profiles to the suggested mechanisms of toxicity observed in vivo, will systematically reveal which molecular frameworks that underlie hepatic toxicity can be recapitulated using the 3D culture system in vitro.
Furthermore, these studies facilitate the elucidation of biomarkers and yet unknown mechanisms of toxicity that can guide future in vivo studies and can aid targeted compound optimization to prevent toxicity while retaining biological activity.
Hepatic spheroids as model system for liver regeneration.
Strikingly, during spheroid aggregation stages, PHH first dedifferentiate, followed by rapid redifferentiation, providing an ideal ex vivo experimental paradigm to study the full spectrum of differentiation state changes that occur in vivo during liver regeneration. Besides extending our mechanistic understanding, this finding opened possibilities for the development of therapeutic approaches as a substitute for orthotopic liver transplantations.
To this end, we work on the establishment of protocols in which PHH isolated from patients proliferate and, after cells sufficiently multiplied, are induced to redifferentiate into functional hepatocytes using our 3D spheroid culture system. We recently showed that miRNAs are important driving forces in the hepatic dedifferentiation process; knowledge which, besides being of mechanistic importance, can be useful for the optimization of hepatic redifferentiation (Lauschke et al., Hepatology, 2016).
Development of microfluidic multi-organ co-culture chips
Type 2 diabetes mellitus (T2DM) affects 435 million patients globally and is characterized by insulin resistance of muscle, liver and adipocyte tissue in combination with progressive failure of pancreatic β‑cells, together resulting in loss of glycemic control. Due to the complexity of interactions between cells and tissues that are involved in the maintenance of human metabolic homeostasis, there is a lack of experimental tools to study T2DM. Pharmacologic therapy only allows for the management of T2DM and its sequelae and no cure is currently available, at least in part due to the lack of physiologically relevant and high-throughput compatible model systems.
We aim to develop a microfluidic multi-organ chip in which we can co-culture tissue models with relevance for T2DM. Specifically, we integrate human microphysiological and long-term stable hepatic, pancreatic, adipocytic and myocytic model systems and utilize this platform to investigate T2DM biology and to screen for novel anti-diabetic medications.
Evaluation of the importance of rare genetic variants on hepatic metabolism and drug response
Genetic variants primarily in drug and metabolite transporters, phase I and phase II drug metabolizing enzymes and nuclear receptors can influence drug response by modulating drug absorption, distribution, metabolism and excretion (ADME). Importantly, while in the past decades an ever-growing arsenal of genetic variants with demonstrated impacts on human drug response has been identified in these pharmacogenes, a substantial fraction of the heritable variability in drug response remains unexplained. Rare genetic variants that only occur in very few individuals and are hence missed in genome-wide association studies have been proposed to contribute to this missing heritability.
We integrate data from recent population-wide Next-Generation Sequencing (NGS) projects to quantify the extent of genetic variability in pharmacogenes on a population level and, using an arsenal of in silico techniques, quantify the impact on hepatic metabolism and pharmacokinetics and -dynamics.
- Swedish Research Council
- Malin and Lennart Philipson Foundation
- Horizon 2020 program of the European Union (U-PGx)
- Lars Hierta Foundation
- Eva och Oscar Ahréns Foundation
The publications are presented at https://www.ncbi.nlm.nih.gov/pubmed/?term=lauschke+v