Lo Chi Y, Weil Brian R, Palka Beth A, Momeni Arezoo, Canty John M, Neelamegham Sriram
Department of Chemical and Biological Engineering, The State University of New York, 906 Furnas Hall, Buffalo, NY 14260, USA; Department of Anesthesiology, The State University of New York, 252 Farber Hall, Buffalo, NY 14214, USA; Division of Cardiovascular Medicine, The State University of New York, Clinical Translational Research Center, 875 Ellicott Street, Buffalo, NY 14203, USA.
Division of Cardiovascular Medicine, The State University of New York, Clinical Translational Research Center, 875 Ellicott Street, Buffalo, NY 14203, USA.
Biomaterials. 2016 Jan;74:19-30. doi: 10.1016/j.biomaterials.2015.09.026. Epub 2015 Sep 25.
Promising results are emerging in clinical trials focused on stem cell therapy for cardiology applications. However, the low homing and engraftment of the injected cells to target tissue continues to be a problem. Cellular glycoengineering can address this limitation by enabling the targeting of stem cells to sites of vascular injury/inflammation. Two such glycoengineering methods are presented here: i. The non-covalent incorporation of a P-selectin glycoprotein ligand-1 (PSGL-1) mimetic 19Fc[FUT7(+)] via lipid-protein G fusion intermediates that intercalate onto the cell surface, and ii. Over-expression of the α(1,3)fucosyltransferse FUT7 in cells. Results demonstrate the efficient coupling of 19Fc[FUT7(+)] onto both cardiosphere-derived cells (CDCs) and mesenchymal stem cells (MSCs), with coupling being more efficient when using protein G fused to single-tailed palmitic acid rather than double-tailed DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine). This non-covalent cellular modification was mild since cell proliferation and stem-cell marker expression was unaltered. Whereas coupling using 19Fc[FUT7(+)] enhanced cell capture on recombinant P-selectin or CHO-P cell surfaces, α(1,3)fucosylation was necessary for robust binding to E-selectin and inflamed endothelial cells under shear. Pilot studies confirm the safety and homing efficacy of the modified stem cells to sites of ischemia-reperfusion in the porcine heart. Overall, glycoengineering with physiological selectin-ligands may enhance stem cell engraftment.
针对心脏病学应用的干细胞疗法的临床试验正在取得令人鼓舞的结果。然而，注入的细胞向靶组织的低归巢和低植入率仍然是一个问题。细胞糖工程可以通过使干细胞靶向血管损伤/炎症部位来解决这一局限性。本文介绍了两种这样的糖工程方法：i. 通过插入细胞表面的脂蛋白G融合中间体非共价结合P-选择素糖蛋白配体-1（PSGL-1）模拟物19Fc[FUT7(+)]；ii. 在细胞中过表达α(1,3)岩藻糖基转移酶FUT7。结果表明，19Fc[FUT7(+)]能有效地偶联到心肌球衍生细胞（CDC）和间充质干细胞（MSC）上，当使用与单尾棕榈酸融合的蛋白G而不是双尾DOPE（1,2-二油酰-sn-甘油-3-磷酸乙醇胺）时，偶联效率更高。这种非共价细胞修饰是温和的，因为细胞增殖和干细胞标志物表达未改变。虽然使用19Fc[FUT7(+)]偶联增强了细胞在重组P-选择素或CHO-P细胞表面的捕获，但α(1,3)岩藻糖基化对于在剪切力下与E-选择素和炎症内皮细胞的强力结合是必需的。初步研究证实了修饰后的干细胞在猪心脏缺血再灌注部位的安全性和归巢功效。总体而言，用生理性选择素配体进行糖工程可能会增强干细胞的植入。
