Human stem cells transformed to mimic early nervous system

The findings published in the journal Nature showed a 3D human organoid, demonstrating stem cell cultures that mimic essential structural and functional features of human organ systems, albeit as incomplete or imperfect replicas.

"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, U-M professor of mechanical engineering and corresponding author of the study.

"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 and Hongjun Song, Perelman Professors of Neuroscience at UPenn and co-authors of the study. They developed protocols for growing and guiding the cells and characterized the structural and cellular characteristics of the model.

Organoids developed using patient-derived stem cells may be used for identifying which drugs offer the most successful treatment. Human brain and spinal cord organoids are being used to study neurological and neuropsychiatric diseases, but they often mimic one part of the central nervous system and are disorganized. The new model, in contrast, recapitulates the development of all three sections of embryonic brain and spinal cord simultaneously.

The model began with stem cells resembling the neural tube of a 4-week-old embryo, adhered to a chip with channels for growth guidance. Adding a gel enabled three-dimensional growth, while chemical signals directed cells to become neural precursors, forming a tubular structure. Further signals prompted cell specialization, mimicking forebrain, midbrain, hindbrain, and spinal cord development over 40 days, akin to 11 weeks post-fertilization. This allowed the team to study gene roles in spinal cord development and cell differentiation in the early human nervous system.

"The system itself is really groundbreaking," said Orly Reiner, the Berstein-Mason Professorial Chair of Neurochemistry at Weizmann and co-author of the study who developed cellular tools to identify neural cell types in the model. "A model that mimics this structure and organization has not been done before, and it offers numerous possibilities for studying human brain development and especially developmental brain diseases."

Reference: A patterned human neural tube model using microfluidic gradients (DOI: 10.1038/s41586-024-07204-7)