Challenging research involving human induced pluripotent stem cells
Brain organoids with optic cups at day 60 of development. (Gabriel et al., Cell Stem Cell, 2021)
The new stem cell technique of growing brain organoids is producing some unsettling results. In a study in Cell Stem Cell, scientists in Germany used human induced pluripotent stem cells (iPSCs) to create brain organoids with an eye structure called the optic cup.
The organoids spontaneously developed bilaterally symmetric optic cups from the front of the brain-like region, demonstrating the intrinsic self-patterning ability of iPSCs in a highly complex biological process.
“Our work highlights the remarkable ability of brain organoids to generate primitive sensory structures that are light sensitive and harbor cell types similar to those found in the body,” says Jay Gopalakrishnan of University Hospital Düsseldorf. “These organoids can help to study brain-eye interactions during embryo development, model congenital retinal disorders, and generate patient-specific retinal cell types for personalized drug testing and transplantation therapies.”
The human brain organoids formed optic cups, which appeared as early as 30 days and matured as visible structures within 50 days. This time frame parallels that of retinal development in the human embryo and could make certain types of developmental neurobiology experiments more efficient.
Across 16 independent batches from four iPSC donors, the researchers generated 314 brain organoids, 72% of which formed optic cups, showing that the method is reproducible. These structures contained diverse retinal cell types, which formed electrically active neuronal networks that responded to light. The optic cup brain organoids also contained lens and corneal tissue and exhibited retinal connectivity to brain regions.
“In the mammalian brain, nerve fibers of retinal ganglion cells reach out to connect with their brain targets, an aspect that has never before been shown in an in vitro system,” Gopalakrishnan says.
In future studies, they plan to develop strategies to keep the optic cups viable for long time periods, using them to investigate mechanisms that cause retinal disorders.
Writing in The Niche, a well-informed commentary on stem cell research, Paul Knoepfler, of UC Davis School of Medicine, asks whether there should be limits on growing embryo-like structures which are becoming increasing complex. He is of two minds:
As to the human embryo models that are starting to be so similar to actual human embryos, I think limits make sense. For human brain organoids not so much. These structures are fairly far removed from actual human brains and reports of neural activity in them don’t show anything like coherent function on a consistent basis.
Michael Cook is editor of BioEdge
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