Epicardial delivery of VEGF and cardiac stem cells guided by 3-dimensional PLLA mat enhancing cardiac regeneration and angiogenesis in acute myocardial infarction

• Published in: Journal of controlled release 2015-05, Vol.205, p.218-230
• Main Authors: Chung, Hye-Jin, Kim, Jong-Tae, Kim, Hee-Jung, Kyung, Hei-Won, Katila, Pramila, Lee, Jeong-Han, Yang, Tae-Hyun, Yang, Young-Il, Lee, Seung-Jin
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inducing Agents - administration & dosage; Angiogenesis Inducing Agents - chemistry; Animals; Cardiac regeneration; Cardiac stem cells; Cell Differentiation - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Chemistry, Pharmaceutical; Combined Modality Therapy; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Kinetics; Lactic Acid - chemistry; Male; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocardium - metabolism; Myocardium - pathology; Neovascularization, Physiologic - drug effects; Phenotype; PLLA mat; Polyesters; Polymers - chemistry; Rats, Sprague-Dawley; Regeneration - drug effects; Regenerative Medicine - methods; Solubility; Stem Cell Transplantation; Stem Cells - metabolism; Stem Cells - physiology; Sustained release; Tissue Scaffolds; Vascular Endothelial Growth Factor A - administration & dosage; Vascular Endothelial Growth Factor A - chemistry; VEGF
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2015.02.013

Congestive heart failure is mostly resulted in a consequence of the limited myocardial regeneration capacity after acute myocardial infarction. Targeted delivery of proangiogenic factors and/or stem cells to the ischemic myocardium is a promising strategy for enhancing their local and sustained therapeutic effects. Herein, we designed an epicardial delivery system of vascular endothelial growth factor (VEGF) and cardiac stem cells (CSCs) using poly(l-lactic acid) (PLLA) mat applied to the acutely infarcted myocardium. The fibrous VEGF-loaded PLLA mat was fabricated by an electrospinning method using PLLA solution emulsified VEGF. This mat not only allowed for sustained release of VEGF for 4weeks but boosted migration and proliferation of both endothelial cells and CSCs in vitro. Furthermore, sustained release of VEGF showed a positive effect on in vitro capillary-like network formation of endothelial cells compared with bolus treatment of VEGF. PLLA mat provided a permissive 3-dimensional (3D) substratum that led to spontaneous cardiomyogenic differentiation of CSCs in vitro. Notably, sustained stimulation by VEGF-loaded PLLA mat resulted in a substantial increase in the expression of proangiogenic mRNAs of CSCs in vitro. The epicardially implanted VEGF-loaded PLLA mat showed modest effects on angiogenesis and cardiomyogenesis in the acutely infarcted hearts. However, co-implantation of VEGF and CSCs using the PLLA mat showed meaningful therapeutic effects on angiogenesis and cardiomyogenesis compared with controls, leading to reduced cardiac remodeling and enhanced global cardiac function. Collectively, the PLLA mat allowed a smart cargo that enabled the sustained release of VEGF and the delivery of CSCs, thereby synergistically inducing angiogenesis and cardiomyogenesis in acute myocardial infarction. [Display omitted]