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Cugurra A, Mamuladze T, Rustenhoven J, Dykstra T, Beroshvili G, Greenberg ZJ, Baker W, Papadopoulos Z, Drieu A, Blackburn S, Kanamori M, Brioschi S, Herz J, Schuettpelz LG, Colonna M, Smirnov I, Kipnis J. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science. 2021 Jun 3; PubMed.
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Both manuscripts extend the concept that the bone marrow in the skull is potentially a special place. Small channels crossing the inner shell of the skull connect bone marrow and the meninges. The data from both labs show that these channels are routes of leukocyte migration from the site of production (marrow) to the CNS. The exciting insight is that the channels may serve as a shortcut, or back door, to the CNS, and work from the Colonna and Kipnis labs implicates the channels’ importance in several inflammatory CNS conditions.
I believe that this is potentially a huge breakthrough because it changes our view of the relatively impregnable blood-brain barrier. Who needs the blood if the marrow can provide leukocytes directly? Since we had seen that the channels exist in humans, the implications for inflammatory disorders (and their treatment) cannot be overstated.
View all comments by Matthias NahrendorfUniversity of California, San Francisco
The finding that a pool of B cells and myeloid cells in the meninges derives from local skull and vertebral bone marrow, as opposed to the blood, raises the possibility that specific pools of these immune cells are uniquely primed to target CNS diseases. That these cells can enter the parenchyma during different neuroinflammatory diseases must alter the way we understand the pathophysiology of many different neurological diseases, as well the methods to treat them.
This work raises many important questions that are critical to understand neuroinflammatory diseases. Are there functional differences between local and blood-derived immune cells? Can we target these differences to modulate the immune response to treat diseases such as multiple sclerosis and Alzheimer’s disease? How do these local skull and vertebral reservoirs change during aging? Does every tissue and organ in the body contain a local reservoir of immune cells primed for organ specific function?
View all comments by Richard DanemanStanford University
Together, these papers point to a previously unknown source of immune cells that are poised to augment the brain’s response to injury, inflammation, and disease.
While skull and vertebrae are known sites of blood formation, it was not known that these sites seed the adjacent, protective covering of the brain—the meninges—with immune cells. Both papers used clever and orthogonal methods to show the origin of the meningeal cells; they likely reach the meninges via special bone channels. These channels, which seem to share some similarities to diploic veins in our skulls, suggest that the idea of local bone marrow sources for infiltration into the CNS can be extrapolated from mice to us! The skull- and vertebra-derived pools of local monocytes, neutrophils, and B cells seem to be at the ready to act when things go awry.
These findings may raise more questions than they answer. Are infiltrating immune cells in the brain always from these sources? Are they genetically, or perhaps more importantly, functionally distinct from cells from more distant bone marrow sources? And how is all of this changed in various conditions, especially in times of craniospinal radiation for malignancy, when these cells are presumably wiped out?
These findings could explain discrepancies between the different functions found for microglia and infiltrating cells. Depending on the experimental paradigm, one might imagine different results if one approach favors more distant sources of cells, whilst another more local sources.
Beyond the brain and spinal cord, the work raises the possibility that there is no such thing as one bone marrow source for immune cells; instead, tissues are populated by their own local bone marrow.
View all comments by Mariko BennettThese two papers are each very interesting and raise many questions. I would just add that bone marrow cells called megakaryocytes were found clogging brain capillaries in an autopsy study of some cases of COVID-19 (Nauen et al., 2021).
References:
Nauen DW, Hooper JE, Stewart CM, Solomon IH. Assessing Brain Capillaries in Coronavirus Disease 2019. JAMA Neurol. 2021 Jun 1;78(6):760-762. PubMed.
View all comments by Charles StromeyerUniversity of Southern California
These are two great papers that, in my opinion, challenge and change our current view on immune privilege and immune responses of the CNS. Both studies use comparable state-of-the-art methods and approaches to convincingly show the presence of monocyte and neutrophil pools in the skulls and vertebral bone marrow that closely associate with the CNS and serve as a reservoir for meningeal and CNS myeloid cells (Cugurra et al.) and provide a lymphopoietic niche in the meninges for B cells (Brioschi et al.).
Besides their obvious importance for the pathogenesis and treatment of CNS disorders, it is intriguing to understand more deeply the relationship between peripheral and central pools of these cell types in other disorders, for example hematological diseases and cancer. Are these pools completely differentially regulated, or is there some synchrony? And could they be interchangeable in function if need be? In other words, can peripheral signals mobilize these closely CNS-associated cells to take an active part in non-CNS disorders?
Another question that is also very intriguing to me is whether cues in the skull and vertebrae, compared to, say, the iliac bone, provide different maturation environments to each other, or if they interact.
View all comments by Berislav ZlokovicMake a Comment
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