Noninvasive evaluation of the migration effect of transplanted endothelial progenitor cells in ischemic muscle using a multimodal imaging agent

Abstract

Background: Endothelial progenitor cells (EPCs) play an important role in repairing ischemia tissues. However, the survival, migration and therapeutic efficacy of EPCs after transplantation need to be better understood for further cell therapy. Purpose: This study investigated the migration effect of EPCs labeled with a multimodal imaging agent in a murine ischemic hindlimb model, using magnetic resonance imaging (MRI) and optical imaging after transplantation. Methods: EPCs derived from mouse bone marrow were labeled with a multimodal imaging agent and were administered through intracardiac delivery to mice with ischemic hindlimbs. The injected EPCs and their migration effect were observed via MRI and optical imaging in vivo, and then compared to a reference standard based on histological data. The quantification of gadolinium in tissue samples was done using inductively coupled plasma mass spectrometry (ICP-MS). Results: Using in vivo MRI and optical imaging, the labeled EPCs were observed to migrate to ischemic muscle on days 3-5 after injection, while ex vivo, the EPCs were observed in the capillary vessels of the injured tissue. There were significant linear correlations between the Gd contents measured using ICP-MS in samples from the ischemic hindlimbs and livers and T1 relaxation times calculated using MRI, as well as the average fluorescence signal intensities recorded in optical images (T1 relaxation time: r=0.491; average signal from optical imaging: r=0.704, P<0.01). EPC treatment upregulated the levels of C-X-C chemokine receptor 4 and vascular endothelial growth factor (VEGF) receptor 2 and enhanced the expression of stromal cell-derived factor-1 and VEGF. Conclusion: Transplanted EPCs can be monitored with noninvasive MRI and optical imaging in vivo and were found to enhance the paracrine secretion of angiogenic factors.