The motivation for the current study rested on two landmark papers published in the 1960s. The first laid the foundation that HSPC circulate in the blood rather than simply reside in the bone marrow35
, whereas the second argued that, in the steady state, the bone marrow is the exclusive monocyte production site.36
Multiple studies since have enriched our understanding of these processes. Extramedullary hematopoiesis occurs in development and in a number of genetic and myeloproliferative conditions.37–41
It involves several discrete steps: first, bone marrow HSPC mobilize; second, mobilized HSPC seed extramedullary sites; third, seeded HSPC proliferate and mature. The cell types that have been described to arise through extramedullary hematopoiesis are terminally-differentiated, and many are tissue-resident. Monocytes, on the other hand, are intermediate, circulating cells, developmentally downstream of HSPC but upstream of dendritic cells and macrophages.2
Our study places extramedullary hematopoiesis in a larger context not only because it shows that a GM-CSF and IL-3-rich splenic environment can produce monocytes and neutrophils that then circulate, but also because it illustrates an extramedullary cascade in which HSPC proliferation, differentiation and terminal maturation are comparmentalized in different organs. In atherosclerosis, our data imply, the bone marrow outsources the production of circulating leukocytes.
Of all the organs, the spleen may be an ideal outsource destination. The organ has an open circulation, allowing for fast exchange with the blood23
, yet it is capable of cell retention through a myriad of adhesive ligands.42, 43
The organ can accomodate vast quantities and fluctuations of cells, especially in the red pulp. It also allows for rapid exit of undifferentiated monocytes, indicating that entry into its parenchyma neither forces differentiation nor precludes recirculation.17
Thus, location, elasticity and architecture render the spleen a perfect seeding ground for the emergency production of inflammatory cells.
It is unknown whether extramedullary hematopoiesis is important in the development of human atherosclerosis. The extent to which the spleen contributes to disease, however, has received some attention. The organ may be dispensable, but it is not unimportant. In humans, splenectomy heightens the risk of infection and ischemic heart disease, probably due to multiple mechanisms involving platelets, B cells, T cells and many of the other components that constitue the organ.44
The observations made here in response to hypercholesterolemia or endotoxin indicate a role for the spleen in supplying Ly-6Chigh
monocytes, which are known to be inflammatory and proteolytic. We show that, by eliminating this splenic source, lesions become less cellular although how this particular profile translates to lesion stability requires further study. Future studies will also need to elucidate how specific splenic functions can be targeted therapeutically and how other functions, such as the protective function of B1 B cells24
can be spared.
That extramedullary generation of Ly-6Chigh monocytes monocytes occurs during atherosclerosis, when hypercholesterolemia forces a continuous leukocyte supply, is worth further discussion. The steady-state spleen houses a reservoir of undifferentiated monocytes which are, in the absence of neighboring splenic HSPC, bone marrow-derived. Extramedullary monocytopoiesis’ contribution during inflammation may be exclusively numerical: with repetitive demand the organism outsources the production of otherwise identical cells. Alternatively, splenic monocytes, produced in an inflammatory GM-CSF and IL-3-rich environment, may differ qualitatively from their medullary counterparts. In the present study we show that monocytes born in extramedullary sites belong to the inflammatory subset, express cytokines, reactive oxygen species, and proteases. They are thus functional and are known to promote the generation of lesions. Future studies will need to determine whether splenic birth or experience influences these cells in additional ways.
HSPC mobilization is important to immunosurveillance and likely plays a role in bone-marrow niche reconstruction.5, 45
HSPC differentiation in extramedullary sites may be essential to the replenishment of dendritic cells and macrophages.46
The extramedullary HSPC production of circulating cells, we now show, contributes importantly to inflammatory diseases. This shift in the hematopoietic topographical hierarchy during inflammation is likely to have significant biological, diagnostic, and therapeutic implications.