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.
Highlights
Cardiovascular diseases are a leading cause of death in developed countries (Khurana et al, 2005)
We demonstrated that there is strong up-regulation of mitosis-related genes during the second day of CM reprogramming
Each member of the gene cocktail is responsible for reducing specific CDK inhibitors and supporting the CM cell cycle, as mentioned in previous studies
Summary
Cardiovascular diseases are a leading cause of death in developed countries (Khurana et al, 2005). We theorized that understanding the process of CM reprogramming may yield clues into the way by which CMs re-enter the cell cycle These clues may be exploited in order to promote efficient heart regeneration after injury. SSEA-1 expression is confirmed as an intermediate cell marker leading to the commitment of iPSC generation, and the Thy1negative stage is reported as necessary for proliferation enhancement, metabolic change, and loss of identity for initiating reprogramming (Hansson et al, 2012; Polo et al, 2012). We sought to closely examine the changes occurring during early CM reprogramming by microarray analysis, and to identify the ideal genetic alteration which could yield the greatest therapeutic potential after MI
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