Accumulating evidence from our lab (
Blocking angiopoietin/Tie2 signaling with the soluble decoy-receptor, Tie2Fc, after 5-FU inhibited platelet recovery as well as vascular reconstitution. There was a paradoxical accumulation of megakaryocytes in the bone-marrow during the prolonged thrombocytopenic phase, which we have previously shown to be due to vascular niche disruption and inability of megakaryocytes to release platelets.
To examine the possibility that Tie2+ progenitors can reconstitute BM sinusoids in the recipient mice, lethally irradiated wildtype mice were transplanted with the BM of Tie2-lacZ knock-in mice. After full recovery, the chimeric mice were challenged with a myelosuppressive dose of 5-FU and Tie2+ neo-vessels were detected histologically on day 5, 10, and 14 by LacZ staining. Remarkably, the reconstituted bone marrow showed the presence of Tie2+ vessels, which unambiguously demonstrates the contribution of donor-derived endothelial progenitors to the reconstitution of the regressed vasculature.
Together, our data support the hypothesis that Tie2/angiopoietin signaling is essential for functional regeneration of BM sinusoidal neo-vessels and contributes to the reconstitution of hematopoiesis, specifically to thrombopoiesis. In addition, the use of Tie2-LacZ mice provides an invaluable model to quantify the number of regenerating BM neo-vessels. Angiopoietins may be used in clinical setting in conjunction with other lineage specific cytokines to enhance hematopoiesis after myelosuppression.