Single-Cell Transcriptomic Comparison of Human Fetal Retina, hPSC-Derived Retinal Organoids, and Long-Term Retinal Cultures
This week we profile a recent publication in Cell Reports from the laboratory of Dr. Thomas Reh (pictured, left) at UW.
Can you provide a brief overview of your lab’s current research focus?
Our lab studies the development and regeneration of the retina to better understand eye diseases and develop new treatments for those that are currently not treatable.
What is the significance of the findings in this publication?
Embryonic stem cells can be used to generate mini-retinas in a dish, and these are being used to model human diseases. These are called retinal organoids. However, before this study, it was not known how closely these organoids follow normal fetal development. We used single cell transcriptomic techniques to compare the organoids to normal fetal development. We find that at least for the first few months of development, the stem cell-derived organoids are pretty close to the normal retina, but as time goes on, they diverge in several ways. For example, the neurons of the normal retina have a very precise organization that helps us see in great detail, but the stem cell-derived organoids do not retain the normal organization, and some of the genes needed for neuron maturation do not get turned on at their normal levels. We also wondered whether the problems the stem cell-derived organoids were having was due to the fact that they are growing in a petri dish, a pretty artificial environment. So we made a new type of organ culture, by dicing the normal fetal retina into organoid sized pieces (called retinospheres), and grew them like stem cell-derived organoids. These retinospheres were much more like the normal fetal cells, even after long periods of time in culture dishes.
What are the next steps for this research?
The fact that the stem cell-derived organoids do not completely recapitulate normal development shows that they still need some work before we can use them to model all types of retinal diseases. Recent reports comparing brain organoid development with normal fetal brain development has come to the same conclusions. But now we can make mini-retinas from normal fetal retina and maintain these in long-term culture, and this will enable us to figure out what the key differences are and work to correct them. Comparing fetal development with stem cell-derived organoid development should get us to the point where use of fetal tissue is not going to be necessary.
This work was funded by:
Paul G. Allen Family Foundation Distinguished Investigator Award was the primary funding source.