Sustained alterations in biodistribution of stem/progenitor cells in Tie2Cre+ alpha4(f/f) mice are hematopoietic cell autonomous

We have generated Tie2Cre4f/f mice with documented 4-integrin ablation in hematopoietic and endothelial cells. A prominent feature in this model is a sus-tained, significant increase in circulating progenitors at levels higher than the lev-els seen with Tie2CreVCAM-1f/f mice. To test whether phenotypic differences are due to contributions by ligands other than VCAM-1 in bone marrow, or to 4-deficient endothelial cells or pericytes, we carried out transplantation experi-ments using these mice as donors or as recipients. Changes in progenitor biodis-tribution after transplantation were seen only with 4-deficient donor cells, sug-gesting that these cells were necessary and sufficient to reproduce the pheno-type with no discernible contribution by 4-deficient nonhematopoietic cells. Because several similarities are seen after transplantation between our results and those with CXCR4/ donor cells, the data suggest that VLA4 / VCAM-1 and CXCR4/CXCL12 pathways contribute to a nonredundant, ongoing signaling re-quired for bone marrow retention of pro-genitor cells during homeostasis. (Blood