Research Summary

The George-Weinstein lab studies mechanisms that regulate the programming of stem cells to form skeletal and cardiac muscle. The process begins soon after fertilization within the epiblast that gives rise to all tissues of the embryo. The epiblast also serves as a source of stem cells with the potential to regenerate damaged tissues of the adult. While most epiblast cells have the capacity to differentiate into multiple cell types, we have discovered that a small subpopulation within this tissue is stably programmed to form skeletal muscle. Other skeletal muscle precursor cells, called myoblasts, arise later in development in structures called somites. Epiblast-derived skeletal muscle stem cells (e-sm stem cells) are incorporated into the somites and promote the differentiation of myoblasts by releasing Noggin, an inhibitor of the bone morphogenetic protein (BMP) signaling pathway. Surprisingly, e-sm stem cells are also integrated into organs that do not give rise to skeletal muscle, including the heart, brain and eye. When sm stem cells are removed from the epiblast, the embryo continues to develop for approximately six days; however, organs become herniated through the body wall due to a dramatic reduction in skeletal muscle. Elimination of e-sm stem cells also results in facial and eye defects. The malformations that arise in the absence of e-sm stem cells resemble those present in humans with Axenfeld-Rieger’s Syndrome. Our current goals are to define the functions of e-sm stem cells in the heart and eye. The hypothesis guiding our experiments is that e-sm stem cells are required to limit the extent of BMP signaling in specific locations within developing and mature tissues. Since BMPs promote the differentiation of cardiac muscle and lens fiber cells, e-sm stem cells are predicted to maintain a population of neighboring cells in the undifferentiated state that can be recruited for tissue regeneration in the adult. E-sm stem cells in mature tissues also may be a source of rhabdomyosarcoma tumors that often arise outside of skeletal muscle. In a separate but related project, we are collaborating with the Knudsen lab to develop protocols to efficiently program stem cells to form cardiac muscle in culture.

Awards

• American Medical Women’s Association Gender Equity Award
• Student National Medical Association’s Mentor Award
• Lindback Award for Distinguished Teaching
  Kappa Sigma Phi Educator Award

Selected Publications

• Gerhart, J., B. Bast, P. Amegbe, C. Neely, S. Iem, R. Niewenhuis, P.F. Cheng, and M. George-Weinstein. 2001. MyoD positive myoblasts are present in mature fetal organs lacking skeletal muscle. J. Cell Biol. 155, 381-391.
• Gerhart, J., C. Neely, B. Stewart, J. Perlman, D. Beckmann, M. Wallon, K. Knudsen, and M. George-Weinstein. 2004. Epiblast cells that express MyoD recruit pluripotent cells to the skeletal muscle lineage. J. Cell Biol. 164, 739-746.
• Gerhart, J., J. Elder, C. Neely, J. Schure, C. Smolenski, T. Kvist, K. Knudsen, and M. George-Weinstein. 2006. MyoD positive epiblast cells regulate skeletal muscle differentiation in the embryo. J. Cell Biol. 175, 283-292.
• Gerhart, J., C. Neely, J. Elder, J. Pfautz, J. Perlman, L Narciso, K. Linask, K. Knudsen, and M. George-Weinstein. 2007. Cells that express MyoD mRNA in the epiblast are stably committed to the skeletal muscle lineage. J. Cell Biol. 178, 649-660.

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• THE FATE AND FUNCTION OF EPIBLAST- DERIVED SKELETAL MUSCLE STEM CELLS