Exosomes — small vesicles released by cells that play an important role in cell communication — carry chemical signals that help regulate the function and development of neural circuits and may even reverse some of the abnormal features observed in a cellular model of Rett syndrome, a study has found.
The findings, “Exosomes regulate neurogenesis and circuit assembly,” were published in PNAS.
Rett syndrome is a rare genetic disorder characterized by developmental and intellectual disabilities. The condition is caused by mutations in the MECP2 gene — located on the X chromosome — that provides instructions to make a protein called MeCP2. This protein is responsible for maintaining synapses — the junctions between nerve cells that allow them to communicate.
“Exosomes are thought to be released by all cells in the body and to be involved in intercellular communication. [They have also been] implicated in cancer and neurodegenerative disorders. [However,] their function in brain development [is still not fully understood],” the researchers said.
In this study, researchers from California’s Scripps Research Institute explored the role of exosomes during the development of neural circuits using different preclinical models.
First, to investigate whether exosomes were able to stimulate the proliferation of human neurons cultured in a lab dish, they started by isolating exosomes from neurons derived from human induced pluripotent stem cells (iPSCs) and adding them to cultures. iPSCs are fully matured cells that can be reprogrammed back to a stem cell state, where they are able to grow into almost any type of cell.
“We found that treatment with exosomes increased [formation of new neurons] by promoting cell proliferation and neuronal differentiation, suggesting that exosomes carry signaling components that influence cell fate in developing neural circuits,” they said.
In addition, they found that when they injected purified mice exosomes into one of the brain ventricles of 4-day-old animals, neurons of the hippocampus started to proliferate. Brain ventricles are cavities in the center of the brain that are filled with fluid, while the hippocampus is a brain region responsible for short-term memory.
“Based on these observations that exosomes affect neural circuit development in vitro and in vivo, we hypothesized that conditions that disrupt neural circuit development may arise from defective exosome signaling,” the researchers said.
To test their hypothesis, investigators then isolated exosomes from neurons derived from iPSCs lacking a functional MECP2 gene — a cellular model of Rett syndrome — and compared their contents to those found on exosomes isolated from neurons derived from normal iPSCs, using a technique called quantitative proteomic analysis.
Results showed that exosomes isolated from iPSCs lacking a functional MECP2 gene were missing a series of signaling proteins essential for the development of neural circuits.
Moreover, investigators found that when they stimulated human neurons lacking MECP2 with normal exosomes, they were able to restore their proliferation, differentiation, ability to form synapses, and synchronize their firing activity.
Conversely, in an opposite experiment in which the team stimulated normal human neurons with exosomes that had been isolated from iPSCs lacking MECP2, they found these exosomes were not able to promote neuron proliferation or differentiation.
“These data indicate that exosomes carry signaling information required to regulate neural circuit development. Furthermore, we show that exosomes are able to reverse some of the pathological [signs] observed in MECP2 mutant neurons, indicating that exosomes could have therapeutic applications in brain disorders,” the scientists concluded.