Heart failure may occur from a variety of causes including ischemic heart disease, toxins, pressure or volume overload. Recovery of cardiac function is hindered by a long known observation that cardiac myocytes do not divide in appreciable numbers during adult life. Physiologic demands for increased cardiac output are met by hypertrophy of existing cardiac myocytes through the formation of additional sarcomeres (the unitary contractile apparatus) within these cells. At the present time, the only remedy for end stage heart failure is cardiac transplant, which is limited by the supply of matched hearts and complicated by the need to suppress immune rejection. We have discovered a previously unknown subpopulation of stem cells in adult murine skeletal muscle that can be transformed into beating cardiomyocytes under primary tissue culture conditions. These cells are not satellite cells, myofibroblasts or myoblasts. A portion of the freshly isolated stem cells, injected into the vein of a mouse with chronic heart failure, will home to the heart and progress along a pathway to cardiac cell differentiation. ? More recently, we have raised a monoclonal antibody to a cell surface antigen unique to another subset of these stem cells. This novel monoclonal in combination with another antibody (Sca 1), defines 3 populations from adult skeletal muscle, which, at the time of isolation are already committed to become either: (1) adipose, (2) neuronal, or (3) cardiac cells, when grown in culture under the same standard conditions. The novel antibody defines an antigen that is present on neuronal stem cells across species and which first appears in the mouse embryo on day 12.5, the first day that neurons can be observed. When the antibody is used to harvest cells from total day 12.5 mouse embryos, the harvested cells grow into neurons in cell culture containing only FGF as a growth factor. Thus, the antigen recognized by the monoclonal is an embryonic antigen present on neuronal stem cells across species. Immunoprecipitation and Mass-Spectroscopy are being replicated to identify the antigen detected by the monoclonal antibody. Plans are underway to clone the gene from a human fetal brain expression array library as well as the screening of a small molecule library. We hope to obtain a peptide that binds the antigen which could be tagged for mouse and perhaps human nuclear studies. Positive identification of the antigen, together with additional injection of these marked cells into mouse hippocampus, remain to be completed before submission of a manuscript this year. ? Recently, prompted by the frequency of inappropriate expression of fetal antigens in injured or cancerous tissue, we have determined that this antigen appears on a subset of brain, breast and kidney cancer. We are now arranging to obtain human tissue from which we can explore the possibility that cancer stem cells may be enriched in the antigen positive cells. Finally, using some of the techniques learned from adult stem cell experiments in our laboratory, we have been working over the last 5 years, to isolate very pluripotent stem cells from a variety of commercially available human tissue. These experiments have been extremely successful. We look forward to submitting the results within the end of this calendar year.
| Epstein, Neal D; Davis, Julien S (2006) When is a fly in the ointment a solution and not a problem? Circ Res 98:1110-2 |
| Winitsky, Steve O; Gopal, Thiru V; Hassanzadeh, Shahin et al. (2005) Adult murine skeletal muscle contains cells that can differentiate into beating cardiomyocytes in vitro. PLoS Biol 3:e87 |
