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Human intestinal tissue grown in the lab

The technique could be used to study disease and tailor therapies.

Stem cells have been grown into structures resembling a gland intsestinal tissue. Credit: Jason Spence

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 Nature1, 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."

Gut instincts

The researchers first added the protein activin A to human embryonic stem cells and iPS cells cultured separately to encourage them to turn into endoderm, a layer of cells that arises during embryo development and eventually differentiates into the gastrointestinal tract and other organ systems. They discovered that adding the protein WNT3A and fibroblast growth factor 4 (FGF4) was necessary for cells to develop into the hindgut, which spans the last part of the gastrointestinal tract. Within a few days, the flat sheet of cells curled into tubes, many of which budded off to form floating spheres of layered tissue that mirror those seen in developing mouse embryos.

The team then placed the spheres into 3D cultures, like those used before, to grow organ-like structures from intestinal stem cells taken from adult mice2. In a process that parallels gut development in mouse fetuses, the spheres expanded and developed columnar cells with finger-like projections and regions that spawned intestinal stem cells. Within a month, the tissue produced all of the major cell lineages found in the gut, including smooth muscle and cells that absorb nutrients and secrete mucous, hormones and enzymes. These cells continued to mature over the next few months.

"Their ability to generate all of the cell types in the intestine was very impressive," Cohn says. "This is really the first time that I'm aware of that we've been able to recapitulate most of the development of an organ in a test tube from a human pluripotent stem cell." iPS cells are a reliable and continuous source for the creation of organ tissue, he adds.

Tailored treatment

Stephen Duncan, a stem-cell biologist at the Medical College of Wisconsin in Milwaukee, agrees that "this represents a major step forward in the gut field" because it opens the doors to examining intestinal development in humans and dissecting the mechanisms of illnesses that cause inflammation or impair nutrient absorption, such as inflammatory bowel disease and short bowel syndrome. Scientists can also use the method to screen for drugs that block cholesterol uptake, he adds.

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.

References

  1. Spence, J. R. et al. Nature advance online publication doi:10.1038/nature09691 (12 December 2010).

  2. Sato, T. et al. Nature 459, 262-265 (2009).

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Weaver, J. Human intestinal tissue grown in the lab. Nature (2010). https://doi.org/10.1038/news.2010.668

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