Department of Cell Biology Faculty

Research Overview

Developmental cardiology, fetal cardiac stem cells, signal transduction mechanisms in heart development and disease, mammalian heart development, transcriptional regulatory mechanisms in heart development and cardiac hypertrophy, neurosphere development and analysis, neural tube/spinal cord development, retinoic acid biology.

Fetal Cardiac Stem Cells as a Model for Generating Cardiomyocytes in the Adult Heart

The goal of regenerative medicine is to restore function to diseased organs by generating cells to replace those lost to disease or injury. Because endogenous regenerative processes fall short of fully regenerating damaged tissues, the use of exogenous cells, most notably stem cells, has become an attractive alternative. One type of stem cell, the fetal stem cell, may provide insights into organ growth that can be applied to the regeneration of cells in adult tissues. In developing organs, fetal stem cells generate new cells at a rate that is "geared" to populate a rapidly growing organ. Recapitulating these same growth processes in adult progenitors may be the most direct way of generating sufficient replacement cells to replace those lost to disease or injury. We are interested in applying this approach to cardiac development and regeneration using the fetal heart as a model for generating new cardiomyocytes from cardiac progenitors. Recent studies suggest that these cells arise from precursors within the epicardial cell layer via an epithelial-to-mesenchyme transformation (EMT) that frees them to migrate into the myocardium where they differentiate into cardiomyocytes. Notably, EMT is required for the generation of cancer stem cells and is likely to be involved in the development of other stem or progenitor cells including cardiac stem cells. Our entry into these issues came with our finding that HMGA2, a chromatin modifier and transcription co-factor, selectively labels fetal epicardial cells as well as presumptive derivatives that have migrated into the trabeculated myocardium. What separates HMGA2 from other epicardial markers is that it has been implicated in imparting "stemness" to cells, in particular cancer cells, by controlling their proliferation through the let7 microRNA. Thus, by understanding how HMGA2 controls the production of cardiomyocyte precursors from epicardial precursors in the developing heart, we may be in a better position to understand how to stimulate these same processes in adult epicardium to generate cardiac replacement cells in diseased hearts.

SELECTED RECENT PUBLICATIONS

1. Wagner, M. and Siddiqui, M.A.Q. Signaling networks regulating cardiac myocyte survival and death. Curr. Opin. In Investigational Drugs. 2009; 10(9):928-37.
2. Espinoza-Derout, J., Wagner, M., Lazar, J., Salciccioli, S., Chaqour, B. and Siddiqui, M.A.Q. Positive Transcription Elongation Factor b Activity in Compensatory Myocardial Hypertrophy is Regulated by Cardiac Lineage Protein-1. Circulation Res. 2009; 104(12):1347-54.
3. Liao WL, Tsai HC, Wang HF, Chang J, Lu KM, Wu HL, Lee YC, Tsai TF, Takahashi H, Wagner M, Ghyselinck NB, Chambon P, Liu FC. Modular patterning of structure and function of the striatum by retinoid receptor signaling. Proc Natl Acad Sci U S A. 2008; 105(18):6765-70.
4. Wagner M and Siddiqui MAQ. Signal Transduction in Early Heart Development (I): Cardiogenic Induction and Heart Tube Formation. Exp. Biol. Med. 2007; 232(7):852-65.
5. Wagner M and Siddiqui MAQ. Signal Transduction in Early Heart Development (II): Ventricular Chamber Specification, Trabeculation and Heart Valve Formation. Exp. Biol. Med. 2007; 232(7):866-80.
6. Espinoza-Derout J, Wagner M, Shahmiri K, Mascareno E, Chaqour B, Siddiqui MAQ. Pivotal role of cardiac lineage protein-1 (CLP-1) in transcriptional elongation factor P-TEFb complex formation in cardiac hypertrophy. Cardiovasc Res. 2007; 75(1):129-38.
7. Liao WL, Wang HF, Tsai HC, Chambon P, Wagner M, Kakizuka A, Liu FC. Retinoid signaling competence and RARbeta-mediated gene regulation in the developing mammalian telencephalon. Dev Dyn. 2005; 232(4):887-900.
8. Huang, F., Wagner, M., Siddiqui, M.A.Q. Ablation of the CLP-1 gene leads to down-regulation of the HAND1 gene and abnormality of the left ventricle of the heart and fetal death. Mech. Dev. 2004; 121:559-572.
9. Miles K, Wagner M. Overexpression of nPKC theta is inhibitory for agrin-induced nicotinic acetylcholine receptor clustering in C2C12 myotubes. J Neurosci Res. 2003; 71(2):188-95.
10. Huang F, Wagner M, Siddiqui M.A.Q. Structure, expression, and functional characterization of the mouse CLP-1 gene. Gene 2002; 292: 245-259.
11. Wagner, M., Miles, K., and Siddiqui, M.A.Q. Early Developmental Expression Pattern of Retinoblastoma Tumor Suppressor mRNA Indicates a Role in the Epithelial-to-Mesenchyme Transformation of Endocardial Cushion Cells. Dev. Dynamics 2001; 220:198-211.
12. Miles, K. and Wagner, M. Overexpression of nPKC-theta is permissive for myogenic differentiation. J. Cell. Biochem. 2000; 79:71-79.

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