Eric M. Small
Associate Professor, Department of Medicine
Aab Cardiovascular Research Institute (CVRI)
2003 | Ph.D. | University of Texas-Austin
1995 | BS | Cell and Molecular Biology | University of Michigan
The overall goal of the Small lab is to better understand the mechanisms that control cell identity and lineage commitment by studying the transcriptional regulation and function of cardiac tissue-restricted genes. Our motivation is to decipher how disruption of cardiac gene expression programs in heart disease contributes to cellular pathophysiology and the decline in cardiac function. There are two major themes of research within the lab that we study using mouse genetics, cell biology, advanced imaging, bioinformatic and biochemical approaches:
- Cardiac fibroblast plasticity and the development of cardiac fibrosis. The transition to heart failure following cardiac insult is the result of irreversible cardiomyocyte loss and the development of cardiac fibrosis, which impedes contractility and can initiate lethal arrhythmias. Cardiac fibrosis arises from the aberrant and persistent stimulation of fibroblasts, the main source of extracellular matrix in the heart, in a pathological attempt to repair damaged tissue. We utilize gene expression profiling in animal models of heart disease and human heart failure patient samples to identify novel regulators of cardiac fibroblast accumulation and myofibroblast activation in health and disease. We also utilize high-throughput screening and pre-clinical animal studies to develop novel pharmacological and gene-targeting strategies to block or reverse cardiac scarring and the progression of heart failure.
- Epicardium-derived progenitor cell mobilization. Epicardium-derived progenitor cells (EPDCs) can differentiate into cardiac fibroblasts and coronary blood vessels, and secrete signals that stimulate cardiac growth during embryonic development. We are striving to understand how EPDCs interpret developmental signals and differentiate into the appropriate cell type based upon their location within the heart. We have identified a mechanosensitive gene program that is essential for EPDC migration and subsequent differentiation into fibroblasts and perivascular cells. Ongoing studies are aimed at evaluating whether disruption of mechanosensitive transcriptional programs within the epicardium might contribute to cardiomyopathy. Our long-term goal is to harness the regenerative potential of the epicardium to improve cardiac repair.
Figure: Epicardium-derived cells
undergoing epithelial- mesenchymal
transition (EMT) exhibit Vinculin-positive
focal adhesions (green) and smooth
muscle actin-positive stress fibers (red).
Figure: Epicardium-derived cells (green)
undergoing EMT and migrating into the
compact myocardium in the developing
heart. Endothelial cells are stained with
- Trembley M.A., Quijada P., Agullo-Pascual E., Tylock M.S., Colpan M., Dirkx R.A., Myers J.R., Mickelsen D.M., Bentley K., Rothenberg E., Moravec C.S., Alexis J.D., Gregorio C.C., Dirksen R.T., Delmar M. and Small E.M.* (2018) Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors is Required for Cadrdiomyocyte Integrity in Load-Induced Ventricular Hypertrophy. Circulation(In press).
- BurkeR.M., LighthouseJ.K., QuijadaP., Dirkx, Jr.R.A., RosenbergA., MoravecC.S., AlexisJ.D., SmallE.M.*(2018) Small Proline Rich Protein 2B Drives Stress Dependent P53 Degradation and Fibroblast Proliferation in Heart Failure.Proc Natl Acad Sci USA115: E3436-3445. PMID: 29581288.
- Guo B., Lyu Q., Slivano O.J., Dirkx R., Christie C.K., Czyzyk J., Hezel A.F., Gharavi A.G., Small E.M., Miano J.M. (2017) Serum Response Factor Is Essential for Maintenance of Podocyte Strucutre and Function. J Am Soc Nephrol. (Epub ahead of print). PMID: 29114040.
- Cao J., Wang J., Jackman C.P., Cox A.H., Trembley M.A., Balowski J.J., Cox B.D., De Simone A., Dickson A.L., Di Talia S., Small E.M.,Kiehart D.P., Bursac N., Poss K.D. (2017) Tension Creates an Endoreplication Wavefront that Leads Regeneration of Epicardial Tissue. Dev. Cell.42:600-615. PMID: 28950101.
- Small E.M.*and Burke R.M.(2017). b-Adrenergic Blockade in Ischemia-Reperfusion Injury: bARKing Up a New Tree. J Am Coll Cardiol. 70:972-974. PMID: 28818207.
- Knight W., Oikawa M., Wu M., Zhou Q., Miller C.L., Cai Y., Mickelsen D.M., Moravec C.S., Small E.M., Abe J., and Yan C. (2016) PDE1C deficiency and inhibition potentiates cardiac protective adenosine-cAMP signaling. Proc Natl Acad Sci USA(Epub ahead of pring) PMID: 27791092.
- Trembley M.A., Velasquez L.S., and Small E.M.*(2016). Epicardial outgrowth culture assay and ex vivo assessment of epicardial-derived cell migration. J Vis Exp.(109) PMID: 27023710
- Luna-Zurita L., Stirnimann C.U., Glatt S., Kaynak B.L., Thomas S., Baudin F., Samee M.A.H, He D., Small E.M., Mileikovsky M., Nagy A., Holloway A.K., Pollard K.S., Muller C.W., and Bruneau B.G. (2016) Complex interdependence regulates heterotypic transcription factor genomic distribution and coordinates cardiogenesis. Cell164:999-1014. PMID: 26875865
- Lighthouse J.K. and Small E.M.*(2016). Transcriptional control of cardiac fibroblast plasticity. J Mol Cell Cardiol.91:52-60. PMID: 26721596
- Trembley M.A., Velasquez L.S., de Mesy Bentley K.L., and Small E.M.*(2015). Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels. Development142:21-30. PMID:25516967. Feature article.
- Velasquez L.S, Sutherland L.B., Liu Z., Grinnell F., Kamm K.E., Schneider J.W., Olson E.N. and Small E.M.*(2013). A small molecular activator of MRTF-A dependent gene expression promotes myofibroblast differentiation and wound healing. Proc Natl Acad Sci USA. 110, 16850-16855.PMID: 24082095.
- Rodés-Cabau J., Dauerman H.L., Cohen M.G., Mehran R., Small E.M., Smyth S.S., Costa M.A., Mega J.L., O'Donoghue M.L., Ohman E.M., Becker R.C. (2013). Antithrombotic Treatment in Transcatheter Aortic Valve Implantation: Insights for Cerebrovascular and Bleeding Events. J Am Coll Cardiol. 62:2349-2359. PMID: 23583252