Zirconium-89-Oxine Complex Enables Quantitative Monitoring of Systemic Bone Marrow Cell Trafficking by Positron Emission Tomography
Noriko Sato, National Cancer Institute, NIH
Bone marrow (BM) transplantation is used in the treatment of various malignancies and pathological conditions. Sufficient BM homing and engraftment of transferred hematopoietic stem cells is a critical determinant of the success of the treatment 1. To this end, we employed zirconium-89 (89Zr)-oxine complex cell labeling technique 2 to visualize and quantitate the BM cell migration by micro-positron emission tomography (PET)/computed tomography (CT) in a mouse BM transplantation model. 89Zr-oxine successfully labeled BM cells without interfering with their differentiation function as demonstrated by their maturation into natural killer cells when cultured with IL-15, and to dendritic cells when cultured with granulocyte macrophage colony stimulation factor. Micro-PET/CT imaging revealed quick migrations of transferred BM cells to the BM, spleen, and liver. As high as 22% of donor cells homed to the BM within 4 h of administration. Interestingly, this rapid migration of the cells to the BM occurred irrespective of prior BM ablation. Inhibition of CXCR4 by plerixafor and plerixafor combined with G-CSF injection, prior to the transplantation, significantly blocked initial BM homing of the cells, indicating a crucial role of the CXCR4-CXCL12 system in the BM homing. Next, we injected plerixafor and G-CSF to mice pre-transferred with 89Zr-oxine labeled BM cells, mimicking a cell mobilization process used for collection of hematopoietic stem cells from the circulation in BM transplantations in patients. The BM mobilization led to more than 3.5-fold increase of 89Zr-labeled BM cells in the circulation compared to non-treated control, which was confirmed by imaging, radioactivity counts in the blood and flow cytometry. This also suggested that the 89Zr-labeled cells homed to the BM were alive and functional. In fact, in BM ablated recipients, 89Zr-oxine labeled donor BM cells engrafted and gave rise to mature peripheral mononuclear cells comparable to non-labeled donor cells. Collectively, 89Zr-oxine PET/CT demonstrated BM homing kinetics of BM cells after transplantation, without impairing differentiation function of the cells, and could, therefore, be a useful method for optimizing BM transplantation.
1. Jenq RR, van den Brink MR. Nat Rev Cancer. 2010;10(3):213-21
2. Sato N, Wu H, Asiedu KO, et al. Radiology. 2015. [Ahead of print]