Cell Biology, Neurobiology & Anatomy

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John W. Lough, PhD
Professor

Department of Cell Biology, Neurobiology & Anatomy
Medical College of Wisconsin
8701 Watertown Plank Road
Milwaukee, WI 53226-0509

Phone: (414) 955-8459
FAX: (414) 955-6517
email: jlough@mcw.edu

 

Education:
PhD, Washington University, St. Louis, 1975
Postdoctoral, Massachusetts Institute of Technology
 

Graduate Programs:
Program in Cell and Developmental Biology

Research Area: Cell and molecular biology of cardiac stem cell differentiation

Our research is focused on adult cardiac regeneration, using principles learned from previous investigation of heart development in the embryo. We are using two independent albeit complementary approaches to address this problem. The first approach extends from our discovery that embryonic tissues, specifically precardiac endoderm and mesoderm, can induce embryonic stem cells (ESCs) to differentiate into beating cardiac myocytes. We are extending this finding by identifying extracellular growth factors, secreted by human definitive endoderm and precardiac mesoderm, which mediate cardiomyogenic induction in human induced pluripotent cells (iPSCs). A near-term goal is to optimize cardiomyogenic induction in iPSCs for transplantation capable of re-muscularizing infarcted adult myocardium. The second approach tests the hypothesis that Tip60 (Tat Interactive Protein, 60 kD), a protein enriched in embryonic and especially adult myocardium, functions to keep adult cardiac myocytes in a non-proliferative state. This possibility is supported by our finding that while homozygous Tip60-/- knockout mice cannot develop past the blastocyst (64-128 cell) stage of mouse embryonic development, cardiomyocytes in stressed hearts of Tip60+/- heterozygous mice attempt to re-enter the cell-cycle. We are conditionally-targeting the Tip60 gene to enable specific depletion of Tip60 protein in adult myocardium, with the expectation that this will mobilize replication of adult cardiomyocytes and/or cardiac progenitor (stem) cells. 

Selected Publications:

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Van Orman JR, Si-Tayeb K, Duncan SA, Lough J. (2009) Induction of cardiomyogenesis in human embryonic stem cells (hESCs) by hESC-derived definitive endoderm. In Revision, 2009
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Zhao M, Barron MR, Li Z, Koprowski S, Hall CL, Lough J. Making Stem Cells Infarct Avid. In press, In press, Cell Transplant., 2009
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Rufer ES, Hacker T, Flentke GR, Drake VJ, Brody MJ, Lough J, Smith SM. Altered Cardiac Function and Ventricular Septal Defect in Avian Embryos Exposed to Low-Dose Trichloroethylene. In press, Toxicol. Sci., 2009
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Hu Y, Fisher JB, Koprowski S, McAllister D, Kim MS, Lough J. Homozygous disruption of the Tip60 gene causes early embryonic lethality. Dev. Dynamics 238:2912-2921, 2009
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Van Orman JR, Weihrauch D, Warltier DC, Lough J. Myocardial interstitial fluid inhibits proliferation and cardiomyocyte differentiation in pluripotent embryonic stem cells. Am J Physiol Heart Circ Physiol. 297:H1369-1376, 2009
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Li Z, Barron MR, Lough J, Zhao M. Rapid single-step separation of pluripotent mouse embryonic stem cells from mouse feeder fibroblasts. Stem Cells Dev. 17:383-387, 2008
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Gorrini C, Squatrito M, Wark L, Martinato F, Sardella D, Bennett S, Marchesi F, Scanziani E, Mai S, Lough J, Amati B. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448:1063-1067, 2007
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Nelson TJ, Ge ZD, Van Orman J, Barron M, Rudy-Reil D, Hacker TA, Misra R, Duncan SA, Auchampach JA, Lough JW. Improved cardiac function in infarcted mice after treatment with pluripotent embryonic stem cells. Anat Rec 288:1216-1224, 2006
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Kim, M-S, X Merlo, C Wilson and J Lough. Co-activation of the atrial natriuretic factor promoter by Tip60 and serum response factor. J Biol Chem 281:15082-15089, 2006.
 
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Rudy-Reil D and J Lough. Avian precardiac endoderm/mesoderm induces cardiac myocyte differentiation in murine ES cells. Circ Res 94:e107-e116, 2004.
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Wendler CC, A Schmoldt, GR Flentke, LC Case, L Quadro, WS Blaner, J Lough and SM Smith. Increased fibronectin deposition in embryonic hearts of retinol-binding protein-null mice. Circ Res 92:920-928, 2003.

 

 

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