By coaxing pluripotent stem cells to grow into functioning human intestinal tissue in a lab, scientists believe they have created unprecedented opportunities to study the human gut and its diseases, and taken a significant step towards growing intestinal tissue for transplantation.
The study is the work of senior researcher Dr James Wells from the division of Developmental Biology at Cincinnati Children’s Hospital Medical Center, and colleagues, and was published in an early online 12 December issue of Nature.
Wells told the press this is the first study to show 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”.
He said he and his team hope these findings will lead to therapies that will benefit people with diseases such as necrotizing enterocolitis, inflammatory bowel disease and short bowel syndromes.
For the study, the researchers used two types of pluripotent stem cells: human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), the latter made by reprogramming human skin cells obtained by biopsy.
They used both types because it is still early days to know whether iPSCs have the full capability of hESCs to become any of the 200 plus different types of cell in the human body.
By working with both, the researchers thought they could further test and compare the range of cell types the stem cells can and cannot transform into and how easily they do it.
They used chemicals and growth factor proteins to create a lab environment similar to that which exists during embryonic intestinal development.
First, they turned turned pluripotent stem cells into an embryonic cell type called definitive endoderm, a type of tissue that forms the lining of the esophagus, stomach and intestines as well as the lungs, pancreas and liver.
Then they programmed the endoderm cells to transform into “hindgut progenitor” cells, and put them in a cell culture system that promotes intestinal growth.
They wrote that this stage 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.”
Within 28 days, the culture had formed a 3D tissue structure that looked like fetal intestinal tissue, and contained all the major types of gut cells, including enterocytes, goblet, Paneth and enteroendocrine cells.
The tissue went on to develop normal properties of human intestinal tissue, such as the ability to absorb and secrete, and form stem cells specific to the human gut.
Using this approach, Wells said he and his team and other scientists around the world will be able to study how the gut develops normally in humans, and also what goes wrong in the case of diseases.
With animal tests, they are already working on establishing if the method is effective in transplant-based treatments of intestinal diseases such as short bowel syndrome. If these are successful, they then want to try it with humans.
Another potential application is to study how the gut absorbs drugs, so that better oral drugs can be designed that are taken up by the body more effectively, since the gut absorbs most that are taken orally, said the researchers.
They told Nature News that they also plan to produce iPS cells from patients with congenital abnormalities to find out what goes wrong when the intestine is developing in these cases. The idea is that perhaps it might be possible to intervene, correct the defect, and ensure healthy tissue forms.
“This is a good first step toward generating replacement tissue for people with degenerative diseases of the intestine,” said Wells.
Grants from the National Institutes of Health and the Juvenile Diabetes Research Foundation helped pay for the study.
“Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro.”
Jason R. Spence, Christopher N. Mayhew, Scott A. Rankin, Matthew F. Kuhar, Jefferson E. Vallance, Kathryn Tolle, Elizabeth E. Hoskins, Vladimir V. Kalinichenko, Susanne I. Wells, Aaron M. Zorn, et al.
DOI:10.1038/nature09691
Additional sources: Cincinnati Children’s Hospital Medical Center press release, Nature News.
Written by: Catharine Paddock, PhD