Lecture
Human hepatocyte organoids for the prognostication of blood glycoproteoform biomarkers
- at -
- ICM Saal 2
- Type: Lecture
Lecture description
Shelley Jager1,2, Albert J.R. Heck*1,2
1 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands
2 Netherlands Proteomics Center, Padualaan 8, 3584 CH Utrecht, the Netherlands
Protein glycosylation provides critical information about cellular origin, maturation, and (dys)function, making glycoproteins in human blood attractive biomarkers. However, the discovery and validation of such biomarkers by plasma glycoproteomics remains challenging due to high interdonor viability and the lack of experimentally traceable systems linking intracellular glycosylation to circulating glycoproteoforms. In vitro cellular or organoid models offer the potential to address such these limitations by providing a controlled environment, thereby reducing variability. Such in vitro systems provide direct access to both intracellular and secreted glycoproteins. However, not all in vitro systems are suitable for the prediction of what occurs in blood. Such a model should reflect a physiologically healthy baseline to be reliable for future biomarker prediction. We hypothesized that
human hepatocyte organoids might present a promising candidate as model system.
Hepatocytes are the major source of most plasma proteins and organoids have a high physiological representation compared to in vivo systems. Therefore, we examine whether this model recapitulates healthy plasma glycoproteoform signatures, by comparing the organoid lysate and secretome glycoproteome to that of human plasma. We observed high concordance in the glycoproteome at both the protein and glycosylation level between organoid-secreted proteins and plasma, with expected exceptions related to the fetal origin of the used hepatocyte organoids. At the glycan level, increased fucosylation in the organoid secretome likely reflects co-occurring secretion pathways associated with bile duct–related trafficking. Together, the data demonstrate that human hepatocyte organoids capture nearly all key features defining plasma glycoprotein composition and provide a mechanistically interpretable manipulatable in vitro platform to investigate and predict blood glycoproteoform biomarkers.
1 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands
2 Netherlands Proteomics Center, Padualaan 8, 3584 CH Utrecht, the Netherlands
Protein glycosylation provides critical information about cellular origin, maturation, and (dys)function, making glycoproteins in human blood attractive biomarkers. However, the discovery and validation of such biomarkers by plasma glycoproteomics remains challenging due to high interdonor viability and the lack of experimentally traceable systems linking intracellular glycosylation to circulating glycoproteoforms. In vitro cellular or organoid models offer the potential to address such these limitations by providing a controlled environment, thereby reducing variability. Such in vitro systems provide direct access to both intracellular and secreted glycoproteins. However, not all in vitro systems are suitable for the prediction of what occurs in blood. Such a model should reflect a physiologically healthy baseline to be reliable for future biomarker prediction. We hypothesized that
human hepatocyte organoids might present a promising candidate as model system.
Hepatocytes are the major source of most plasma proteins and organoids have a high physiological representation compared to in vivo systems. Therefore, we examine whether this model recapitulates healthy plasma glycoproteoform signatures, by comparing the organoid lysate and secretome glycoproteome to that of human plasma. We observed high concordance in the glycoproteome at both the protein and glycosylation level between organoid-secreted proteins and plasma, with expected exceptions related to the fetal origin of the used hepatocyte organoids. At the glycan level, increased fucosylation in the organoid secretome likely reflects co-occurring secretion pathways associated with bile duct–related trafficking. Together, the data demonstrate that human hepatocyte organoids capture nearly all key features defining plasma glycoprotein composition and provide a mechanistically interpretable manipulatable in vitro platform to investigate and predict blood glycoproteoform biomarkers.
