Bone marrow cell homing to sites of acute tibial fracture: 89Zr-oxine cell labeling with positron emission tomographic imaging in a mouse model

Kingsley O Asiedu; Munira Ferdousi; Phuongnga T Ton; Stephen S Adler; Peter L Choyke; Noriko Sato

doi:10.1186/s13550-018-0463-8

Bone marrow cell homing to sites of acute tibial fracture: ⁸⁹Zr-oxine cell labeling with positron emission tomographic imaging in a mouse model

EJNMMI Res. 2018 Dec 13;8(1):109. doi: 10.1186/s13550-018-0463-8.

Authors

Kingsley O Asiedu¹, Munira Ferdousi¹, Phuongnga T Ton¹, Stephen S Adler², Peter L Choyke¹, Noriko Sato³

Affiliations

¹ Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Building 10, Room B3B406, Bethesda, MD, 20892-1002, USA.
² Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, 21702, USA.
³ Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Building 10, Room B3B406, Bethesda, MD, 20892-1002, USA. saton@mail.nih.gov.

Abstract

Background: Bone fracture healing is dependent upon the rapid migration and engraftment of bone marrow (BM) progenitor and stem cells to the site of injury. Stromal cell-derived factor-1 plays a crucial role in recruiting BM cells expressing its receptor CXCR4. Recently, a CXCR4 antagonist, plerixafor, has been used to mobilize BM cells into the blood in efforts to enhance cell migration to sites of injury presumably improving healing. In this study, we employed zirconium-89 (⁸⁹Zr)-oxine-labeled BM cells imaged with positron emission tomography (PET)/computed tomography (CT) to visualize and quantitate BM cell trafficking following acute bone injury and to investigate the effect of plerixafor on BM cell homing. Unilateral 1-mm incisions were created in the distal tibia of mice either on the same day (d0) or 24 h (d1) after ⁸⁹Zr-oxine-labeled BM cell transfer (n = 4-6, 2-2.3 × 10⁷ cells at 9.65-15.7 kBq/10⁶ cells). Serial microPET/CT imaging was performed and migration of ⁸⁹Zr-labeled cells to the bone injury was quantified. The effects of three daily doses of plerixafor on cell trafficking were evaluated beginning on the day of fracture generation (n = 4-6). The labeled cells localizing to the fracture were analyzed by flow cytometry and immunohistochemistry.

Results: In d0- and d1-fracture groups, 0.7% and 1.7% of administered BM cells accumulated within the fracture, respectively. Plerixafor treatment reduced BM cell migration to the fracture by approximately one-third (p < 0.05 for both fracture groups). Flow cytometry analysis of donor cells collected from the injured site revealed a predominance of CD45⁺ stem/progenitor cell populations and subsequent histological analysis demonstrated the presence of donor cells engrafted within sites of fracture repair.

Conclusion: ⁸⁹Zr-oxine labeling enabled visualization and quantitation of BM cell recruitment to acute fractures and further demonstrated that plerixafor plays an inhibitory role in this recruitment.

Keywords: Bone injury; Bone marrow cell; Cell tracking; Fracture; Positron emission tomography; Zirconium-89; Zirconium-89 (89Zr)-oxine.