For the first time, scientists have engineered a miniature stomach, which displays cellular and functional complexity similar to its human counterpart.
Organoids grown in a laboratory dish are increasingly used to mimic human organs and model diseases (see BioNews 1120, 1113 and 1111). Typically, this is achieved by genetically reprogramming human induced pluripotent stem cells (iPSCs) to develop into organ-specific cells, which then self-assemble into three dimensional structures. Although these structures may display some rudimentary function (see BioNews 1109), they usually lack the cellular diversity and structural complexity of a real organ. Now, scientists at the Cincinatti Children's Hospital, Ohio have used separate lines of human iPSCs to create stomach organoids with a three-layered structure and gastric function such as smooth muscle contraction and glandular secretion.
'We started with cells from the three primary germ layers – enteric neuroglial, mesenchymal, and epithelial precursors – all separately derived from PSCs,' explained first author Dr Alexandra Eicher. 'From these we generated stomach tissue that contained acid-producing glands, surrounded by layers of smooth muscle containing functional enteric neurons that controlled contractions of the engineered antral stomach tissue.'
Publishing their findings in Cell Stem Cell, the team led by Professor James Wells took their research a step further and transplanted the miniature stomachs into mice, where they continued to grow, reaching several millimetres in size. The scientists then exploited this system to investigate how interactions between the three germ layers determine the fate of the developing organoid. By changing the balance between the three components they obtained structures corresponding to different parts of the upper gastro-intestinal (GI) tract. The ability to model the development of the human GI tract offers a tool to understand how it is damaged by genetic disorders or injury.
In addition, the researchers also created a human oesophagus organoid to demonstrate that their approach can be used to generate a variety of complex organs, with the potential to serve as a basis for regenerative medicine.
'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,' said Professor Wells.
However, the authors do caution that much more work is required before organoid tissue is developed that would be suitable for transplantation. Furthermore, it is unlikely that organs grown in laboratory animals would be approved for human use. 'So we would need a way to grow organoids larger without a host. This would require a way to mimic active nutrient and gas exchange in vitro.' added Dr Eicher.