Exploring the human intestine in a dish: From physiology to disease
- Author(s): Forster, Ryan
- Advisor(s): Hockemeyer, Dirk
- et al.
The differentiation potential of pluripotent stem cells allows the possibility of
making nearly any cell type given the right set of cues. As developmental
biology continues to reveal how a cell is instructed to proceed to its fate, it
is now possible to recreate in vitro methods to guide a cell to a specified
fate. In addition to signaling cues in the form of growth factors or their
analogs, some cells owe their identity to a specialized supportive
environment that integrates a variety of cues. In the human intestine, the
intestinal stem cell niche provides a physically supportive matrix with
multiple overlapping gradients of growth factor signals. This niche can be
reconstructed in vitro to maintain the progenitors that would maintain the
epithelium for the life of a human. We call these in vitro tissues organoids.
These cultures comprise progenitor stem cells that make the different cells
of the intestine in a self-organizing tissue that has some of the functions of
the intestine. While more complex than traditional cell cultures, an organoid
is a reduced model of a tissue that allows for the observation of more
stereotypical physiology and can be manipulated to model disease. This
new mode of cell biology intersects with a time where genetic engineering
technologies have expanded, become refined and now are easily
accessible experimental systems.
Using gene editing in pluripotent stem cells we made a system that
genetically identified a human intestinal stem cell that was derived from the
spontaneous differentiation of embryonic stem cells into a benign tumor
grown in a mouse. By creating a culture system to maintain these cells in a
normal state long term in vitro, this has provided a model to biological
questions that have not been experimentally achievable in human thus far.