Induced Pluripotent Stem Cells Differentiated into Intestinal Cells

Even the liver is the main organize when it comes to the metabolization of drugs, the small intestine also plays an important role in all aspects of drug metabolism. Unfortunately, no laboratory system exists at present that serves as a standardized system for evaluating the way drugs interact with the small intestine.

A new study by Tamihide Matsubara and his colleagues from Nagoya City University in Japan has sought to alleviate this problem. Matsubara and his coworkers used human induced pluripotent stem (iPS) cells to produce functional human intestinal enterocytes and showed that they faithfully recapitulated the drug metabolism of normal, human intestinal enterocytes.

To make intestinal enterocytes from iPS cells, Matsubara and others treated these cells with chemicals called activin A and fibroblast growth factor 2 to drive the cells to become intestinal-like stem cells. These cultured intestinal-like stem cells them differentiated into enterocytes when grown in a culture medium that contained epidermal growth factor and other small-molecule compounds.

The differentiated cells expressed intestinal marker genes and drug transporters. For example, they expressed sucrase-isomaltase, an intestine-specific marker, and enterocyte drug-metabolizing enzymes such as CYP1/2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT, and SULT. Inhibitor studies showed that the intestinal oligopeptide transporter SLC15A1/PEPT1 was inhibited by the pain reliever ibuprofen, just like in naturally-occurring enterocytes. Also, active forms of vitamin D increased the expression of the enzymes CYP3A4 and CYP3A4/5, which is also observed in naturally-occurring human enterocytes.

These results show that Matsubara and his colleagues have successfully generated enterocyte-like cells that have the same drug metabolizing capacities as naturally-occurring enterocytes. These cells would be very useful for developing novel evaluation systems to predict individual human intestinal drug metabolism.