Every tissue requires a different recipe for the production of a functioning structure from the starting point of a few cells: different signals, different environment, different timing. Researchers in the heavily funded tissue engineering community are working their way through the lengthy and costly task of establishing those recipes for every type of organ that might be replaced or repaired. At the same time, there is at present no reliable way to produce the capillary networks needed to support tissues thicker than a few millimeters. The result is an era of organoids, tiny functional sections of organ tissue that are primarily used to accelerate research rather than for the production of therapies. Therapies are nonetheless possible in some cases: sheets of functional tissue can in principle be transplanted onto or into an organ, or even used to generate free-standing tiny assistive organs elsewhere in the body, as demonstrated by the ongoing work at Lygenesis. The set of organoid recipies is expanding and the quality of the end results are improving, with the report here being a representative example of the state of progress in this field.
Scientists working to bioengineer the entire human gastrointestinal system in a laboratory now report using pluripotent stem cells to grow human esophageal organoids. The newly published research is the first time scientists have been able to grow human esophageal tissue entirely from pluripotent stem cells (PSCs), which can form any tissue type in the body. Scientists have already used PSCs to bioengineer human intestine, stomach, colon, and liver. "Disorders of the esophagus and trachea are prevalent enough in people that organoid models of human esophagus could be greatly beneficial. In addition to being a new model to study birth defects like esophageal atresia, the organoids can be used to study diseases like eosinophilic esophagitis and Barrett's metaplasia, or to bioengineer genetically matched esophageal tissue for individual patients."
The scientists based their new method for using human PSCs to general esophageal organoids on precisely timed, step-by-step manipulations of genetic and biochemical signals that pattern and form embryonic endoderm and foregut tissues. They focused in part on the gene Sox2 and its associated protein - which are already known to trigger esophageal conditions when their function is disrupted. The scientists used mice, frogs, and human tissue cultures to identify other genes and molecular pathways regulated by Sox2 during esophagus formation. The scientists report that during critical stages of embryonic development, the Sox2 gene blocks the programming and action of genetic pathways that direct cells to become respiratory instead of esophageal. In particular, the Sox2 protein inhibits the signaling of a molecule called Wnt and promotes the formation and survival of esophageal tissues.
After successfully generating fully formed human esophageal organoids - which grew to a length of about 300-800 micrometers in about two months - the bioengineered tissues were compared biochemically to esophageal tissues from patient biopsies. Those tests showed the bioengineered and biopsies tissues were strikingly similar in composition. The research team is continuing its studies into the bioengineering process for esophageal organoids and identifying future projects to advance the technology's eventual therapeutic potential.