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
Research in the Small Lab is focused on understanding the molecular mechanisms that control how a cell responds to its surroundings during development or following tissue injury. Specifically, we are interested in characterizing the gene regulatory circuits that are activated following cardiac injury, and how these circuits define a cellular response.
The transition to heart failure (HF) following an initial insult is partially caused by the development of cardiac fibrosis. Fibrosis is a form of scarring that increases the rigidity of muscular tissue, decreases cardiac contractility and can lead to 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. Although current therapeutic strategies improve contractility by targeting the cardiomyocyte, without a complementary approach to block or reverse the development of fibrosis and regenerate functioning myocardium, treatment options often represent a bridge to cardiac transplantation.
The Small Lab uses mouse genetics, cell biology and biochemical approaches to define the molecular mechanisms that control fibroblast plasticity and progenitor cell differentiation during development and disease with the ultimate goal of developing novel therapeutic approaches to block or reverse the progression of HF. The first focus of my lab revolves around our recent finding that cardiac fibroblasts exhibit distinct gene expression programs (GEP) in physiological (exercise training/sustained cardiac function) versus pathological (disease states/deterioration of cardiac function) remodeling. We are currently using mouse genetics and cell biological approaches to test the hypothesis that some genes that are expressed in fibroblasts specifically during exercise might abrogate the development of cardiac fibrosis. A related project is aimed at identifying novel small molecules that might block pathological fibroblast activation and the development of cardiac fibrosis.
The second major focus my lab is aimed at defining the gene regulatory mechanisms leading to the mobilization and differentiation of an important population of cardiovascular progenitors, called epicardium- derived progenitor cells (EPDCs). EPDCs give rise to fibroblasts and perivascular cells in the embryo and can repopulate damaged myocardium in the adult. We have recently found that Myocardin-related transcription factors drive EPDC motility, pericyte differentiation and coronary vessel maturation. This study is expected to accelerate the development of strategies to stimulate progenitor cell mobilization for neovascularization and cardiac regeneration.
Taken together, our lab is well positioned to define the cellular and molecular mechanisms that regulate cardiac progenitor cell differentiation and fibroblast plasticity and use this knowledge to devise novel and innovative therapeutic strategies to reduce cardiac fibrosis and promote regeneration in HF patients.
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
- Guo B, Lyu Q, Slivano OJ, Dirkx R, Christie CK, Czyzyk J, Hezel AF, Gharavi AG, Small EM, Miano JM., Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function, J Am Soc Nephrol. 2018 Feb;29(2):416-422. doi: 10.1681/ASN.2017050473. Epub 2017 Nov 7.
- Cao J, Wang J, Jackman CP, Cox AH, Trembley MA, Balowski JJ, Cox BD, De Simone A, Dickson AL, Di Talia S, Small EM, Kiehart DP, Bursac N, Poss KD, Tension Creates an Endoreplication Wavefront that Leads Regeneration of Epicardial Tissue, Dev Cell. 2017 Sep 25;42(6):600-615.e4. doi: 10.1016/j.devcel.2017.08.024.
- Small EM, Burke RM., β-Adrenergic Blockade in Ischemia-Reperfusion Injury: βARKing Up a New Tree, J Am Coll Cardiol. 2017 Aug 22;70(8):972-974. doi: 10.1016/j.jacc.2017.06.062. No abstract available.
- Knight WE, Chen S, Zhang Y, Oikawa M, Wu M, Zhou Q, Miller CL, Cai Y, Mickelsen DM, Moravec C, Small EM, Abe J, Yan C., PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction, Proc Natl Acad Sci U S A. 2016 Oct 20. pii: 201607728. [Epub ahead of print].
- Trembly MA, Velasquez LS, Small, EM., Epicardial Outgrowth Culture Assay and Ex Vivo Assessment of Epicardial-derived Cell Migration., J. Vis Exp. 2016 Mar 18;(109).
- Luna-Zurita L, Stirnimann CU, Glatt S, Kaynak BL, Thomas S, Baudin F, Samee MA, He D, Small EM, Mileikovsky M, Nagy A, Holloway AK, Pollard KS, Müller CW, Bruneau BG., Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis., Cell. 2016 Feb 25;164(5):999-1014.
- Lighthouse JK, Small EM., Transcriptional control of cardiac fibroblast plasticity., J Mol Cell Cardiol. 2016 Feb;91:52-60
- Trembley MA, Velasquez LS, de Mesy Bentley KL, Small EM. Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels. Development. 2015;142(1):21-30.
- Velasquez LS, Sutherland LB, Liu Z, et al. Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing. Proc Natl Acad Sci U S A. 2013;110(42):16850-16855.
- Small EM. The actin-MRTF-SRF gene regulatory axis and myofibroblast differentiation. J Cardiovasc Transl Res. 2012;5(6):794-804.
- Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469(7330):336-342.
- Miano JM, Small EM. MicroRNA133a: a new variable in vascular smooth muscle cell phenotypic switching. Circ Res. 2011;109(8):825-827.
- Small EM, Thatcher JE, Sutherland LB, et al. Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction. Circ Res. 2010;107(2):294-304.
- Small EM, Sutherland LB, Rajagopalan KN, Wang S, Olson EN. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling. Circ Res. 2010;107(11):1336-1344.
- Small EM, O'Rourke JR, Moresi V, et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc Natl Acad Sci U S A. 2010;107(9):4218-4223.
- Small EM, Frost RJ, Olson EN. MicroRNAs add a new dimension to cardiovascular disease. Circulation. 2010;121(8):1022-1032