New research by NIH investigators demonstrates for the first time that a bone marrow-derived cell, the mast cell, can cause disease in a solid organ through the transmission of small sacs of molecules through the bloodstream. Specifically, the study shows that in people with a rare disorder called systemic mastocytosis, some of these sacs, known as extracellular vesicles, travel from mast cells to liver cells and deliver a protein that causes liver disease. Published online in the Proceedings of the National Academy of Sciences (PNAS) in October, the study adds to a growing body of evidence that extracellular vesicles can enable one type of cell to influence the behavior of an entirely different cell type.
Dean Metcalfe, M.D., chief of the Mast Cell Biology Section in the NIAID Laboratory of Allergic Diseases, and Ana Olivera, Ph.D., a staff scientist in the same laboratory section, led the new research conducted by Do-Kyun Kim, Ph.D., a visiting fellow in the section. The study included 21 patients with systemic mastocytosis and 10 healthy volunteers.
Mastocytosis occurs when a person has too many mast cells. In systemic mastocytosis (SM), mast cells accumulate in internal tissues and organs, such as the liver, and frequently cause disease there.
The researchers found that the concentration of extracellular vesicles in the blood of SM patients was significantly greater than in the blood of healthy volunteers and strongly correlated with levels of biological markers of SM. The scientists also found that the extracellular vesicles in SM patients contained proteins that are hallmarks of mast cells, demonstrating that most of the vesicles originated there.
To investigate whether mast-cell-derived extracellular vesicles play a role in liver disease in people with SM, the researchers examined the interaction of these vesicles with a type of liver cell called a hepatic stellate cell (HSC). Activated HSCs are a primary driver of liver fibrosis, a condition in which the liver becomes scarred and therefore cannot work as well as it normally would. The scientists demonstrated in cell culture that mast-cell-derived extracellular vesicles from SM patients (SM-EVs) were taken up by HSCs, inducing the cells to proliferate and differentiate into fibrosis-producing cells.
Next, the scientists investigated the role of a mast-cell protein called KIT in this process. Mutations in the gene that codes for KIT usually cause SM. The researchers showed that HSCs did not produce KIT proteins. Rather, the cells acquired KIT after treatment with SM-EVs but not with vesicles from healthy volunteers. The scientists also demonstrated that other cell types that took up SM-EVs did not acquire KIT—the protein expression was specific to HSCs. Then the researchers showed that inhibiting KIT suppressed the activation of HSCs by SM-EVs. Finally, the scientists injected human SM-EVs into mice and demonstrated that HSCs took up human KIT from the vesicles, and fibers accumulated in the liver around the HSCs.
Taken together, the findings suggest that in patients with SM, extracellular vesicles shuttle aberrant KIT from mast cells into HSCs, driving them to proliferate and differentiate, and this process promotes liver fibrosis. The study further suggests that preventing HSCs from taking up SM-EVs may help prevent liver disease in these patients.
Reference: D-K Kim, et al. Mastocytosis-derived extracellular vesicles exhibit a mast cell signature, transfer KIT to stellate cells, and promote their activation. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1809938115 (2018).