Using Small Molecules to Covert Donated Stomach Cells into Stem Cells that Can Cure Liver Disease

A collaboration between Yunfang Wang from the Tissue Engineering Lab at the Beijing Institute of Transfusion Medicine in Beijing, China and Xuetao Pei, from the Stem Cell and Regenerative Medicine Lab, also at the Beijing Institute of Transfusion Medicine has produced a remarkable result.

Wang and Pei and their colleagues have used small molecules to convert human gastric epithelial cells into endodermal progenitors.  Endodermal stem/progenitor cells have diverse potential applications in research and regenerative medicine.  They can differentiate into just about any cell type in the gastrointestinal tract, including liver cells, and pancreatic cells.  Thus these cells may have a variety of uses in research, and perhaps even in the clinic.

In this experiment, gastric epithelial cells were isolated from human donors and cultured in the presence of a carpet of tissue-specific mesenchymal cells as support cells to help the gastric epithelial cells survive in primary culture.  These cells were then treated with a cocktail of small molecules that drove the cells to dedifferentiate into induced endodermal progenitor cells (hiEndoPCs). These cells can grow in culture, expand rapidly and express a variety of stem cell markers.

In culture, the hiEndoPCs were able to differentiate into liver cells (hepatocytes, pancreatic endocrine cells, and intestinal epithelial cells.  The differentiation protocols used in this paper all involved the use of small molecules – no genetic engineering of the cells was necessary.

Small molceules that convert gastric epithelial cells into hiEndoPCs

Then liver cells made from hiEndoPCs were transplanted into mice that had messed up livers (Fah -/- Rag2-/-).  Fah-mutant mice lack the enzyme fumarylacetoacetate hydrolase, and without this enzyme, the liver is incapable to processing toxic ammonium, which builds up in the liver and kills it.  Rag2 mutations prevent the mouse from rejecting implanted livers cells.  In these experiments, transplanted hepatocytes rescued liver failure in these mice.  hiEndoPCs had the added advantage of no causing teratomas, like embryonic stem cells.

Human gastric epithelial cells are easily isolated from human donors without causing harm to the donor.  They can be isolated from patients of a variety of ages and this strategy can easily convert those cells into a cell population that is readily expandable and can be personalized into cells from treating patients with abnormal livers, pancreases, or intestinal tracts.  This fascinating proof-of-principle paper brings such personalized medicine one step closer.

The article was published in Cell Stem Cells 2016,