Digesting new esophageal organoids papers

Esophageal organoids
Esophageal organoids, Cincinnati Children's
Esophageal organoids
Esophageal organoid growing in culture, Cincinnati Children’s

There’s a new paper in Cell Stem Cell on esophageal organoids that has really caught people’s attention. It is entitled, “3D Modeling of Esophageal Development using Human PSC-Derived Basal Progenitors Reveals a Critical Role for Notch Signaling.” It comes from a team led by Jianwen Que.

Update: I didn’t realize when I first did this post that there were 2 related esophageal organoids papers in the same issue of the journal and the second one led by James M. Wells at Cincinnati Children’s has some cool results too (see image at right). Both reported on the role of SOX2.

Below are some quick thoughts I had mainly on the paper by the Que team. You can read my previous posts on The Niche regarding organoids more generally here.

Past relevant studies

While others have reported esophageal organoids in the past (most notably in an important paper from a team led by Hiroshi Nakagawa in January of this year), those were produced from clinical specimens rather than pluripotent stem cells. The new paper seems to be the first report of making human esophageal organoids from IPS cells, which is exciting. Future work will determine whether esophageal tissue or IPS cells is a better starting material. It’s possible IPS cell-derived esophageal organoids may grow bigger or exhibit a better ability to produce all the different cells of the esophagus given their pluripotency, but we’ll see. Progenitor or stem cells in the esophagus itself have potential too.

SOX2, NOTCH, and complex GF interplay

Both the Nakagawa team paper and the new ones provide insights into the complex interplay between many coordinate growth factor signaling pathways that is required to generate esophageal organoids that bear some similarity to the natural esophagus. The new papers highlight the key role of the transcription factor SOX2 in regulating growth factors in esophageal development. It’s interesting as well since SOX2 is most well known for its role in reprogramming of somatic cells to make IPS cells in the first place, but clearly SOX2 has other functions in more committed cells as has been reported for years. I didn’t know it was functioning in the developing esophagus.

Full differentiation; looming lumen?

More broadly, getting fully mature and functional differentiated tissues from IPS cells has been a challenge for the field as differentiated cells produced from IPS cells are often more akin to fetal tissues than that of adults. This new paper is striking for producing tissue with some signs of getting closer to full differentiation of specific esophageal cell types. However, one thing that stood out to me as a further challenge is the possible absence of a clear, large lumen in the esophageal organoids. The lumen is the open space where the food would be. Some of the organoids may have had something that could have been a small lumen, but hard to say.

Clinical impact potential

Overall, this is still probably a long way from producing a functional esophageal segment that could in principle be used for transplantation, but it’s encouraging that such a feat might someday be possible. At present though it seems like this technology is most exciting for its potential use to model esophageal disease, which is very common. If clinical use is someday possible, the use of IPS cells as a starting material could be the only way forward for some patients who do not have healthy esophageal tissue to use to try to make organoids.

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