The Vascular Network

As for other vasculatures throughout the body, the BM vasculature is a network of arteries, arterioles, capillaries, and veins. However, there is a structure highly specific for the BM, which is the marrow sinus that connects capillaries to the venous system.

The Network

In mouse long bones, the arterial blood supply comes from two sources. The first source is the nutrient artery that penetrates the bony cortex through the nutrient canal. In the marrow cavity it bifurcates into ascending and descending arteries, which give rise to radial branches that travel to the inner surface of the cortex and penetrate it. In the cortex, they become capillaries forming the bone canalicular system, then reenter the marrow parenchyma where they give rise to the branching network of marrow sinuses. Blood from the sinuses is collected in a larger, central sinus from which emissary veins depart, crossing back the cortex to enter the systemic venous circulation. The second source of blood supply is derived from muscular arteries giving rise to periosteal capillaries that enter the cortex, where they anastomose with the radial capillaries issuing from the nutrient artery.

In long bones (in particular in rodents where they have been extensively studied), the concentric structure of the vascular network is conspicuous, with vessels running along the bone longitudinal axis, that is, the nutrient artery and the central sinus. However, in flat bones and in vertebrae, the marrow vascular network appears to be more complex, bony trabeculae of significant thickness being found within the central region and large sinuses being observed in the immediate juxtaosseous region.

BM arteries and arterioles are similar to structures found in other tissues, comprising an intima, a media, and an adventitia. The intima is made of endothelial cells (ECs). The media comprise one or several layer(s) of vascular smooth muscle cells (VSMCs). The adventitia is made of loose connective tissue, with often nerve structures. In mice, a particular cell type, the periarterial adventitial cell, concentrically surrounds both nerves and arterioles.

BM capillaries comprise, as for other capillaries throughout the body, an endothelial lining and, on the abluminal or adventitial side of the ECs, pericytes forming a discontinuous cover.

Sinuses are usually small (5 to 30 mm in diameter in mouse long bones, but they may be larger in human flat bones). They are made of an endothelial lining flanked on the abluminal side by cells with VSMC characteristics. These abluminal cells are called by different names— adventitial reticular cells, myoid cells, barrier cells— depending on the author who first described them. Abluminal cells are separated from ECs by a thin and interrupted basement membrane.

The Cells

ECs express, as usual, the membrane antigens CD31 and CD34 and, in the cytoplasm, the von Willebrand factor. Sinusal ECs are broad and flattened with often overlapping and interdigitated junctions. In some cells, away from the prominent nucleus, the cytoplasm thickness may attenuate to a diameter approaching that of a double plasma membrane, forming fenestrae with a diaphragm. The looseness of the junctions, the presence of fenestrae, and the interrupted underlying basement membrane are features specific for the BM sinus endothelial lining.

VSMCs contain, as usual, myofibers expressing alpha-SM actin (ASMA). Pericytes also express ASMA. Ablumi-nal cells from BM sinuses are all believed to be contractile cells akin to VSMCs: Adventitial reticular cells contain bundles of microfilaments, myoid cells are ASMA-positive, and barrier cells are similar to wound-healing myofibroblasts. Abluminal cells are flattened cells covering, in the unperturbed mouse, approximately 65 percent of the endothelial abluminal surface. However, in situations of stress or in leukemias the coverage may substantially decrease. Ablu-minal cells also present long cytoplasmic extensions within the cord, being in contact with many surrounding hematopoietic cells. Some myoid cells might even be observed within the parenchyma, without obvious relation to a BM sinus. Hence, myoid or barrier cells form a network joining one sinus to the other. The network is reinforced in case of stress. In particular, in the mouse after administration of the proinflammatory cytokine interleukin-1, the network extends almost continuously from bone endosteal surfaces to medullary sinuses, coursing within the parenchyma and enveloping hematopoietic cells.

In conclusion, the BM sinus is characterized not only by a particular endothelial lining, but also by a sheath of ablu-minal contractile cells forming a regulated outer vascular coat. The highly specialized cell types found in these specific structures are involved in the regulation of hematopoiesis, that is, both proliferation/differentiation of HSCs and hematopoietic cell trafficking.

The Vasculature during Development

In human long bones, at 6 to 8 gestational weeks (gw), the bone rudiments are entirely cartilaginous. Numerous CD34-positive capillaries are found in the perichondral limb mesenchyme, running parallel to the rudiments. At 8 to 9gw BM cavities appear: chondrolysis is actively proceeding and capillaries invade the rudiments. At 9 to 10.5 gw the vascular bed develops between ossifying trabeculae. In the diaphyseal region loose connective-tissue chambers are observed. They are centered by an arteriole with an intima of CD34-positive cells and a media of ASMA-positive VSMCs. They are limited from the surrounding vascular space by an endothelial lining of CD34-positive cells flanked by ASMA-positive myoid cells. At this stage, these structures, called primary logettes, do not contain hematopoietic cells. At 11 to 15gw hematopoietic cells appear within the primary logettes. The chambers then extend considerably within the diaphyseal vascular space, being attached to the juxtaosseous tissue by a short pedicule. They are now centered by an artery. The number of myoid cells lying in an abluminal position to the outer endothelial lining or observed within the logette increases. Maximal extension of the primary logette is observed by 15 gw. The central artery is on some sections connected to a perforating artery, a situation similar to what is observed in long bones of adult rodents. From gw 16 onward the hematopoietic parenchyma fills almost all the space within the diaphyseal medullary area, hampering the visualization of logettes. It is only after birth that BM human hematopoiesis declines in long bones. In rodents the sequence of events before and after the onset of BM hematopoiesis (by day 16 post-coitus) has not been studied in detail.

In conclusion, vascular structure formation precedes the onset of hematopoiesis and vascular organization appears to be a prerequisite for hematopoiesis.

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