Harvard scientists say a recently discovered cellular messaging mechanism might lead to a new approach for delivering therapeutics to diseased tissues. The team, from the Harvard T.H. Chan School of Public Health, found that a type of extracellular vesicle (EV) known as ARMMs, or arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles, also carries receptors that allow signaling without direct contact between cells. This capability may make ARMMs uniquely suited to be engineered to send therapeutics directly to affected areas of the body, according to Quan Lu, Ph.D., associate professor of environmental genetics and pathophysiology.

“EVs are like messages in a bottle between cells,” said Dr. Lu. “We think that within the next few years, we may be able to swap the endogenous molecules in ARMMs for therapeutic cargos—such as antibodies—and to engineer ARMMs to home in on a particular tissue.”

The study (“Plasma Membrane-Derived Extracellular Microvesicles Mediate Non-Canonical Intercellular NOTCH Signaling”) appears in Nature Communications

“ARMMs…are extracellular vesicles that bud directly at the plasma membrane; however, little is known about the molecular composition and physiological function of these vesicles. Here we report that ARMMs contain active NOTCH receptors and mediate a non-canonical intercellular NOTCH signaling,” write the investigators.

“We identify over 100 proteins that are significantly enriched in ARMMs, including ARRDC1, TSG101 and multiple ESCRT complex proteins. About a third of ARMMs-enriched proteins are plasma membrane proteins, including the NOTCH2 receptor. The incorporation of NOTCH2 into ARMMs is facilitated by the ITCH E3 ligase and the metalloprotease ADAM10, both of which are also secreted into ARMMs. NOTCH2 in ARMMs can be delivered into recipient cells, and upon activation by γ-secretase cleavage, induces NOTCH-specific gene expression. Together, our findings reveal a role for ARMMs in a novel NOTCH signaling pathway that acts in distance and is independent of direct cell–cell contact.”

Scientists think that EVs carry molecules that include the fingerprints of disease and harmful environmental exposures, and researchers are looking to develop a liquid biopsy to test EVs in a drop of blood. 

In the current study, the team found that ARMMs contain molecules used for NOTCH signaling, a type of intercellular communication that normally requires cell-to-cell contact. NOTCH receptors are plasma membrane proteins involved in critical physiological roles, such as embryonic development, tissue homeostasis, and stem cell function. According to the new findings, ARMMs are able to facilitate NOTCH receptor signaling at a distance. 

“Our research on ARMMs has tremendous potential for therapeutics and public health,” Dr. Lu said. “It will likely be at least 10 years before we see these methods used in a clinical setting. But the path forward is clear.”

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