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

  • Author(s): Forster, Ryan
  • Advisor(s): Hockemeyer, Dirk
  • et al.
Abstract

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.

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