Abstract
BackgroundBone 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.ResultsIn 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.Conclusion89Zr-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.
Highlights
Bone fracture healing is dependent upon the rapid migration and engraftment of bone marrow (BM) progenitor and stem cells to the site of injury
BM cells labeled with 89Zr-oxine show rapid homing to bone marrow and bone injury site We first tracked 89Zr-oxine-labeled BM cells transferred to mice without a fracture, as a control, by microPET/computed tomography (CT) imaging beginning 1 day after the cell transfer (n = 4)
BM cell 89Zr-oxine-labeling with microPET/CT imaging revealed that acute fracture results in the redistribution of BM cells to the fracture within 24 h
Summary
Bone fracture healing is dependent upon the rapid migration and engraftment of bone marrow (BM) progenitor and stem cells to the site of injury. Mice treated with either SDF-1 neutralizing antibody or TF14016, a CXCR4 antagonist, demonstrated decreased stem cell engraftment and bone formation [15] These data suggest that CXCR4 inhibition and subsequent mobilization of CXCR4+ cells may, or may not, improve bone injury healing by releasing high number of stem/progenitor cells into the circulation, making more available for localization within the injury site. We have previously reported a method of cell labeling using 89Zr-oxine followed by positron emission tomography (PET) that can label various cell types without altering their cellular viability or function [16] Using this technology, we have successfully visualized BM cell migration in murine models of BM transplantation [17]. We examined the trafficking of BM cells and the effect of plerixafor on the short-term BM cell homing to the bone injury
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