The first organized stem cell culture model that resembles all three sections of the embryonic brain and spinal cord, and produces a full model of the early stages of the human central nervous system, has been developed by a team of engineers and biologists at the University of Michigan(U-M), the Weizmann Institute of Science, and the University of Pennsylvania (UPenn).
“Models like this will open doors for fundamental research to understand early development of the human central nervous system and how it could go wrong in different disorders,” said Jianping Fu, PhD, professor of mechanical engineering at University of Michigan.
This work is published in Nature in the paper, “A Patterned Human Neural Tube Model Using Microfluidic Gradients.”
“We try to understand not only the basic biology of human brain development, but also diseases—why we have brain-related diseases, their pathology, and how we can come up with effective strategies to treat them,” said Guo-Li Ming, PhD, who along with Hongjun Song, PhD, both Perelman professors of Neuroscience at UPenn, developed protocols for growing and guiding the cells and characterized the structural and cellular characteristics of the model.
Human brain and spinal cord organoids are currently used to study neurological and neuropsychiatric diseases, but they often mimic one part of the central nervous system and are disorganized. More specifically, they “fail to recapitulate neural patterning along both rostral-caudal (R–C) and dorsal-ventral (D–V) axes in a three-dimensional (3D) tubular geometry, a hallmark of NT development.”
This new model, in contrast, recapitulates the development of all three sections of embryonic brain and spinal cord simultaneously—something that has not been achieved in previous models.
While the model is faithful to many aspects of the early development of the brain and spinal cord, the team notes several important differences. For one, neural tube formation—the very first stage of central nervous system development—is very different. The model can’t be used to simulate disorders that stem from improper closure of the neural tube such as spina bifida.
Instead, the model started with a row of stem cells roughly the size of the neural tube found in a four-week-old embryo—about 4 millimeters long and 0.2 millimeters in width. The team stuck the cells to a chip patterned with tiny channels that they used to introduce materials that enabled the stem cells to grow and guided them toward building a central nervous system.
The team then added a gel that allowed the cells to grow in three dimensions and chemical signals that nudged them to become the precursors of neural cells. In response, the cells formed a tubular structure. Next, they introduced chemical signals that helped the cells identify where they were within the structure and progress to more specialized cell types. As a result, the system organized itself to mimic the forebrain, midbrain, hindbrain and spinal cord in a way that mirrors embryonic development.
The cells grew for 40 days, simulating development of the central nervous system to about 11 weeks post-fertilization. In this time, the roles of specific genes in spinal cord development were demonstrated, and uncovered how certain cell types in the early human nervous system differentiate into different cells with specialized functions.
The team plans to apply the model to study different human brain diseases using patient derived stem cells.
Xufeng Xue, PhD, a postdoctoral fellow in mechanical engineering at the University of Michigan hopes to continue using this model to study the interplay among different parts of the brain during development. He is also interested in studying how the brain sends instructions for movement via the spinal cord. This line of inquiry, which could shed new light on disorders like paralysis, would require the neurons to link up into working circuits—something that was not observed in this study.
Insoo Hyun, a bioethicist at the Museum of Science in Boston who was not part of the study, notes that experiments like these are closely scrutinized before they are allowed to move forward. “Research groups must be clear about the scientific question they are trying to answer—and that the degree of development they allow in the model is the minimum to answer the question,” he said.
The model does not include peripheral nerves or functioning neural circuitry—features that are critical for humans’ ability to experience our environment and process that experience.
The system has the potential to advance our knowledge of brain development and developmental brain diseases. It may also be used to test potential treatments. Because it works with stem cells derived from adults, it may be useful for exploring treatment options specific to individual patients.
