Platelet-Targeted Delivery of Peripheral Blood Mononuclear Cells to the Ischemic Heart Restores Cardiac Function after Ischemia-Reperfusion Injury

• Published in: Theranostics Vol. 7; no. 13; pp. 3192 - 3206
• Main Authors: Ziegler, Melanie, Wang, Xiaowei, Lim, Bock, Leitner, Ephraem, Klingberg, Franco, Ching, Victoria, Yao, Yu, Huang, Dexing, Gao, Xiao-Ming, Kiriazis, Helen, Du, Xiao-Jun, Haigh, Jody J, Bobik, Alex, Hagemeyer, Christoph E, Ahrens, Ingo, Peter, Karlheinz
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2017
• Subjects: Animals; Blood Platelets - metabolism; Cell Adhesion; CHO Cells; Cricetinae; Cricetulus; Cytokines - metabolism; Disease Models, Animal; Heart Function Tests; HEK293 Cells; Humans; Inflammation - pathology; Leukocytes - metabolism; Leukocytes, Mononuclear - transplantation; Mice, Inbred C57BL; Mutation - genetics; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - physiopathology; Myocardial Reperfusion Injury - therapy; Myocardium - pathology; Neovascularization, Physiologic; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Research Paper; Single-Chain Antibodies - metabolism; Ventricular Remodeling; targeting; cell tracking; myocardial infarction; cell delivery; PBMC; regenerative cell therapy; single-chain antibody
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.19698

One of the major hurdles in intravenous regenerative cell therapy is the low homing efficiency to the area where these cells are needed. To increase cell homing toward areas of myocardial damage, we developed a bispecific tandem single-chain antibody (Tand-scFv ) that binds with high affinity to activated platelets via the activated glycoprotein (GP)IIb/IIIa receptor, and to a subset of peripheral blood mononuclear cells (PBMC) which express the stem cell antigen-1 (Sca-1) receptor. The Tand-scFv was engineered, characterized and tested in a mouse model of ischemia-reperfusion (IR) injury applying left coronary artery occlusion for 60 min. Fluorescence cell tracking, cell infiltration studies, echocardiographic and histological analyses were performed. Treatment of mice undergoing myocardial infarction with targeted-PBMCs led to successful cell delivery to the ischemic-reperfused myocardium, followed by a significant decrease in infiltration of inflammatory cells. Homing of targeted-PBMCs as shown by fluorescence cell tracking ultimately decreased fibrosis, increased capillary density, and restored cardiac function 4 weeks after ischemia-reperfusion injury. Tand-scFv is a promising candidate to enhance therapeutic cell delivery in order to promote myocardial regeneration and thereby preventing heart failure.