Targeted Repair of Vascular Injury by Adipose-Derived Stem Cells Modified with P-Selectin Binding Peptide
Targeted Repair of Vascular Injury by Adipose-Derived Stem Cells Modified with P-Selectin Binding Peptide
复制标题
P-选择素结合肽修饰的脂肪干细胞靶向修复血管损伤
DOI：
10.1002/advs.201903516
复制
发表时间：
2020-04-22
期刊：
影响因子：
15.1
通讯作者：
Wang, Kai
中科院分区：
文献类型：
--
作者：
Yan, Hongyu;Mi, Xingyan;Wang, Kai
用于治疗冠状动脉疾病的经皮冠状动脉介入治疗常常导致病理性血管损伤，其特征是 P-选择素过度表达。由于 ADSC 在受损血管中的靶向性和保留能力较差，因此脂肪干细胞 (ADSC) 的治疗效果仍然难以捉摸。在此，使用缀合的 P-选择素结合肽 (PBP) 与聚乙二醇缀合的磷脂衍生物 (DMPE-PEG) 连接体 (DMPE-PEG-PBP；DPP) 通过 DMPE-PEG 和磷脂双层之间的疏水相互作用促进 PBP 修饰到 ADSC 细胞表面。 DPP修饰既不影响ADSCs增殖，也不影响凋亡/旁分泌因子基因表达。总共 5 x 10(-6) m DPP 修饰的 ADSC (DPP-ADSC) 在体外与 P-选择素展示的活化血小板和内皮细胞 (EC) 强烈结合，并在动脉内注射时与线损伤的大鼠股动脉结合。 ADSC 的靶向结合可保护损伤部位免受血小板和白细胞粘附，从而减少损伤部位的炎症。此外，ADSC 的靶向结合可恢复受损的 EC 功能，并减少血小板引发的血管平滑肌细胞 (VSMC) 趋化迁移。离体实验也证明了 DPP-人 ADSC 与球囊损伤的人股动脉的靶向结合。总体而言，DPP-ADSC 可促进血管修复、抑制新生内膜增生、增加内皮功能并维持正常的 VSMC 排列，支持临床前无创利用 DPP-ADSC 治疗血管损伤。
Percutaneous coronary intervention for coronary artery disease treatment often results in pathological vascular injury, characterized by P-selectin overexpression. Adipose-derived stem cells (ADSCs) therapeutic efficacy remains elusive due to poor ADSCs targeting and retention in injured vessels. Here, conjugated P-selectin binding peptide (PBP) to polyethylene glycol-conjugated phospholipid derivative (DMPE-PEG) linkers (DMPE-PEG-PBP; DPP) are used to facilitate the modification of PBP onto ADSCs cell surfaces via hydrophobic interactions between DMPE-PEG and the phospholipid bilayer. DPP modification neither has influence on ADSCs proliferation nor apoptosis/paracrine factor gene expression. A total of 5 x 10(-6) m DPP-modified ADSCs (DPP-ADSCs) strongly binds to P-selectin-displaying activated platelets and endothelial cells (ECs) in vitro and to wire-injured rat femoral arteries when administered by intra-arterial injection. Targeted binding of ADSCs shields injury sites from platelet and leukocyte adhesion, thereby decreasing inflammation at injury sites. Furthermore, targeted binding of ADSCs recovers injured ECs functionality and reduces platelet-initiated vascular smooth muscle cells (VSMCs) chemotactic migration. Targeted binding of DPP-human ADSCs to balloon-injured human femoral arteries is also demonstrated in ex vivo experiments. Overall, DPP-ADSCs promote vascular repair, inhibit neointimal hyperplasia, increase endothelium functionality, and maintain normal VSMCs alignment, supporting preclinical noninvasive utilization of DPP-ADSCs for vascular injury.