A group of scientists at the Cincinnati Children's Hospital has used separate lines of human induced pluripotent stem cells (iPSCs) to create stomach organoids with a three-layered structure and gastric function such as smooth muscle contraction and glandular secretion. The team reported its results in the December 2021, issue of Cell Stem Cell.

In vitro human organoid systems that mimic human organs are being increasingly used as disease modeling systems. They are generated by genetically reprogramming human iPSCs into organ-specific cells, which can then self-assemble into three-dimensional structures.

However, most of these engineered organ systems exhibit only rudimentary function, lacking the cellular diversity and structural complexity of a real organ.

Speaking to BioWorld Science, senior author James Wells said, "the general concept was that we could generate the separate components of a given tissue and engineer a complex organ. In this case, as a proof of principle, we used the stomach as a representative organ system. We started with cells from the three primary germ layers -- enteric neuroglial, mesenchymal and epithelial precursors -- all separately derived from PSCs. From these, we generated the inner lining of the stomach that contains the acid-producing glands, surrounded by layers of smooth muscle which mixes what we eat into a small slurry. This layer contained the functional enteric neurons that control contractions of the engineered antral stomach tissue. Combining them at the right time and place to approximate normal assembly of the stomach, which happens in the developing embryo, we were able to get them to self-organize to form these highly complex and physiologically normal looking segments of stomach."

Wells is a professor of pediatrics at the University of Cincinnati and leads their Center for Stem Cell and Organoid Medicine. The Wells group focuses on generating 3-dimensional human tissues from pluripotent stem cells and using these as human models of diabetes and digestive disease.

According to the authors, the engineered gastric tissue displayed several properties of bona fide human stomach antrum, the part of the stomach that holds digested food on its way to the intestines. They also applied the same concept of assembling organoids from separately derived germ layer progenitors to both fundus and esophagus, suggesting that this technology could be broadly applied to tissue engineer other organs, like lung, liver and bladder.

Wells and his team also transplanted the miniature stomachs into mice, where they continued to grow, reaching several millimeters in size. The living system acted as an incubator and provided the blood flow and biological space to allow much more growth to the petri dish-generated organoids to form mini organs, closely resembling naturally grown human tissue at similar stages of development. In the paper, the authors highlight the critical importance of cellular communication between all three germ layers for proper assembly and morphogenesis of stomach tissue. Interestingly, by changing the balance between the three germ components they obtained structures corresponding to different parts of the upper gastrointestinal tract (fundus/antrum).

In addition to demonstrating a three-layered approach for developing stomach organoids, the team also applied a similar approach to make a more sophisticated esophageal organoid. Wells hopes that these more complex organoids will serve as useful tools for studying genetic variations and other cell signaling dysfunctions that contribute to gastric diseases -- and can serve as improved platforms for evaluating potential treatments. "Given that this technology is broadly translatable to other organs, it is possible that engineered tissue might serve to reconstruct the elements of the upper GI tract that are damaged by congenital disorders or acute injuries. The goal would be to introduce them into a patient and have them in that patient's very own intestine, patch up damage, so essentially to repair and restore normal function of a damaged organ," he said.

However, he added that much more work is required before organoid tissue is developed that would be suitable for transplantation. "Members of this team, with a recent grant awarded from Cincinnati Children's Hospital, are now working to scale up production of therapeutic quality organoid tissues with the goal of transplantation into patients by the end of the decade," Wells concluded.