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 have been used to to identify the antigen detected by the monoclonal antibody. The result has been corroborated through the use of the antibody against a panel of 17,000 human ESTs from human brain. We hope to obtain a peptide that binds the antigen which could be tagged for mouse and perhaps human nuclear studies. ? ? Recently, prompted by the frequency of inappropriate expression of fetal antigens in injured or cancerous tissue, we have determined that this antigen appears in a subset of brain, breast and kidney cancer. We have identified a cancer cell line that expresses the identified antigen on its surface and many lines in which the antigen is trapped within the cell in an internal structure called an """"""""exocyst"""""""" This perinuclear structure is mostly unknown to cell biologists with the exception of those who study yeast. The exocyst sits next to Golgi bodies outside the nucleus and is responsible for processing proteins and membrane delived to the cell surface. We intend to explore its role in both stem cells and cancer over the next 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 |
