Novel Culture System Turns Stem Cells into Human Intestinal Tissue

Cell biologists have used a novel three-dimensional culture system to turn stem cells into functioning human intestinal tissues.

Pluripotent stem cells of either embryonic origin (hESCs) or obtained through manipulation of differentiated cells (induced pluripotent stem cells or iPSCs) can be guided by a series of molecular signals to develop into any number of mature cell types. For example, human pluripotent stem cells have been differentiated into monolayer cultures of liver hepatocytes and pancreatic endocrine cells that have demonstrated therapeutic efficacy in animal models of liver disease and diabetes, respectively.

In the current study, investigators at Cincinnati Children's Hospital Medical Center (OH, USA; www.cincinnatichildrens.org) used both hESCs and iPSCs to establish a robust and efficient in vitro process to direct the differentiation of these cells into intestinal tissue using a temporal series of growth factor manipulations to mimic embryonic intestinal development.

The initial step involved activin-induced definitive endoderm formation. Endoderm gives rise to the lining of the esophagus, stomach, and intestines. Next, FGF/Wnt signaling was used to induce posterior endoderm pattering, hindgut specification and morphogenesis. Then, a prointestinal culture system was established to promote intestinal growth, morphogenesis, and cytodifferentiation.

Results published in the December 12, 2010, online edition of the journal Nature revealed that after four weeks these steps generated three-dimensional tissue resembling fetal intestine that contained all the major intestinal cell types – including enterocytes, goblet, Paneth, and enteroendocrine cells. The three-dimensional intestinal "organoids” consisted of a polarized, columnar epithelium that was patterned into villus-like structures and crypt-like proliferative zones that expressed intestinal stem cell markers. The tissue continued to mature and acquired both the absorptive and secretory functionality of normal human intestinal tissues.

"This is the first study to demonstrate that human pluripotent stem cells in a petri dish can be instructed to efficiently form human tissue with three-dimensional architecture and cellular composition remarkably similar to intestinal tissue,” said senior author Dr. James Wells, professor of developmental biology at Cincinnati Children's Hospital Medical Center. "The hope is that our ability to turn stem cells into intestinal tissue will eventually be therapeutically beneficial for people with diseases such as necrotizing enterocolitis, inflammatory bowel disease, and short bowel syndromes.”

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