By Nelson Chao, MD

2009-07-01

Dr. Chao indicated no relevant conflicts of interest.

Hooper AT, Butler JM, Nolan DJ et al. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell. 2009;4:263-74.

The bone marrow is an intricate organ that produces the cellular elements found in the blood. The interplay between the hematopoietic stem cells (HSCs) and the cells of its niche has been an area of intense research. The balance between the HSCs, osteoblasts, osteoclasts, osteoMACS (macrophages lining the periosteum), endothelial cells, and reticular cells has been suggested to impact cellular output. These cellular interactions are critical for the recovery from myelosuppression seen with chemotherapy and radiation, especially with hematopoietic stem cell transplantation. Recent data have suggested two possible niches for HSC: an osteoblastic niche and a vascular niche. Whether these two areas are a continuum or distinct remains an area of research.

It is not surprising that the vascular architecture must be re-established after myeloablative injury. In considering what one sees soon after the use of an ablative or myelotoxic regimen, the bone marrow is essentially empty of most cellular elements, and there is extensive hemorrhage and proteinaceous material with loss of fine architecture. As the marrow recovers, the HSCs, committed precursors, and the differentiated cells cannot simply float into the serosanguineous or hemorrhagic areas. There is a highly choreographed process of cellular egress that occurs through the vascular endothelium. As a reminder, the manner in which a platelet fragment appears in the circulation is for megakaryocytes to extrude their processes through a sinusoidal vessel wall, and then shear flow forces break off pieces of the megakaryocte resulting in a circulating platelet. Without this conduit for platelets and other cells, they cannot get into the peripheral circulation. Therefore, the re-establishment of a roadwork or conduit is absolutely necessary before peripheral counts can return to normal.

Hooper et al., from Shahin Rafii’s lab at Cornell, utilized immunohistochemistry and flow cytometry to demonstrate the morphology of the bone marrow vasculature. They were able to differentiate the arterioles from the sinusoidal endothelial cells (SECs) (where about 60% of the HSCs are in close proximity) by using VEGFR3 and Sca1 to distinguish HSCs from SECs. They noted that the SECs are in close proximity to osteoblasts, suggesting that the two niches may not be so distinct. Following characterization of the SEC, the authors then damaged the bone marrow and demonstrated that VEGFR2 and VEGFR3 are differentially expressed during recovery, suggesting that these receptors and their ligands VEGF-A and VEGF-C may be important in regenerating the sinusoidal vasculature. To confirm this, treatment with a monoclonal antibody against VEGFR2 given at the time of recovery resulted in continued hematopoietic defects, including a decrease in marrow cellularity and loss of HSCs and progenitors (with VEGFR3 playing a minor role). These data suggest that there is an endothelial niche regulated by VEGFR2 that is necessary for marrow recovery. It will be interesting to determine whether manipulation of this microenvironment would result in accelerating hematopoietic recovery or increase the numbers of HSCs.

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