Song Suk-Won, Chang Woochul, Song Byeong-Wook, Song Heesang, Lim Soyeon, Kim Hye-Jung, Cha Min-Ji, Choi Eunju, Im Sin-Hyeog, Chang Byung-Chul, Chung Namsik, Jang Yangsoo, Hwang Ki-Chul
Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
Stem Cells. 2009 Jun;27(6):1358-65. doi: 10.1002/stem.47.
Mesenchymal stem cells (MSCs) therapy has limitations due to the poor viability of MSCs after cell transplantation. Integrin-mediated adhesion is a prerequisite for cell survival. As a novel anti-death strategy to improve cell survival in the infarcted heart, MSCs were genetically modified to overexpress integrin-linked kinase (ILK). The survival rate of ILK-transfected MSCs (ILK-MSCs) was augmented by about 1.5-fold and the phosphorylation of ERK1/2 and Akt in ILK-MSCs were increased by about three and twofold, respectively. ILK-MSCs demonstrated an increase of twofold in the ratio of Bcl-2/Bax and inhibited caspase-3 activation, compared with hypoxic MSCs. The adhesion rate of ILK-MSCs also had a 32.2% increase on the cardiac fibroblast-derived three-dimensional matrix and ILK-MSCs showed higher retention by about fourfold compared to unmodified MSCs. Six animals per group were used for the in vivo experiments analyzed at 1 week after occlusion of the left coronary artery. ILK-MSC transplanted rats had a 12.0% +/- 3.1% smaller infarct size than MSC-treated rats after ligation of left anterior descending coronary artery. Transplantation of ILK-MSCs not only led to a 16.0% +/- 0.4% decrease in the fibrotic heart area, but also significantly reduced the apoptotic positive index by two-thirds when compared with ligation only. The mean microvessel count per field in the infarcted myocardium of ILK-MSCs group was increased relative to the sham group and MSCs group. In conclusion, the ILK gene transduction of MSCs further assisted cell survival and adhesion, and improved myocardial damage when compared with MSC only after transplantation.
间充质干细胞（MSCs）疗法由于细胞移植后MSCs的存活率低而存在局限性。整合素介导的黏附是细胞存活的前提条件。作为一种改善梗死心脏中细胞存活的新型抗死亡策略，对MSCs进行基因改造以使其过表达整合素连接激酶（ILK）。ILK转染的MSCs（ILK-MSCs）的存活率提高了约1.5倍，并且ILK-MSCs中ERK1/2和Akt的磷酸化分别增加了约3倍和2倍。与缺氧的MSCs相比，ILK-MSCs的Bcl-2/Bax比值增加了两倍，并抑制了caspase-3的激活。ILK-MSCs在心脏成纤维细胞衍生的三维基质上的黏附率也增加了32.2%，并且与未修饰的MSCs相比，ILK-MSCs的保留率高约4倍。每组6只动物用于在左冠状动脉闭塞后1周进行分析的体内实验。在结扎左前降支冠状动脉后，ILK-MSC移植的大鼠梗死面积比MSC治疗的大鼠小12.0%±3.1%。与仅结扎相比，ILK-MSCs的移植不仅使纤维化心脏面积减少了16.0%±0.4%，而且还使凋亡阳性指数显著降低了三分之二。ILK-MSCs组梗死心肌中每视野的平均微血管计数相对于假手术组和MSCs组有所增加。总之，与仅移植MSCs相比，MSCs的ILK基因转导进一步促进了细胞存活和黏附，并改善了心肌损伤。
