Scientists have built all kinds of human tissue models to help them understand disease progression, optimize drug discovery, and even to regenerate diseased organs. A Tufts University-led team has now developed 3D models of the central nervous system that could aid future research into neurodegenerative diseases like Alzheimer’s.
Rather than using human neurons, the Tufts team used human-induced pluripotent stem cells (iPSCs) to build their models. The resulting models carried the key structural and functional features of the brain and maintained neural activity for at least nine months, the team reported in the journal ACS Biomaterials Science & Engineering.
Because they observed similar cell growth and gene expression in tissue models built with source cells from patients with Alzheimer’s disease and Parkinson’s disease, the researchers believe their approach opens another door for examining CNS disease and response to treatments.
“The growth of neural networks is sustained and very consistent in the 3D tissue models, whether we use cells from healthy individuals or cells from patients with Alzheimer’s or Parkinson’s disease,” said the study’s first author, William Cantley, in a statement. “That gives us a reliable platform to study different disease conditions and the ability to observe what happens to the cells over the long term.”
Previous CNS models were challenging to build, due to a limited supply of human neurons. Those donated neurons had to be retrieved from patients after they passed away. iPSCs, on the other hand, can be generated from a wide range of adult cells in plentiful sources like skin. Those cells can be reprogrammed into an embryonic-like stem cell phase and then turned into many different types of cells, including neurons. One advantage is that these reprogrammed cells still carry the defects from the patient source, providing a way to gain insight into particular diseases.
There have been other iPSC-derived mini-brains, but they usually have cells clutched together, making it difficult to single out individual cells for observation in real time, according to the Tufts team. And cells in the center of such models may not get enough oxygen or nutrients to function properly.
The 3D scaffold the Tufts team made consisted of collagen and silk protein, materials that provide moisture retention and skin adhesion, so it successfully overcame those limitations. “The silk-collagen scaffolds provide the right environment to produce cells with the genetic signatures and electrical signaling found in native neuronal tissues,” study lead author David Kaplan said in the statement.
Stem cells have been widely used to create other mini-organs, or organoids. Tufts University itself has used the silk structure to create 3D model of the human small intestine, which they hope could be used to study inflammatory bowel disease. A team from Cincinnati Children’s recently grew esophageal organoids entirely from stem cells.
The Tufts-built CNS models will make it possible to “uncover early-stage biomarkers of the disease state supporting earlier diagnosis, improving understanding of disease progression," they wrote in the study. As they perfect the models, they hope they will be able to be used for investigating drug targets in neurodegenerative diseases.
In the future, the researchers plan to apply their methods to other cell types, such as microglia and endothelial cells, to create a more complete model of the brain environment that embodies complex cell interactions.