Improving in vitro models to study the human intestine

IBEC’s Biomimetic Systems for Cell Engineering group has published a review about possible new strategies to study drug absorption in the intestine in the high-ranking journal Trends in Molecular Medicine.

Together with their collaborators at the Universidade do Porto, Elena Martinez’s group examines the current state-of-the-art of cell-based intestinal models, which have been used for drug absorption and metabolism studies since the 1980s. However, current models, which use Caco-2 cells derived from human intestinal tumors, are not fully representative of the human small intestine.

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Image: Schematic representation of the in vitro differentiation of intestinal tissue from pluripotent stem cells.

The paper suggests using iPSCs and differentiating them to become intestinal-like cells as a reliable and promising strategy to develop models that provide more true-to-life predictions on the behavior and prospects of new drugs. “Enterocyte-like cells obtained from iPSCs have more similarities with primary enterocytes than Caco-2, which is the current ‘gold standard’,” says first author Helena Macedo, a Porto PhD student co-supervised by Elena. “Using these cells in intestinal models may enable more reliable correlation with the in vivo situation.”

However, several hurdles remain. While it’s possible to obtain enterocyte-like cells from iPSCs, the percentage of immature cells remains high, indicating that current differentiation protocols don’t yield a population with the required level of homogeneity. Not only that, but while iPSC-derived enterocyte-like cells show higher expression of most transporters and enzymes than Caco-2 cells, they are still far from typical in vivo levels. The costs and time associated with differentiating iPSCs are also disadvantages.

“For iPSCs to be seen as a promising tool for intestinal models in the future, the differentiation protocols would have to be improved,” says group leader Elena Martinez. “That would further increase the similarities between these cells and enterocytes, making them even more promising for use in intestinal models.”

Source article: Maria Helena Macedo, Francisca Araújo,  Elena Martínez, Cristina Barrias, and Bruno Sarmento (2018). iPSC-Derived Enterocyte-like Cells for Drug Absorption and Metabolism Studies. Trends in Molecular Medicine, 24, 8, 696-708