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α4-integrin-positive microvesicles and SDF-1 in peripheral blood stem cell harvest

Cellular microvesicles (MVs) are released by various cell types such as circulating blood cells and cells from the vessel wall during cell activation by agonists and physical stress.1 MVs contribute to many pathophysiologic processes and are able to transfer various receptors. It is previously reported that MVs play a role in SCT.2, 3 In particular, Janowska-Wieczorek et al.2 reported that platelet-derived MVs bind to hematopoietic stem/progenitor cells and enhance their engraftment.

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine and a known chemotactic for lymphocytes and monocytes. SDF-1 is also the predominant chemokine that mobilizes stem/progenitor cells and has been shown to be upregulated in many damaged tissues as part of the injury response.4 In contrast, endothelial progenitor cells are a subtype of BM-derived progenitor cells expressing surface antigens of both hematopoietic stem cells and endothelial cells.5 Recently, Deregibus et al.6 found that endothelial progenitor cell-derived MVs were incorporated in endothelial cells by interaction with α4- and β1-integrins expressed on MV surfaces and suggested that endothelial progenitor cells may activate angiogenesis in endothelial cells by releasing MVs, which are able to trigger an angiogenic program. Some previous experimental studies have suggested that transplantation of stem and progenitor cells may have a beneficial effect on functional and structural recovery in several organs. However, there have been few investigations of the relationship between MVs and SDF-1 during PBSC harvest. We measured the levels of CD42b-negative/α4-integrin-positive MVs, SDF-1 and soluble CD40 ligand in plasma obtained from patients undergoing PBSC harvest.

For mobilization of PBSC, malignant lymphoma patients (n=22) received priming chemotherapy and administration of rhG-CSF. For CD34 assay, a sample of each patient's PBSCs was analyzed by flow cytometry (Cytoron Absolute, Ortho Diagnostic Systems, Tokyo).7 All samples were washed to remove platelets and incubated with two kinds of monoclonal antibody (FITC-α4-integrin and PE-CD42b). MVs were defined as elements <1.5 μ in size with CD42b-negative and α4-integrin-positive.6 We also measured plasma levels of SDF-1 (R&D Systems, Mineapolis MN. USA) and soluble CD40 ligand (Chemicon International Inc., Temecula, CA, USA). We compared samples on days 0 and 5 after rhG-CSF treatment; numbers of CD34-positive cells peaked on day 5 (days 0 vs 5; 3.2±0.8 vs 77.9±8.4/μl, respectively, P<0.0001; Figure 1). MVs, SDF-1 and soluble CD40 ligand exhibited the same changes (days 0 vs 5: MVs, respectively, 219±35 vs 492±53/μl, P<0.01; SDF-1, 1.219±271 vs 1.789±430 pg/ml, P<0.05; soluble CD40 ligand, 1.8±0.4 vs 4.1±0.6 ng/ml, P<0.01; Figure 1).

Figure 1
figure1

Changes in CD34+ cells (/μl), α4-integrin-positive MVs (/μl), SDF-1 (pg/ml) and sCD40L (ng/ml) on days 0, 3 and 5 after PBSC harvest. Controls were 15 healthy blood donors. Error bars represent +standard deviation. Student's t-test was used for statistical comparisons. CNT=cintrol; MV=microvesicle; SDF-1=stromal cell-derived factor-1; sCD40L=soluble CD40 ligand.

Janowska-Wieczorek et al.8 suggested that MVs actively released from cells may have an important role in cell-to-cell communication. The reports by Deregibus et al.6 and Ratajczak et al.9 have developed this view. In particular, the indication that MVs may deliver mRNA to target cells is very interesting, as MVs express surface molecules characteristic of the original cells. Although we observed that CD42b-negative/α4-integrin-positive MVs exhibited the same changes as SDF-1 and soluble CD40 ligand in company with an increase of CD34+ stem cells during PBSC harvest, the importance of our findings is presently unclear both for the mechanism of mobilization and for events post transplantation. However, SDF-1 has a major role in the pathology of tissue repair, and α4-integrin contributes to hematopoietic progenitor cell recruitment into BM following transplantation.10 Therefore, CD42b-negative/α4-integrin-positive MVs are possible to have an unique role in SCT. Further investigation is necessary to better elucidate this possibility.

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Nomura, S., Ishii, K., Inami, N. et al. α4-integrin-positive microvesicles and SDF-1 in peripheral blood stem cell harvest. Bone Marrow Transplant 41, 1071–1072 (2008). https://doi.org/10.1038/bmt.2008.38

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