Discovery of vascular channels that connect the skull and brain

Following a stroke, inflammation occurs in the brain tissue and immune cells flock to the site of the injury. Inflammation is a key process in tissue repair, and inflammatory molecules draw neutrophils to the site. These cells fulfil a protective role as they defend the body against infection; but they can also cause cellular damage. Neutrophils are known to play a key role in ischaemic injury following a stroke as the brain tissue is starved of oxygen. Recent studies have shown a direct link between influx of neutrophils and severity of brain damage¹.

The response of neutrophils is not just of great interest to stroke researchers who are trying to treat brain injury, but also to those who aim prevent it altogether. These cells are involved in the development of atherosclerosis and thrombosis – conditions that can result in a stroke as blood vessels within the brain become narrowed and blocked.

The number of immune cells in circulation has been found to fluctuate after a stroke, as they are recruited to the ischaemic tissue. Neutrophils are produced in the bone marrow, and it was believed that the cells travelled from the bones of the arms and legs and reached the brain through the bloodstream. However, after inducing a stroke in mice, Dr Nahrendorf and his colleagues from Massachusetts General Hospital and Harvard Medical School discovered that the majority of neutrophils at the injury site had originated in the bone marrow of the skull itself².

They were able to determine the source of the neutrophils by fluorescently tagging cells produced in the tibia and those in the skull. This was achieved using spectrally-resolved cell tracker dyes which were introduced through microinjection into each site. The researchers observed that microinjection slightly reduced cell viability, however, it did not impact on the neutrophils’ ability to migrate to the injury site. The immune cells were counted six hours on from the induced stroke using flow cytometry, revealing far fewer neutrophils in the bone marrow of the skull. This would suggest that this area contributed more cells to the injured tissue.

Contrary to previous belief, this result implies that immune cells responding to ischaemia are not supplied from both production sites equally, and that the response could vary depending on the site of injury. The researchers hypothesised that there must be some communication between the injured brain tissue and the bone marrow of the skull. Due to their close proximity, Dr Nahrendorf’s group used confocal microscopy and an organ bath to examine the interface of the skull and brain, searching for vascular channels. They were able to locate a number of channels connecting the marrow cavity and the dura mater. The flow of blood through these channels was directional towards the cavity, however, following induction of a stroke, neutrophils could be seen migrating against this flow. They passed through the channels, effectively taking a ‘shortcut’ to the injured brain tissue.

This is the first time that scientists have observed channels connecting the bone marrow of the skull to the surface of the central nervous system. The result was confirmed using electron microscopy, where researchers could see that in adult mice, the channels were approximately 22 µm in diameter and connected with vasculature in the dura. These microvascular channels have also been observed in humans by imaging craniectomy specimens. The channels were five times larger than those in mice but researchers have yet to determine whether neutrophils pass through the channels in humans. If they do, this could have implications in a number of neurodegenerative diseases where inflammation is believed to be involved, including multiple sclerosis and Alzheimer’s disease.

References

1. Streker, J-K., Schmidt, A., Schäbitz W-R., Minnerup, J. (2016). Neutrophil granulocytes in cerebral ischemia – Evolution from killers to key players. Neurochemistry International.

2. Herisson, F., Frodermann, V., Courties, G., Rohde, D., Sun, Y., Vandoorne, K., Wojtkiewicz, G.R., Masson, G., Vinegoni, C., Kim, J., Dong-Eog, K., Weissleder, R., Swirski, F.K., Moskowitz, M.A., Nahrendorf, M. (2018). Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nature Neuroscience.

Banner image credit: Herrison et al./Nature Neuroscience

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