분화 유도된 근육줄기세포의 내막증식 억제 효과

Abstract

Purpose: Although progenitor cells may contribute to intimal hyperplasia (IH) after arterial injury, positive contribution of IH is variable with type of injury or cells. This study was designed to examine whether differentiated muscle derived stem cells (MDSC) attenuate IH in rat. Methods: MDSCs were retrieved using preplate techniques from rat calf muscle and MDSCs (preplate 6th culture fraction, pp6) were exposed to VEGF (50 ng/ml) for endothelial differentiation prior to injection. Male rats were divided into two groups (cell treated vs. control) and underwent carotid balloon injury with 2-Fr catheter. The virus containing Green fluorescent protein (GFP) gene was transfected into cells for monitoring. Cells (5x10(6)) were indwelled into carotid artery for 30 minutes after injury and then blood flow was restored. Arteries were harvested at various intervals (1, 2 and 4 weeks) after injury. The intima to media thickness ratio (IMTR) was calculated with morphometric analysis. Results: Endothelial surface markers such as VE-CADHERIN were strongly expressed on differentiated MDSCs. At 4 weeks after injury, IH was predominantly observed in control group compared to cell treated group. The intensity of OFF was strongly observed at 1 week and declined at 4 weeks in carotid artery wall at MDSC group. CD31(+) endothelial cells were observed at MDSC group compared to control. The mean IMTR in cell treated groups were significantly lower than control at 2 weeks (P=0.005) and 4 weeks (P <= 0.001). Conclusion: Our study demonstrates that MDSCs therapy promotes re-endothelialization and leads to attenuation of IH after balloon injury in rat. 동맥 폐색질환 환자들에서 시행되는 많은 동맥 우회술 혹은 혈관 내 치료들이 초기의 우수한 성공률에도 불구하고 장기간 추적관찰 시 재협착 혹은 폐색을 흔히 보인다. 주요한 폐색원인으로 알려진 내막 증식증 내막손상 후 혈관 평활근 세포의 내막이동 및 증식과 결체조직의 침착으로 혈관내강의 협착이 초래되어 발생하며 상기 치료들의 실패요인으로 이해되었다.(1) 그러나 최근에 혈관전구세포의 발견 및 관련된 많은 연구를 통해서 내막 증식증을 초래하는 병태생리 개념이 새롭게 대두되었다. 즉 혈중, 조직, 혹은 골수 내에 존재하는 전구세포들이 혈관손상부위로 원격 이동하여 내막증식을 초래하는 주 세포원이라는 주장이 제기되고 있다. 그러나 전구세포들에 의한 내막증식연구는 손상모델에 따라서 혹은 전구세포들의 종류에 따라서 내막 증식의 억제 혹은 촉진 등의 다양한 결과를 나타내고 있다.(2) 저자들은 근육 내 존재하는 줄기세포를 내피세포로의 유도 후 백서 경동맥 손상부위에 투여하여 내막증식억 제 여부를 분석하고 그 기전을 규명하고자 본 연구를 시행하였다.