The emergence of the calvarial hematopoietic niche in health and disease

Abstract

The diploë region of skull has recently been discovered to act as a myeloid cell reservoir to the underlying meninges. The presence of ossified vascular channels traversing the inner skull of cortex provides a passageway for the cells to traffic from the niche, and CNS-derived antigens traveling through cerebrospinal fluid in a perivascular manner reaches the niche to signal myeloid cell egress. This review will highlight the recent findings establishing this burgeoning field along with the known role this niche plays in CNS aging and disease. It will further highlight the anatomical routes and physiological properties of the vascular structures these cells use for trafficking, spanning from skull to brain parenchyma.

Keywords: B cells; BBB; CSF; T cells; aquaporin-4; arteries; arterioles; astrocytes; blood-brain barrier; bone marrow; calvaria; capillaries; cerebrospinal fluid; glymphatic; hematopoietic; hematopoietic stem cells; monocytes; neutrophils; pericytes; sinusoids; skull bone marrow; smooth muscle cells; venules.

FIGURE 1

Anatomy and physiology of myeloid cell egress from the calvarial bone marrow stem cell niche. (A) Overview of anatomical structures relevant to myeloid cell egress. Starting at top, capillaries (red) and sinusoids (blue) in the diploë region form a vascular network, where sinusoids feed into ossified vascular channels traversing the inner table of skull and feed into the dural layer of the meninges. This dural layer forms the first of three layers, and it is here that sinusoidal structures, such as the superior sagittal sinus (SSS), feed into brain parenchyma. Running alongside and parallel to the SSS are meningeal lymphatic vessels (magenta). Arteries (red) begin their descent in the arachnoid (second meningeal layer), which contains the cerebrospinal fluid (cyan)‐filled subarachnoid space. As they penetrate through the inner meningeal, or pial layer, they are surrounded by the Virchow–Robin space, which is a continuation of the subarachnoid space. Surrounding and meeting this space beginning at the pial layer are astrocyte endfeet, which form the glia limitans (not shown here). As arteries dive deeper into brain, they transition to smaller arterioles, precapillary arterioles, capillaries, postcapillary venules, and finally ascending venules. Note that CSF flow (indicated in cyan and cyan arrow) flow perivascularly from arteries to venules, eventually reaching the skull bone marrow niche. (B) Arterioles (red) in the diploë region maintain hematopoietic stem cells in a quiescent state. These cells can differentiate into monocytes, neutrophils, and B cells, which can traffic along sinusoids and through ossified channels in the inner table of skull to the underlying dural layer. T cells (orange) are largely localized to sinusoidal regions within the dural layer. (C) CSF flow (cyan) progresses from arteries to venules through convective flow. Arteriole pulsatility and aquaporin 4‐expression (cyan) on astrocyte endfeet are vital to CSF flow. Note that vascular mural coverage varies in morphology as one progresses through various vascular zones. Ring‐like and fast contractile smooth muscle cells on arteries and arterioles transition to ensheathing pericytes (yellow) on precapillary arterioles, and eventually to mesh and thin strand pericytes. Smooth muscle cells are also located on ascending venules, but their morphology differs from that of arteries and arterioles. Postcapillary ascending venules are also the site of immune cell entrance into CNS parenchyma. For a reference on mural cell morphology and vessel size along the vascular tree in brain parenchyma, see Hill et al.