The team of Paula Alves is a step closer to reproducing the complexity of the human liver in vitro. The research work is published at Hepatology, a science journal of international impact, and is highlighted in the April cover. This work is a progress towards the substitution of animal experimentation (in vivo testing) by cell culture models ( in vitro testing).
This study brings an innovative method that allows both the evaluation of drug metabolization and toxicity of chemicals, through an in vitro model of the human liver.
The research was developed by the Bioprocess Lab at the Animal Cell Technology (ACT) Unit of Instituto de Biologia Experimental e Tecnológica (iBET)/Instituto de Tecnologia Química e Biológica-Universidade Nova de Lisboa (ITQB-UNL), in collaboration with Cellartis (Sweden), the first company in the world to enter the market with hepatic and cardiac cells derived from human embryonic stem cells to be used in the discovery of new pharmaceuticals.
What is new about this study? On the one hand the capacity to maintain human liver cells (hepatocytes) in culture for long periods of time, forming 3D aggregates (spheroids), alongside with production of hepatic enzymes responsible for the metabolism of pharmaceuticals. On the other hand, for the first time spheroids develop a matrix of functional bile canaliculi, a recapitulation of a very fundamental liver architecture trait responsible for secretion in this organ.
Everything points out that this 3D model better mimics the human liver function. It is therefore a more reliable method for in vitro toxicity and metabolism tests by pharmaceutical companies. Researchers may also use this model as a tool to study hepatic diseases. Making use of human cells is vital as many human hepatic enzymes metabolize drugs and chemicals in different way than equivalent animal enzymes do. Moreover, systems that warrant the functionality of liver cells open new venues for the clinical field, for instances the development of artificial organs to backup intensive care scenarios.
Currently, human hepatocyte cultures are the golden standard for toxicity tests by both the FDA and EMA, therefore this study positively impacts on the evolution of test systems. “The fact that we can maintain hepatic function for a month allows the use of the same population of hepatocytes in metabolic studies during repetitive doses of the same pharmaceutical, this is paramount for the pre-clinical development that precedes the approval of new pharmaceuticals” says the study´s lead author Paula Alves.
The technological innovation of this work is the utilization for the first time of perfusion stirred bioreactors, an equipment that allows the flow of nutrients and oxygen to the hepatocyte culture in specific and controlled conditions. The system developed by the researchers can still be improved and applied to other organs whose in vitro models are scarcely represented. The ACT team- Bioprocess lab (iBET/ITQB) continues to work on this project, as well as in others that aim for the development of other in vitro models. brain and cancer in vitro models. Currently the team has a collaboration with TECNIMEDE a Portuguese pharmaceutical company, to develop brain models, and within the E.U. project consortium PREDECT, funded by Innovative Medicine Iniciative http://www.imi.europa.eu/) aiming to develop cancer in vitro models.
This research was made possible by funding from the Fundação para a Ciência e Tecnologia (Portugal) / MIT Portugal Program and the European Commission FP7 Programme.