Brain organoids, derived from human stem cells, are the key tools used for many vital medical studies, but current state-of-the-art brain organids suffer from limited reproducibility, scalability, and structural accuracy, thereby preventing their broader applications. Now, Yubing Sun, an assistant professor in the Mechanical and Industrial Engineering Department and an adjunct in the Biomedical Engineering Department, has received a two-year, $411,450 grant from the National Institutes of Health to transform the production of brain organids and help resolve all those issues.
“Very briefly,” says Sun, “this project is to derive better brain organoids.”
Not only will Sun’s vital research produce pioneering brain organoids that are potent tools to study fundamental mechanisms underlying human brain development and neurological disorders, but his innovative organids also have the potential to be used as a high-throughput platform for therapeutic screening.
In addition, says Sun, a specific group of these newly derived organids, the fully patterned human forebrain organids, "offer a versatile model to better dissect the cellular and tissue scale features of neurological diseases, such as schizophrenia and autism, and have the potential to be used as a drug screening platform to improve the treatment strategies for these diseases.”
Current brain organoids are 3D aggregates of neuronal cells spontaneously developed from stem cells. Because the environment in the culture dishes is different from that in embryos, current organids are lacking instructive cues that exist in vivo, one of which is the gradient of morphogens.
According to an article in Nature, “A morphogen gradient is an important concept in developmental biology, because it describes a mechanism by which the emission of a signal from one part of an embryo can determine the location, differentiation, and fate of many surrounding cells.”
Sun’s work will reproduce these morphogen gradient cues in the production of organids. He and his research team will advance the biomanufacturing of organoids by providing easy-to-use devices to produce reproducible, complete, and region-specific brain organoids with proper patterning that are much more similar to those found in human embryos and brains.
“Leveraging the micro-engineered devices we developed,” explains Sun, “we now are able to reconstruct such an environment outside our body to grow something more similar to real developing brains – both structurally and functionally.
Sun’s work will help solve the problems of current state-of-the-art brain organoids having limited reproducibility, scalability, structural accuracy, and therefore applicability; issues that make it challenging to study the diverse cell biology, maturation, and functional interactions among different brain subdivisions.
“Recent studies and our preliminary results strongly suggest that the extrinsic concentration gradient of morphogens can effectively pattern brain organoids,” says Sun. “Here, we aim to efficiently and reproducibly impose such morphogen gradients to human pluripotent stem cell aggregates by developing two novel microdevices that can generate sustained and customized morphogen concentration gradients.”
Sun’s project is in collaboration with a neurobiologist, Dr. ChangHui Pak from the UMass Amherst Department of Biochemistry and Molecular Biology, and has received generous support from the Initiative of Neurosciences (IONs).