Stem cell transplantation is used to reconstitute bone marrow function after high-dose chemo- or radiotherapy. After reinfusion, CD34+ hematopoietic progenitor cells migrate to the bone marrow, a process called homing. Stromal cell-derived factor-1 (SDF-1) is a chemokine produced by bone marrow stromal cells that induces migration of CD34+ cells. In this study we compared spontaneous and SDF-1-induced migration of CD34+ cells from bone marrow (BM), peripheral blood (PB) and cord blood (CB) across Transwell filters. Under all circumstances, CB-CD34+ cells showed significantly more migration than did BM- or PB-CD34+ cells. SDF-1 induced migration of BM-CD34+ cells was higher than that of PB-CD34+ cells, possibly due to differences in sensitivity towards SDF-1. Indeed, PB-CD34+cells showed a significantly lower expression of the receptor for SDF-1 (CXCR-4) than did BM- and CB-CD34+ cells. The sensitivity to SDF-1, as measured by migration towards different concentrations of SDF-1, was identical for BM- and CB-derived CD34+ cells, consistent with expression levels of CXCR-4 by these cells. Coating of the filters with the extracellular matrix protein fibronectin (FN) strongly enhanced the SDF-1-induced migration of PB-CD34+ cells (2.5 times) and of BM-CD34+ cells (1.5 times). SDF-1 induced migration of PB-CD34+ cells over FN-coated filters was blocked by antibodies against beta1-integrins.
Next, we analyzed whether SDF-1 preferentially promoted migration of subsets of CD34+ cells. Actively cycling CD34+cells, which were present in BM (14%) but hardly in PB (2.2%) or CB (1.2%), were found to migrate preferentially towards SDF-1. In the input, 14 ± 2.5% of the BM-CD34+ cells were in G2/M and S phase, whereas in the migrated fraction 20 ± 5.7% of the cells were actively cycling. We did not observe preferential migration of phenotypically recognizable primitive CD34+ subsets, despite the fact that CB-CD34+cells are thought to contain a higher percentage of immature subsets.
In conclusion, the relatively lower migration of PB-CD34+cells seems to be due to a lower sensitivity towards SDF-1, and the higher migrational capacity of CB-CD34+ cells as compared to BM- and PB-CD34+ cells seems to have an as yet unknown intrinsic cause. The increased migration of CB-CD34+ cells may favor homing of these cells to the bone marrow, which might reduce the number of cells required for hematological reconstitution after transplantation. |
