Bone Marrow Cell Trafficking Analyzed by ⁸⁹Zr-oxine Positron Emission Tomography in a Murine Transplantation Model

Abstract

Purpose: The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow. However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using zirconium-89 (⁸⁹Zr)-oxine cell labeling combined with PET imaging, we sought to visualize and quantify donor cell homing in a mouse bone marrow transplantation model.

Experimental Design: The effect of ⁸⁹Zr-oxine labeling on bone marrow cell viability and differentiation was evaluated in vitro. ⁸⁹Zr-labeled bone marrow cells (2 × 10⁷ cells, 16.6 kBq/10⁶ cells) were transferred intravenously, and serial microPET images were obtained (n = 5). The effect of a CXCR4 inhibitor, plerixafor (5 mg/kg) and G-CSF (2.5 μg) on bone marrow homing and mobilization were examined (n = 4). Engraftment of the transferred ⁸⁹Zr-labeled cells was evaluated (n = 3).

Results: ⁸⁹Zr-oxine–labeled bone marrow cells showed delayed proliferation, but differentiated normally. Transferred bone marrow cells rapidly migrated to the bone marrow, spleen, and liver (n = 5). Approximately 36% of donor cells homed to the bone marrow within 4 hours, irrespective of prior bone marrow ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the bone marrow homing (P < 0.0001, vs. nontreated, at 2 hours), confirming a crucial role of the CXCR4–CXCL12 system. Mobilization of approximately 0.64% of pretransplanted bone marrow cells induced a 3.8-fold increase of circulating bone marrow cells. ⁸⁹Zr-labeled donor cells engrafted as well as nonlabeled cells.

Conclusions: ⁸⁹Zr-oxine PET imaging reveals rapid bone marrow homing of transferred bone marrow cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT. Clin Cancer Res; 23(11); 2759–68. ©2016 AACR.