Cord blood endothelial progenitor cells as therapeutic and imaging probes

Abstract

Numerous studies demonstrated that neovascularization processes associated with severe tissue ischemia commonly found in conditions such as cardiovascular disorders and tumor growth occur via angiogenic and vasculogenic mechanisms. Over the past decade, it has been demonstrated that endothelial progenitor cells (EPCs) play a significant role in neo-angiogenic and neovasculogenic processes. Due to their ability to self-renew, circulate, home to the ischemic sites and differentiate into mature endothelial cells, EPCs derived from various sources hold enormous potential to be used as therapeutic agents in pro- or anti-angiogenic strategies for the treatment of ischemic and tumor conditions, respectively. However, the development of EPC-based therapies requires accompanying, noninvasive imaging protocol for in vivo tracking of transplanted cells. Hence, this review focuses on cord blood-derived EPCs and their role in neovascularization with emphasis on the potential use of EPCs as a therapeutic and imaging probe.

Figure 1. Migration and accumulation of administered In-111-oxine and SPIO-labeled endothelial progenitor cells in tumors

Five million In-111-labeled EPCs followed by 5 million magnetically labeled EPCs were administered in tumor-bearing rats. Both In-111- and SPIO-labeled EPCs were injected at the same time in the same animals. Following intravenous administration, SPECT images were obtained on days 0, 1 and 3. MRI images were obtained on day 7 to allow the decay of the radioactivity. SPECT images of the tumor obtained at 3 h (A), 24 h (B) and 72 h (C) showed increased activity at the site of tumor, indicating accumulation of In-111 labeled EPCs. Note a few of the iron-positive cells also make the lining of blood vessels (inset, black arrows). MRI was obtained by a clinical 3T system on day 7 following last SPECT. (D) T₂-weighted image with an echo time of 35 ms, (E) T₂-weighted image with an echo time of 20 ms and corresponding R2* map (F). Note the low signal intensity areas on T₂-weighted image (E, black arrows) and corresponding R2* map (F, yellow arrows) indicating accumulation of iron-positive cells, which is proved by diaminobenzidine-enhanced Prussian blue staining (G). Inset showing the iron-positive cells lining the blood vessels. EPC: Endothelial progenitor cell. Reproduced with permission from [101].

Figure 2. Migration and accumulation of transgenic SPIO-labeled endothelial progenitor cells in tumors

Ten million transgenic (hNIS-carrying) endothelial progenitor cells (EPCs; half of them were labeled with SPIO) were intravenously administered in glioma-bearing rats after 14 days of tumor implantation. MRI and technetium-99m SPECT were obtained on days 7 and 8, respectively. (A) Preinjection MRI (before injection of labeled EPCs). (B) Postinjection MRI (after injection of labeled EPCs). (C–E) Technetium-99m SPECT images in sagittal, coronal and axial plans. Note the low signal intensity areas on MRI in tumor following intravenous administration of SPIO-labeled EPCs (B, circle). SPECT images show increased accumulation of technetium-99m in the tumor compared with the contralateral brain (white dotted areas, which showed almost no activity). (F) Prussian blue and (G–I) immunohistochemistry stains show presence of iron-positive cells and expression of CD31 and hNIS. FITC: Fluorescein isothiocyanate; NIS: Sodium iodide symporter; TRITC: Tetramethylrhodamine-5-(and 6)-isothiocyanate. Adapted from [88].