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December 12, 2010

Pluripotent stem cells turned into intestinal tissue

Nature - Human intestinal tissue grown in the lab Wells and his collaborators are working on approaches to create intestinal nerve cells in the cultures and transplant the tissue in mouse models of intestinal disorders.

They also plan to produce iPS cells from patients with congenital abnormalities and use the culture system to pinpoint what goes wrong during intestinal development. Then they might be able to correct the defect and restore the tissue in patients. "This is a good first step toward generating replacement tissue for people with degenerative diseases of the intestine," Wells says.

The technique could be used to study disease and tailor therapies. By mimicking stages of embryonic development, scientists have prodded human stem cells to produce three-dimensional (3D) organ tissue that resembles the intestine and recapitulates its major cell types.

The work, reported today in Nature, represents the first example of human embryonic stem cells being coaxed into forming a specific 3D organ tissue in culture, says lead investigator James Wells, a developmental biologist at Cincinnati Children's Hospital Medical Center in Ohio. Scientists can use the protocol to investigate the molecular basis of human intestinal development and disease, design drugs that get absorbed better and grow tissue for transplantation therapies, he says.

Wells and his team used human embryonic stem cells, which can turn into any type of tissue, as well as human induced pluripotent stem (iPS) cells — adult cells that have been reprogrammed to behave like embryonic cells. The researchers enticed these cells to transform into intestinal cells and then into 3D structures by using a sequence of growth factors — substances that promote cell growth and specialization


The structures started to imitate the intestine once they were placed into 3D cultures filled with a mixture of different growth factors that foster growth and further development into advanced intestinal organ-like structures2.

"This is really a major advance in the field because it provides an experimental system for studying the development of the human intestine," says Steven Cohn, a gastroenterologist at the University of Virginia School of Medicine in Charlottesville. "This will allow one to study human organ development in the test tube in a way that we haven't been able to do before."

Journal Nature - Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro
Studies in embryonic development have guided successful efforts to direct the differentiation of human embryonic and induced pluripotent stem cells (PSCs) into specific organ cell types in vitro. For example, human PSCs have been differentiated into monolayer cultures of liver hepatocytes and pancreatic endocrine cells that have therapeutic efficacy in animal models of liver disease and diabetes, respectively. However, the generation of complex three-dimensional organ tissues in vitro remains a major challenge for translational studies. Here we establish a robust and efficient process to direct the differentiation of human PSCs into intestinal tissue in vitro using a temporal series of growth factor manipulations to mimic embryonic intestinal development. This involved activin-induced definitive endoderm formation11, FGF/Wnt-induced posterior endoderm pattering, hindgut specification and morphogenesis and a pro-intestinal culture system to promote intestinal growth, morphogenesis and cytodifferentiation. The resulting 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 epithelium contained functional enterocytes, as well as goblet, Paneth and enteroendocrine cells. Using this culture system as a model to study human intestinal development, we identified that the combined activity of WNT3A and FGF4 is required for hindgut specification whereas FGF4 alone is sufficient to promote hindgut morphogenesis. Our data indicate that human intestinal stem cells form de novo during development. We also determined that NEUROG3, a pro-endocrine transcription factor that is mutated in enteric anendocrinosis18, is both necessary and sufficient for human enteroendocrine cell development in vitro. PSC-derived human intestinal tissue should allow for unprecedented studies of human intestinal development and disease.




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