ABSTRACT
Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regulation of several mitosis-related genes at this stage of reprogramming. Several candidate genes were selected and tested for their ability to induce CM proliferation. Delivering a cocktail of three genes, FoxM1, Id1, and Jnk3-shRNA (FIJs), induced CMs to re-enter the cell cycle and complete mitosis and cytokinesis in vitro More importantly, this gene cocktail increased CM proliferation in vivo and significantly improved cardiac function and reduced fibrosis after myocardial infarction. Collectively, our findings present a cocktail FIJs that may be useful in cardiac regeneration and also provide a practical strategy for probing reprogramming assays for regeneration of other tissues.
Subject(s)
Cell Proliferation , Genetic Therapy/methods , Myocardial Infarction/therapy , Myocytes, Cardiac/physiology , Regeneration , Animals , Dependovirus/genetics , Forkhead Box Protein M1/genetics , Genetic Vectors , Inhibitor of Differentiation Protein 1/genetics , Mice, Inbred C57BL , Mitogen-Activated Protein Kinase 10/genetics , RNA, Small Interfering/genetics , Regenerative Medicine/methods , Transduction, Genetic , Treatment OutcomeABSTRACT
Nanoparticles represent an attractive option for systemic delivery of therapeutic compounds to the heart following myocardial infarction. However, it is well known that physicochemical properties of nanoparticles such as size, shape and surface modifications can vastly alter the distribution and uptake of injected nanoparticles. Therefore, we aimed to provide an examination of the rapid size-dependent uptake of fluorescent PEG-modified polystyrene nanoparticles administered immediately following cardiac ischaemia-reperfusion injury in mice. By assessing the biodistribution of nanoparticles with core diameters between 20 nm and 2 µm 30 minutes after their administration, we conclude that 20-200 nm diameter nanoparticles are optimal for passive targeting of the injured left ventricle.
Subject(s)
Myocardial Reperfusion Injury/metabolism , Myocardium/metabolism , Nanoparticles/metabolism , Polystyrenes/pharmacokinetics , Animals , Drug Delivery Systems/methods , Heart Ventricles/metabolism , Heart Ventricles/pathology , Male , Mice , Myocardium/pathology , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Particle Size , Polyethylene Glycols/chemistry , Polystyrenes/administration & dosage , Polystyrenes/chemistry , Reproducibility of Results , Time Factors , Tissue DistributionABSTRACT
All research investment has the goal of improving quality of life and health status. In recent years, the emerging technologies in nanomedicine research provide us a new frontier in the fight against human disease. By taking advantage of the unique physicochemical properties of nanoparticles (NPs), nanomedicine where drugs are blended into nanomaterials readily offers a wide range of applications in the tracing, diagnosis and treatment of disease. Although the application of therapeutic NPs is predominantly for cancer treatment, growing evidence has demonstrated the feasibility and potency of utilizing NPs for cardiovascular disease therapy. However, more consideration is required in this aspect due to limitations such as unfavorable particle retention in the contractile heart and the lack of cardiomyocyte markers for targeting.
