In this era of online shopping and digital marketplaces, we all know the joy and satisfaction when our packages arrive on time. Well, at the cellular level, there is also a parcel delivery service, which often satisfies the needs of neighboring cells that are in the developmental process. These molecular packets, called exosomes, are continuously deployed from all cells in the body—each one brimming with an assortment of contents that another cell may unpack and use. By sending off these biological parcels, cells communicate with each other via shared proteins and genetic material.
Now, investigators at the Scripps Research Institute have published new data showing that exosomes are not only integral to the development of neurons and neural circuits, but they can restore health to brain cells affected by developmental disease. Findings from the new study were published recently in PNAS through an article titled, “Exosomes regulate neurogenesis and circuit assembly.”
Once simply thought to be microscopic sacks of cellular “garbage,” exosomes are now understood to hold immense importance for our health. An outflowing of research in recent years has even shown they can transport molecules that are linked to the spread of cancer and neurodegenerative disorders such as Alzheimer’s. Yet, until recently, their role in brain development remained a mystery.
“During different stages of brain development, signaling between cells is absolutely essential,” explained senior study investigator Hollis Cline, PhD, co-chair of the department of neuroscience at Scripps Research and director of the Dorris Neuroscience Center. “We found that exosomes are one of the ways cells communicate these signals.”
Exosomes are a type of vesicle tasked specifically with transporting various biological cargo—lipids, proteins, RNA—from one cell to another. Cline’s research determined that proteins, in particular, were responsible for the cell-to-cell signaling capabilities of exosomes. In this current study, the research team examined exosomes from healthy human neurons and those from a disease model of Rett syndrome, a genetically-driven, developmental brain disorder that causes autism-like symptoms.
Experiments were designed to clearly identify and compare exosome bioactivity from healthy neurons and diseased neurons. Through multiple cellular and functional assays, they found that the Rett-affected exosomes didn’t contain any harmful proteins, but also didn’t have essential signaling proteins found in healthy exosomes.
“They did not have bad stuff, but lacked the good stuff,” noted lead study investigator Pranav Sharma, PhD, a neuroscientist in Cline’s lab.
Additionally, the team used CRISPR gene-editing technology to correct the mutation that causes Rett syndrome, and then examined whether the signaling functions of the neural exosomes were restored as a result. “Fixing the mutation reversed the deficits,” Sharma stated.
“We tested whether neural exosomes can regulate the development of neural circuits. We show that exosome treatment increases proliferation in developing neural cultures and in vivo in the dentate gyrus of P4 mouse brain,” the authors wrote. “We compared the protein cargo and signaling bioactivity of exosomes released by hiPSC-derived neural cultures lacking MECP2, a model of the neurodevelopmental disorder Rett syndrome, with exosomes released by isogenic rescue control neural cultures. Quantitative proteomic analysis indicates that control exosomes contain multiple functional signaling networks known to be important for neuronal circuit development. Treating MECP2-knockdown human primary neural cultures with control exosomes rescue deficits in neuronal proliferation, differentiation, synaptogenesis, and synchronized firing, whereas exosomes from MECP2-deficient hiPSC neural cultures lack this capability.”
Amazingly, the researchers also tested whether adding healthy exosomes to a culture-dish model of Rett syndrome would provide a therapeutic effect. It did.
“That was perhaps our most exciting finding: that exosomes from healthy cells can indeed rescue neurodevelopmental deficiencies in cells with Rett syndrome,” Cline remarked. “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.”
Interestingly, the investigators also injected healthy exosomes into a mouse hippocampus—a brain region involved in learning and memory—and observed increased neuron proliferation. This in vivo facet of the study proved that the exosome bioactivity seen in cell cultures carried over to an animal model.
Armed with their remarkable findings, Cline and her team now intend to dig deeper into their results and explore a slew of new questions related to exosome bioactivity and potential clinical applications: Could exosomes be measured in a blood test to detect disease or treatment efficacy? Do these findings also apply to autism spectrum disorders (ASDs) and other neurodevelopmental diseases, such as Fragile X? Could exosome-based therapies one day help patients with brain disorders?
“This research has huge relevance for many diseases related to brain development,” Cline concluded. “It’s very interesting biology that has a lot of scientists excited about the possibilities.”