Watch immune cells 'glue' broken blood vessels back together

Watch immune cells 'glue' broken blood vessels back together

As we age, tiny blood vessels in the brain stiffen and sometimes rupture, causing "microbleeds." This damage has been associated with neurodegenerative diseases and cognitive decline, but whether the brain can naturally repair itself beyond growing new blood-vessel tissue has been unknown. A zebrafish study published on May 3 in Immunity describes for the first time how white blood cells called macrophages can grab the broken ends of a blood vessel and stick them back together.

"Microbleeding occurs very often in the human brain, particularly in elderly people," says Lingfei Luo, a developmental geneticist at Southwest University in China. "We believe that this macrophage behavior is the major cellular mechanism to ruptures of blood vessels and avoid microbleeding in the brain."

To simulate a human brain microbleed, Luo and his colleagues shot lasers into the brains of live zebrafish to rupture small blood vessels, creating a clean split in the tissue with two broken ends. Then, the researchers used a specialized microscope to watch what happened next.

The repair process started about a half hour after the laser injury. A macrophage showed up at the damaged blood vessel site and extended two "arms" from its body toward the ends of the broken blood vessel, producing a variety of to attach itself. Then, it pulled the two broken ends together to mediate their repair. The researchers suspect that adhesion molecules produced by the blood-vessel tissue also play a role in reattachment. Once they were adhered, the macrophage left the scene. The whole process took about three hours.

Irradiation from a multi-photon laser on the brain's vascular endothelial cells (green) leads to rupture of the blood vessel and cerebral hemorrhage (red). White asterisk indicates the pulse of multi-photon laser irradiation. Red circle indicates the irradiation site. Duration of imaging is 20 seconds. Credit: Liu et al./Immunity 2016

"At the beginning, we weren't sure this was a repairing behavior," says Chi Liu, a PhD student at Southwest University. "After we confirmed that the macrophage mediates this repair through direct physical adhesion and generation of mechanical traction forces, we were excited. This is a previously unexpected role of macrophages."

A similar repair process also occurred outside the brain. When the researchers ruptured a blood vessel in the zebrafish fin using a laser, a macrophage arrived at the injury site and extended its protrusions to pull the broken blood vessel back together.

The researchers did observe a few quirks in the process. When they used a laser strike to destroy the first macrophage that arrived at a laser-wound site in the brain, no other macrophages came to help repair the breakage (but another macrophage arrived to eat the dead one). Rarely, two macrophages would arrive at the injury on their own, each grab a broken end of the blood vessel, and then simply disengage without fixing the damage.

After the cerebrovascular rupture, a macrophage (green) migrates to the lesion, extends protrusions (arrowhead), adheres to and pulls the ends of the blood vessel (orange) together, and finally leaves the lesion when the repair is accomplished. Duration of imaging is 285 minutes. Credit: Liu et al./Immunity 2016

Macrophages aren't the brain's only repair mechanism for small broken , though they look to be the fastest and most efficient. When the researchers watched blood-vessel repair in zebrafish that lacked macrophages, they saw the broken ends of the blood vessel slowly extending on their own to connect over a period of six hours.

"Several aspects of vascular development and remodeling, associated with macrophages, are conserved in human and zebrafish," notes Luo. "Microglia [a subset of ] are required for the repair of blood-brain barrier injury in mice, and can be found surrounding most capillary microbleeds in humans. We believe that the macrophage repair system in our study is very much likely replicated in humans and mice."

This movie shows two ruptures in the blood vessels (red). On the left, a macrophage (green) successfully repairs a lesion. On the right, the dangling ends of a broken blood vessel are in contact with two different macrophages. One macrophage eventually departs, leaving the end of the blood vessel, which shrinks (white arrowhead). Duration of imaging is 90 min. Credit: Liu et al./Immunity 2016

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Immune cells in organ cavities play essential role in fast tissue repair

More information: Immunity, Liu et al.: "Macrophages Mediate the Repair of Brain Vascular Rupture through Direct Physical Adhesion and Mechanical Traction" DOI: 10.1016/j.immuni.2016.03.008
Journal information: Immunity

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