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PRECLINICAL STUDY

The Effect of Stem Cell Mobilization by Granulocyte-Colony Stimulating Factor on Neointimal Hyperplasia and Endothelial Healing After Vascular Injury With Bare-Metal Versus Paclitaxel-Eluting Stents

Hyun-Jai Cho, MD^_*,,, Tae-Youn Kim, BA, Hyun-Ju Cho, MS, Kyung-Woo Park, MD^_*,,, Shu-Ying Zhang, MD, Ji-Hyun Kim, MS, Sung-Hwan Kim, MD^_*,,, Joo-Yong Hahn, MD^_*,,, Hyun-Jae Kang, MD^_*,,, Young-Bae Park, MD^_*,, and Hyo-Soo Kim, MD, PhD^_*,,,_*

^_* Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
Cardiovascular Center, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea
Cardiovascular Research Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.

Manuscript received October 24, 2005; revised manuscript received December 2, 2005, accepted December 13, 2005.

^_* Reprint requests and correspondence: Dr. Hyo-Soo Kim, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea. (Email: hyosoo{at}snu.ac.kr).

OBJECTIVES: The goal of this study was to investigate the effect of mobilized stem cells by granulocyte-colony stimulating factor (G-CSF) on neointimal growth, the biologic impact on vascular healing process, and the utility of paclitaxel-eluting stent (PES) in this circumstance.

BACKGROUND: Questions have been raised on the safety of stem cell mobilization because of the tendency of neointimal overgrowth in a recent clinical trial, despite improvement of cardiac function.

METHODS: Rabbits underwent iliac artery injury with bare-metal stent (BMS) or PES and then received rhG-CSF or placebo for 6 days. Morphometric analysis and scanning electron microscopy for re-endothelialization were performed. The characteristics of mobilized peripheral blood mononuclear cells were determined in vitro, and the fate of these cells was evaluated by re-infusion with tagging in vivo.

RESULTS: At day 60 after stenting, neointimal overgrowth was observed at BMS with G-CSF. The tendency of neointimal overgrowth was substantially reduced on PES. Intriguingly, the delayed endothelial recovery on PES was restored to normal after G-CSF treatment. The G-CSF increased not only the endothelial progenitor cells, but also putative smooth muscle progenitor cells. Paclitaxel, at working concentration, preferentially inhibited proliferation of smooth muscle lineage cells rather than endothelial lineage cells.

CONCLUSIONS: Our findings demonstrate that G-CSF mobilizes putative vascular progenitor cells in peripheral blood, which induces neointimal overgrowth at stented vasculature. Unique differential action of paclitaxel results in the enhanced endothelial healing with reduced neointimal growth after G-CSF treatment, suggesting that drug-eluting stents might be the optimal modality for revascularization in cytokine-based stem cell therapy.

Abbreviations and Acronyms   BMS = bare-metal stent   BrdU = bromodeoxyuridine   EC = endothelial cell   ELISA = enzyme-linked immunosorbent assay   EPC = endothelial progenitor cell   G-CSF = granulocyte-colony stimulating factor   PDGF = platelet-derived growth factor   PES = paclitaxel-eluting stent   SEM = scanning electron microscopy   SMA = smooth muscle actin   SMC = (vascular) smooth muscle cell   SPC = smooth muscle progenitor cell   VEGF = vascular endothelial growth factor   VPC = vascular progenitor cell

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