Yamanaka Factors as Drivers of Recovery in a Mouse Model of Heart Failure

Abstract

Introduction Yamanaka Factors (OCT3/4, SOX2, KLF4 and C-MYC-OSKM) are a group of genes recently identified by Yamanaka et al. as important for the creation of induced pluripotent stem cells (iPSC). OSKM genes have shown effects on Mesenchymal to Endothelial transition (MET), a process that leads to the transition of a fibroblast to an endothelial cell. We have previously shown in a non-ischemic HF model of recovery that the phenotype of HF can reverse with natural mechanisms with a normalization of ejection fraction and resolution of fibrosis. Hypothesis Expression of OSKM genes is elevated in the early phase of recovery in a non-ischemic mouse model of HF recovery. Methods We used our non-ischemic mouse model of recovery from HF which consists of implantation of an osmotic pump which delivers angiotensin II (angII), combined with the addition of L-NAME and NaCl in the drinking water to induce heart failure. At the end of 5 weeks (HF) the pump runs out of angII and the water is returned to normal water to begin the recovery phase following heart failure. Mice were euthanized at different time points to observe gene expression from tissues collected from control mice, as well as week 3 and 5 (HF) and weeks 7 and 9 (recovery). Expression was represented as increase fold change compared to control. We assessed fibrosis and heart weight as surrogate markers of the degree of heart failure or recovery. PCR was used to quantitate OSKM gene expression. Results There is a trend of overall elevated expression in OSKM genes in the weeks after the injury was removed, which are considered the recovery weeks. SOX2, OCT4, and KLF4 are expressed in a progressive way from low to high, peaking by the end of recovery. Fibrosis percentage showed a statistically significant decrease in recovery compared to HF (p-value Conclusions The increased expression of OSKM in recovery period vs. HF suggest that Yamanaka factors might play an important role in recovery from HF. This could reflect contribution of these factors through stem cells or cell transitions (mesenchymal to endothelial) that finally mediate a recovery or antifibrotic process.