Macrophages Physically Relay Signals Between Cell Types

Time-lapse imaging shows the immune cells transferring chemical signals during pigment pattern formation in developing zebrafish.

By | May 1, 2017

CELL ESCORT: As they mature, zebrafish develop a pattern of black stripes made up of dark pigmented cells called melanophores. Researchers have now shown that organization of the pattern is achieved by the ferrying activity of immune cells called macrophages. First, xanthoblasts (orange)—precursors to yellow pigment cells residing in zebrafish skin—form vesicles (red) filled with signaling molecules at their surface (1). Then, macrophages (blue) pick up these vesicles, which remain attached to xanthoblasts by thin filaments (2). On encountering a melanophore (black), the macrophage deposits its cargo on the surface of the pigment cell (3). This long-distance communication represents an entirely new function for macrophages. ZEBRAFISH © ISTOCK.COM/MIRKO_ROSENAU

The paper
D.S. Eom, D.M. Parichy, “A macrophage relay for long-distance signaling during postembryonic tissue remodeling,” Science, doi:10.1126/science.aal2745, 2017.

Macrophages are increasingly appreciated as important mediators of many physiological processes, from homeostasis to tissue remodeling. But the recent discovery of a new role for the immune cells comes from an unexpected source: the stripes that give zebrafish their name.

Widely used as a model organism for developmental biology because the young are transparent, Danio rerio as adults have a characteristic black-and-yellow striping that runs the lengths of their bodies. “Nobody really pays much attention to the later stages” of the fish’s development, says University of Virginia biologist David Parichy. “But for years, [our lab] has worked on pigmentation and pattern formation.”

Zebrafish pigmentation is directed by precursors to the skin’s yellow-pigment cells called xanthoblasts. During development, these cells produce long, thin filaments tipped with vesicles containing signaling molecules that land on black-pigment cells called melanophores; once docked, these vesicles help arrange melanophores into orderly black stripes.

Last year, while using time-lapse imaging to watch labeled vesicles, Parichy and Dae Seok Eom, his colleague at the University of Washington, were struck by the peculiar way they moved. “These things were so weird,” says Parichy. “They cruise around like they have a mind of their own. Looking at them, we started to think, well, maybe there’s something tractoring them around.”

The vesicles’ wanderings were reminiscent of another cell type: the macrophage. Indeed, when the pair depleted macrophages in baby zebrafish, they found that abnormal dark blotches appeared between the black stripes, indicating communication failure between xanthoblasts and melanophores.

Further time-lapse imaging in normal zebrafish—this time with macrophages also labeled—revealed what was going on: the immune cells were engulfing xanthoblast vesicles and dragging them around intact. Then, on encountering a melanophore, each macrophage deposited its cargo and wandered off elsewhere.

The study provides the first evidence of macrophages physically transferring a signal in this way, notes Richard Lang of Cincinnati Children’s Hospital. “From a technical perspective, it’s quite gorgeous,” he says. “The images give you a really important insight into the way this works.”

The researchers proposed how macrophages might identify the vesicles, too. A phospholipid called phosphatidylserine—a well-known “eat me” signal recognized by macrophages—is concentrated on xanthoblasts’ vesicle-forming surfaces, and fewer filaments extend from xanthoblasts in its absence. Perhaps phosphatidylserine was coopted by these vesicles to hitch a ride with macrophages, says Parichy, noting a colleague’s suggestion that as vesicles are not degraded during the process, a more appropriate descriptor for this signal could be, “bite me.”

For now, many parts of the mechanism remain unclear. Nevertheless, the research prompts reflection on whether other systems might use this sort of signaling. “It could be a fish-specific thing,” says Parichy, “but I doubt it.” Lang, who studies vascular system organization, says one could imagine “anything that requires a regular pattern” involving something similar. “It’s a fascinating beginning to an unusual story.”

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