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MARK MERCOLA, PH.D.
Professor, Stem Cells and Regenerative Biology
858.795.5242 (phone)
858.795.5274 (fax)
mmercola@burnham.org
RESEARCH FOCUS, BIOGRAPHY, PUBLICATIONS
Research Focus
Research is directed at discovering molecules that promote differentiation of cardiomyocyte progenitors that will ultimately be useful for regeneration of muscle cells that are lost in heart disease. To do this, we 1) study heart formation during embryonic development to learn about the natural cell and tissue interactions that control heart formation, 2) study cardiomyocyte differentiation in mouse and human embryonic stem cells (ESCs), and 3) use robotic screening approaches to discover small molecules for cardiomyocyte production from ESCs.
Recent studies from the laboratory led to the discovery of signaling cascades that specify cardiogenic mesoderm in the early embryo and, subsequently, control the formation of certain cardiac tissues, such as heart muscle cells. Signaling cascades initiated by Wnt, BMP and Notch proteins are critical, as are complex interactions with tissues outside the heart field such as cells of the developing nervous system. Knowledge of the pathways that produce heart tissue in embryos is being applied to cardiomyogenesis for regenerative medicine applications.
A second emphasis of the lab focus is the production of pancreatic beta cells for diabetes applications. As for cardiomyocytes, the approach is to develop automated screening procedures to discover genes, proteins and small molecules that can be used to produce beta cells. Starting cell sources are ESCs as well as primary and immortalized human pancreatic cells.
Biography
Mark Mercola earned his Ph.D. from the University of California, Los Angeles in 1985. Dr. Mercola trained as a postdoctoral fellow at the Dana-Farber Cancer Institute and Department of Microbiology at Harvard Medical School in Boston, MA. He was appointed Assistant Professor in the Department of Cell Biology at Harvard Medical School in 1991 and Associate Professor in 1996. Dr. Mercola joined the Burnham Institute for Medical Research in 2002 where he is Professor in the Neurodegeneration and Aging Centerand is also an adjunct Professor in the Department of Pathology at the University of California, San Diego School of Medicine.
Selected Publications
Woda J.M., Pastagia J., Mercola M., and Artinger K.B. Dlx proteins position the neural plate border and determine adjacent cell fates. Development 130:331-42, 2003.
Rones, M.S., McLaughlin, K.A., Raffin, M. and Mercola, M. Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis. Development 127:3865-3876, 2000.
Schneider, V. and Mercola, M. Wnt antagonism is required for heart induction. Genes and Development 15:304-315, 2001.
Mercola, M. and Levin, M. Left-Right Asymmetry Determination in Vertebrates. Annual Review of Cell and Developmental Biology 17:779-805, 2001.
Levin, M., Thorlin, T., Robinson, K.R, Nogi, T., and Mercola, M. Asymmetries in H+/K+-ATPase and Cell Membrane Potentials Comprise a Very Early Step in Left-Right Patterning. Cell 111: 77-89, 2002.
List of Publications via PubMed
(NIH National Library of Medicine)
Research Report
EMBRYONIC AND STEM CELL CARDIOGENESIS
(Download report as PDF)
Heart disease is a major cause of mortality and morbidity in developed countries. Repair of heart muscle following injury is clinically negligible; instead, scar tissue replaces damaged myocardium leading to impaired heart function and a reduction in quality of life. Our laboratory studies cardiogenesis in embryos and stem cells as a means of discovering factors that would promote efficacious regeneration or rejuvenation of cardiac tissue.
Heart formation during embryogenesis is promoted by numerous diffusible proteins, including bone morphogenetic proteins (BMPs) and fibroblast growth factor (FGF) isoforms. These proteins regulate the production and activity of cardiac transcription factors, which direct differentiation by reprogramming gene expression in the individual heart cells. Our laboratory recently demonstrated that two Wnt antagonists, known as Dickkopf-1 and Crescent, are needed to initiate cardiogenesis in embryos. Exposure of embryonic mesoderm to either of these factors results in the formation of beating heart tubes in vitro (Figure). Thus, a cardiogenic program is now emerging. Initiation of the program is triggered by proteins such as Dickkopf1 to block ƒÒ-catenin-dependent transcription and also by JNK signaling. Progression subsequently requires BMPs and other proteins to regulate transcription factors such as Nkx2.5, GATA4, myocardin, and Tbx5. As heart developing continues, other signals specify distinct cell fates. Of interest to our lab are those that determine cardiomyocytes and we have found that signaling from the transmembrane protein Notch influences heart muscle fates and subsequently regulates other cardiac cell fate decisions.
The details of embryonic heart formation suggest strategies for the efficient stimulation of cardiac regeneration following injury. Protocols are being developed that use signalling proteins to stimulate human embryonic stem (ES) cells to form heart tissues. In addition, a drug discovery program is underway to identify small molecules that could be used to promote efficient heart cell differentiation from human ES cells. Lastly, multipotent cells in the adult heart might also permit cardiac regeneration directly in damaged hearts, but the factors that control their differentiation and proliferation are largely unknown. We are searching for endogenous cardiac stem cells and hope to identify natural and synthetic factors that could be used to promote their differentiation.
The laboratory is also interested in understanding the basis for left-right asymmetry that characterizes the heart, as well as most internal organs, and is essential for cardiac function. We have been working to understand how left-right asymmetry is oriented with respect to the embryo's dorsoventral and anteroposterior axes. We have found two signals that work very early during embryogenesis to regulate the well-characterized left- and right-sided cascades of gene expression. These are gap junctions, which appears to mediate the propagation of low molecular weight determinants to coordinate LR asymmetry, and potassium flux dependent on a H/K exchanger. The H/K exchanger is the earliest known step in asymmetry determination.
Induced hearts produced in vitro by exposure of non-cardiogenic tissue to Dkk1 (Schneider and Mercola, Genes and Development, (2001) 15,304-315). The beating heart tube is in the center of the tissue in the upper left panel and stained in red (antibody toTroponin-T) in the upper right panel. A histological cross section (bottom panel) reveals a well formed tube heart tube. The blue stain in the bottom panel labels all cell nuclei.
