A multidisciplinary team from Scripps Research (CA, USA) examined exosomes from a disease model of Rett syndrome and from healthy human neurons. Through several experiments, the research team found evidence suggesting exosomes could play an important role in brain circuits, cell signaling and communication.
The research is available to read in the Proceedings of the National Academy of Sciences.
“During different stages of brain development, signaling between cells is absolutely essential,” explained study author Hollis Cline (Scripps Research). “We found that exosomes are one of the ways cells communicate these signals.”
For this study, the team obtained human neurons derived from induced pluripotent stem cells from individuals with Rett syndrome. Cline and her research team collaborated with many others from Scripps Research, in order to gain quantifiable proteomic date needed to characterize the exosomes.
Experiments were designed to identify and compare exosome bioactivity from healthy neurons and Rett-affected neurons. Multiple functional and cellular assays revealed that the Rett-affected exosomes contained none of the essential signaling proteins found in healthy exosomes, but they also contained no harmful proteins.
“They did not have bad stuff, but lacked the good stuff,” said co-author Pranav Sharma (Scripps Research).
Cline and her research team then used CRISPR gene-editing technology to correct the gene mutation that causes Rett syndrome and examined whether the exosomes signaling functions where restored. “Fixing the mutation reversed the deficits,” Sharma stated.
The team also found that adding healthy exosomes to a culture-dish model of Rett syndrome provided a therapeutic effect.
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“That was perhaps our most exciting finding: that exosomes from healthy cells can indeed rescue neurodevelopmental deficiencies in cells with Rett syndrome,” explained Cline. “We see this as very promising because of the many neurodevelopmental disorders in need of a treatment. These are disorders for which we already have a deep understanding of the underlying gene deficiencies but are still lacking a therapy to address the disease itself.”
“The brain is a very complicated organ, and neurons are more complex than normal cells,” said Sharma. “We didn’t want to get lost in the complexity, so we decided on a reductionist approach to test what these vesicles are capable of and what they contain.”
Cline and the team then conducted an in vivo experiment, where they injected healthy exosomes into a mouse hippocampus and observed an increase in neuron proliferation. This important step demonstrated that the exosome bioactivity observed in cell cultures can also be transferred into an animal model.
Looking ahead to future research, the team plan to delve into their results to investigate the clinical applications of exosomes and their bioactivity.
Cline concluded: “This research has huge relevance for many diseases related to brain development. It’s very interesting biology that has a lot of scientists excited about the possibilities.”
Sources: Sharmaa P, Mescic P, Carromeuc C et al. Exosomes regulate neurogenesis and circuit assembly. Proc. Natl Acad. Sci. doi:10.1073/pnas.1902513116 (2019) (Epub ahead of print); www.scripps.edu/news-and-events/press-room/2019/20190719-cline-exosome.html