Search for: All records

The present study explores an RNA we have discovered in human heart that induces differentiation of mouse embryonic stem cells and human induced pluripotent stem cells into cardiomyocytes in vitro. We have designated this RNA as Cardiac Inducing RNA or CIR. We now find that CIR also induces mouse embryonic fibroblasts (MEF) to form cardiomyocytes in vitro. For these studies, human-derived CIR is transfected into MEF using lipofectamine. The CIR-transfected mouse fibroblasts exhibit spindle-shaped cells, characteristic of myocardial cells in culture, and express cardiac-specific troponin-T and cardiac tropomyosin. As such, the CIR-induced conversion of the fibroblasts into cardiomyocytes in vitro appears to take place without initial dedifferentiation into pluripotent stem cells. Instead, after CIR transfection using a lipofectamine transfection system, over the next 8 days there appears to be a direct transdifferentiation of ˃80% of the cultured fibroblasts into definitive cardiomyocytes. Fewer than ˂7% of the untreated controls using non-active RNA or lipofectamine by itself show cardiomyocyte characteristics. Thus, discovery of CIR may hold significant potential for future use in repair/regeneration of damaged myocardial tissue in humans after myocardial infarction or other disease processes such that affected patients may be able to return to pre-heart-disease activity levels. 

We have discovered a cardiac-inducing RNA (CIR) in the axolotl, Ambystoma mexicanum, (a salamander) and two cardiac inducing RNAs (CIR-6 and CIR-30) in human heart that have the ability to induce the differentiation of non-muscle cells, including induced pluripotent stem cells from human skin, mouse embryonic stem cells, and mouse fibroblasts into cardiomyocytes in vitro. Although the primary sequences of salamander and human RNAs are not homologous, their secondary structures are very similar and we believe account for their shared unique abilities to promote differentiation of non-muscle cells into definitive cardiomyocytes. We are beginning to explore the potential for repair/regeneration of cardiac muscle in vivo using mouse and rat models with induced acute myocardial infarctions (AMI) to determine if pluripotent stem cells or fibroblasts transfected with the human CIRs or CIRs alone injected into the damaged areas of the hearts can effect repair of the damaged cardiac muscle tissue, and return the infarcted hearts and the AMI animal models to pre-heart-attack function again. If cardiac cells damaged in heart attacks can be replaced with living, functioning cardiomyocytes, patients with heart disease would be able to have normal heart function restored and could return to normal pre-heart-attack activity levels. Understanding how CIR transforms non-muscle cells into vigorously contracting, functional cardiac muscle and effectively replacing damaged heart cells with newly-formed cardiac muscle tissue would represent a major breakthrough in modern biology and medicine with the potential to have a significant impact on the survival rate and quality of life of millions of individuals worldwide who suffer heart attacks each year.