Exploring the human intestine in a dish: From physiology to disease

The differentiation potential of pluripotent stem cells allows the possibility ofmaking nearly any cell type given the right set of cues. As developmentalbiology continues to reveal how a cell is instructed to proceed to its fate, itis now possible to recreate in vitro methods to guide a cell to a specifiedfate. In addition to signaling cues in the form of growth factors or theiranalogs, some cells owe their identity to a specialized supportiveenvironment that integrates a variety of cues. In the human intestine, theintestinal stem cell niche provides a physically supportive matrix withmultiple overlapping gradients of growth factor signals. This niche can bereconstructed in vitro to maintain the progenitors that would maintain theepithelium for the life of a human. We call these in vitro tissues organoids.These cultures comprise progenitor stem cells that make the different cellsof the intestine in a self-organizing tissue that has some of the functions ofthe intestine. While more complex than traditional cell cultures, an organoidis a reduced model of a tissue that allows for the observation of morestereotypical physiology and can be manipulated to model disease. Thisnew mode of cell biology intersects with a time where genetic engineeringtechnologies have expanded, become refined and now are easilyaccessible experimental systems.Using gene editing in pluripotent stem cells we made a system thatgenetically identified a human intestinal stem cell that was derived from thespontaneous differentiation of embryonic stem cells into a benign tumorgrown in a mouse. By creating a culture system to maintain these cells in anormal state long term in vitro, this has provided a model to biologicalquestions that have not been experimentally achievable in human thus far