Payne Thomas R, Oshima Hideki, Okada Masaho, Momoi Nobuo, Tobita Kimimasa, Keller Bradley B, Peng Hairong, Huard Johnny
Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
J Am Coll Cardiol. 2007 Oct 23;50(17):1677-84. doi: 10.1016/j.jacc.2007.04.100.
We investigated whether vascular endothelial growth factor (VEGF) was associated with the angiogenic and therapeutic effects induced after transplantation of skeletal muscle-derived stem cells (MDSCs) into a myocardial infarction (MI).
Because very few MDSCs were found to differentiate into new blood vessels when injected into the heart, the mechanism underlying the occurrence of angiogenesis after MDSC transplantation is currently unknown. In the present study, we used a gain- or loss-of-VEGF function approach with skeletal MDSCs engineered to express VEGF or soluble Flt1, a VEGF-specific antagonist, to identify the involvement of VEGF in MDSC transplantation-induced neoangiogenesis.
Vascular endothelial growth factor- and soluble Flt1-engineered MDSCs were injected into an acute MI. Angiogenesis and cardiac function were evaluated by immunohistochemistry and echocardiography.
Both control and VEGF-overexpressing MDSCs induced angiogenesis, prevented adverse cardiac remodeling, and improved function compared with saline-injected hearts. However, these therapeutic effects were diminished in hearts transplanted with MDSCs expressing soluble Flt1 despite successful cell engraftment. In vitro experiments demonstrated that MDSCs increased secretion of VEGF in response to hypoxia and cyclic stretch (likely conditions in ischemic hearts), suggesting that transplanted MDSCs release VEGF in vivo.
Our findings suggest that VEGF is essential for the induction of angiogenesis and functional improvements observed after MDSC transplantation for infarct repair.
我们研究了血管内皮生长因子（VEGF）是否与骨骼肌来源的干细胞（MDSCs）移植到心肌梗死（MI）后诱导的血管生成及治疗效果相关。
由于发现极少的MDSCs注入心脏后能分化成新血管，MDSC移植后血管生成发生的潜在机制目前尚不清楚。在本研究中，我们采用功能获得或功能缺失的VEGF方法，对经基因工程改造以表达VEGF或可溶性Flt1（一种VEGF特异性拮抗剂）的骨骼肌MDSCs进行研究，以确定VEGF在MDSC移植诱导的新生血管形成中的作用。
将经血管内皮生长因子和可溶性Flt1基因工程改造的MDSCs注入急性心肌梗死模型。通过免疫组织化学和超声心动图评估血管生成和心脏功能。
与注射生理盐水的心脏相比，对照和过表达VEGF的MDSCs均能诱导血管生成，防止不良心脏重塑，并改善心脏功能。然而，尽管细胞成功植入，但在移植表达可溶性Flt1的MDSCs的心脏中，这些治疗效果减弱。体外实验表明，MDSCs在缺氧和周期性拉伸（可能是缺血心脏中的情况）刺激下会增加VEGF的分泌，提示移植的MDSCs在体内释放VEGF。
我们的研究结果表明，VEGF对于MDSC移植后梗死修复所观察到的血管生成诱导和功能改善至关重要。
