SDF-1 directs megakaryocyte relocation

In this issue of Blood, Niswander et al answer the questions: (1) Does stromal cell-derived factor 1 (SDF-1) direct megakaryocyte spatial distribution in the bone marrow? and (2) What effect does local SDF-1 concentration have on platelet output?¹  If José Arcadio Buendía in One Hundred Years of Solitude²  had followed SDF-1, as megakaryocytes do, perhaps he would not have wandered the jungle for so long before founding Macondo at the riverside. Although we may never know what drew José Buendía to his city at the water's edge, megakaryocytes (parent cells to circulating blood platelets) appear to follow a chemotactic SDF-1 gradient as they migrate through the bone marrow endosteum to rest adjacent to sinusoidal blood vessels. There, they extend and sequentially release platelets, and larger preplatelet/proplatelet intermediates into the circulating blood. Although the physiological triggers governing platelet production from megakaryocytes are still being resolved, it is certain that without direct access to the bloodstream, megakaryocytes cannot produce the roughly 1000 to 2000 individual platelets that are so critical to clot formation and blood vessel repair.

There are a number of reasons to suspect that SDF-1 regulates platelet production. Sustained elevation of SDF-1 in the blood increases megakaryocyte association with the vasculature,^3,4  (see panel A) which is also caused by vascular endothelial growth factor receptor A-mediated upregulation of CXCR4 (SDF-1 receptor) on megakaryocytes.⁵  Both instances are linked to increased platelet production (thrombopoiesis). Indeed, SDF-1 was among the first chemokines to be implicated in megakaryocyte maturational chemotaxis to the vascular niche (traditionally considered to be the microenvironment immediately surrounding blood vessels).⁶  It has also been known for some time that SDF-1 signaling occurs through the CXCR4 membrane receptor, which becomes polarized along the SDF-1 gradient—presumably directing megakaryocyte migration. Although there are several cell types (eg, osteoblasts, endothelial cells, perivascular mesenchymal stromal cells) in the bone marrow that produce SDF-1, osteoblasts, endothelial cells, and perivascular mesenchymal stromal cells being chief among them, the acute and endogenous effects of SDF-1 on megakaryocyte localization, and more importantly, platelet production, have remained unclear.

In this study, the authors show that intravenous administration of SDF-1 and stabilization of endogenous SDF-1 increase megakaryocyte-vascular association and thrombopoiesis¹  (see panel C). Furthermore, in the setting of radiation injury, there is a reversal in the SDF-1 concentration gradient toward the endosteum that correlates with increased megakaryocyte occupancy of this bone marrow space and decreased circulating platelet counts (see panel B). SDF-1 does not appear to affect total megakaryocyte number. The authors demonstrate this through a series of elegant experiments that leverage megakaryocyte progenitor colony assays, flow cytometry, and immunohistochemistry of murine femurs to quantify megakaryocyte differentiation and platelet production, and they directly visualize megakaryocyte localization, receptor expression, and migration relative to sinusoidal blood vessels.

Although Niswander et al’s¹  work certainly advances this field, we are inevitably left with further questions. First, what physiological triggers in the vascular niche drive proplatelet extension and platelet release? There is increasing evidence to suggest that cell-cell, cell-matrix, and soluble factor interactions of the bone marrow stroma, as well as vascular shear stresses of circulating blood contribute to megakaryocyte mobilization, proplatelet extension, and platelet formation. Although more recent cell culture approaches have shed new light on the environmental determinants of platelet production, they have been unable to recreate the entire bone marrow microenvironment, exhibiting limited individual control of extracellular matrix composition,⁷  bone marrow stiffness, endothelial cell contacts,^4,8  or vascular shear rates⁹ ; they have been unsuccessful also in synchronizing proplatelet production, resulting in nonuniform platelet release over a period of 6 to 8 days. It is equally unclear what role megakaryocytes are playing in the endosteum after radiation damage. We know megakaryocytes express extracellular matrix proteins such as fibronectin, type IV collagen, and laminin, as well as multiple cytokines and growth factors, which they can release in the bone marrow.¹⁰  After radiation damage, it is likely that megakaryocytes are recruited to damaged bone marrow, where they help reconstruct the surrounding matrix and promote osteoblastic hematopoietic stem cell niche expansion and stem cell engraftment.¹¹  Indeed, total body irradiation-induced migration of megakaryocytes to the endosteal niche depends on thrombopoietin (TPO) signaling through the c-MPL receptor on megakaryocytes, as well as CD41 integrin-mediated adhesion.¹¹ 

The clinical implications are significant. Niswander et al’s¹  work suggests that regulation of vascular SDF-1 concentration could be used to increase platelet production after radiation injury. The authors show that SDF-1 administration can improve radiation-induced thrombocytopenia in a manner that is additive with earlier TPO treatment. This is important because TPO supports megakaryocyte differentiation from hematopoietic stem cells in the bone marrow, although it does not promote proplatelet production or platelet release. As a result, all TPO mimetics must inevitably work within the same time line (ie, 5 days to increase platelet counts and 12 days to reach maximal effect). In principle, direct stimulation of megakaryocyte migration to the vascular niche may initiate platelet production sooner and could result in a more rapid “auto-transfusion” that complements TPO-based treatments. A system this complex does not operate without balance, and clinical advances on this front must be considered in the context of the putative role megakaryocytes may be playing in the endosteum after radiation treatment. As with the Buendía family, deciphering the functional roles of megakaryocytes in different compartments of the bone marrow may take us generations, but it is certain that the answer to our platelet fortunes and misfortunes are buried in this subtext.