Since 1996, the Murry lab has worked to understand the mechanisms that underlie cardiovascular disease and to develop new treatments. We have a longstanding interest in the biology of myocardial infarction (heart attacks), and in particular, how the heart heals after infarction. The lab has a major focus in stem cell biology and tissue engineering, where we seek to understand the molecular basis for cardiovascular differentiation, and to harness the potential of stem cells to repair the heart. We are one of the leading groups in the use of human pluripotent stem cells for heart regeneration. Our current work is focused on non-human primates, and we are moving toward therapeutic trials in human patients.
Recently, our group has begun to use stem cell approaches to study genetically based cardiomyopathies. We are deriving induced pluripotent stem cells (iPSCs) from patients with cardiomyopathy, and using cell biology and tissue engineering for “disease in a dish” studies. Our current foci are on disorders involving mutations in myosin (MYH7) and myosin binding protein-C (MYBPC).
Myocardial infarctions (heart attacks) are the number one cause of death in the industrialized world. Infarcts occur when a coronary artery becomes obstructed, resulting in the rapid death of myocardium from ischemia (deficiency of blood flow). The heart has no significant intrinsic regenerative ability. As a result, infarcts heal by scar formation, and many patients suffer from heart failure after an infarct. Our group is interested in the biology of myocardial infarction, both in defining the molecular mechanisms that underlie the heart’s normal wound healing processes and in developing molecular and cell-based approaches to improve infarct repair. We are a multidisciplinary group, doing basic work in molecular biology and regulation of gene expression, cell biology, tissue engineering, mouse models of disease, and analyses of human tissues. The following serves to highlight some of the work underway in the lab.
Stem Cell Studies
Our lab is working with both adult and pluripotent (embryonic and iPSC) stem cells, with an aim to develop cellular approaches to regenerate the heart. Our work in adult stem cells is focused on creating transgenic/knock-in mice to track progenitor cells in the heart. We will use genetic pulse-chase techniques to mark candidate progenitor populations and then follow their appearance into other compartments of the heart such as muscle cells or blood vessels. We are working with mesenchymal stem cells to enhance survival of transplanted cardiomyocytes via paracrine signaling pathways. Pluripotent stem cell studies are focused on molecular pathways involved in cardiovascular differentiation, including the use of high throughput sequencing to understand chromatin remodeling and transcription factor binding. We recently identified key roles for signaling through Wnt and VEGF pathways in determining cardiac, smooth muscle and endothelial fate. We are also using these early cells to repair the infarcted heart via cell transplantation and have shown that stem cell-derived human myocardium prevents development of heart failure after experimental infarction. Recently we have succeeded in partially regenerating the hearts of non-human primates, and we hope to translate these studies to first-in-human trials of heart repair in several years.
Tissue engineering is a new discipline that combines the worlds of cell biology, materials science and quantitative approaches to mathematical modeling and analyses typical of engineering. Our goals are threefold: 1) to create a ”patch” of contractile tissue ex vivo and implant this onto an infarcted heart for cardiac repair; 2) to understand the rules of tissue assembly, growth and development to make myocardium that is useful for drug screening or disease modeling; and 3) to use engineered heart tissues to model genetically based human heart muscle diseases. Current approaches involve seeding cells onto synthetic, biodegradable scaffolds and utilizing a ”cells in gels” approach, where cells are seeded into hydrophilic gels containing microencapsulated growth factors and cytokines for timed release.
Human Disease Modeling
We are using human induced pluripotent stem cells (hiPSCs) obtained from patients with childhood- and adult-onset cardiomyopathies to study these genetically based diseases in vitro. We have developed single-cell and engineered heart tissue assays to assess contractile function and electrical function. A major goal is to promote the in vitro maturation of human cardiomyocytes such that they better reflect the physiology of the postnatal heart.
Fellowship, Experimental and Diagnostic Cardiovascular Pathology, 1996
Residency, Anatomic Pathology, University of Washington, 1992
MD, Duke University, 1989
PhD (pathology), Duke University, 1988
BS, University of North Dakota, 1982
2014 UW Presidential Entrepreneurial Faculty Fellow ($10,000 prize)
2014 University of Missouri James O. Davis Lecture 2013 Elected as American Association for the Advancement of Science Fellow
2013 Keynote Lecture, Weinstein Cardiovascular Development Meeting, University of Arizona
2013 Fyler Lecture, Children’s Hospital of Boston
2012 Alumni Lecture, University of North Dakota
2012 Elected to Washington State Academy of Sciences
2011 Oregon Health Sciences University, James Metcalfe Lecture
2011 Keith Reimer Distinguished Lecture, International Society for Heart Research
2010 Association of American Physicians
2008 Distinguished Basic Science Teacher Award, UW School of Medicine ($5000 prize)
2007 Wall of Fame, Bismarck High School
2006 Basic Science Professor of the Quarter, UW School of Medicine
2005 Basic Science Professor of the Quarter, UW School of Medicine
2003 Basic Science Professor of the Quarter, UW School of Medicine
2003 Alumnus of the Year, Bismarck State College
2000 Presidential Early Career Award in Science and Engineering
1999 American Heart Association Council on Basic Cardiovascular Sciences Research Prize (Received $30,000 for support of a research fellow)
Fellowship: 1996 Burroughs Wellcome Career Award in the Biomedical Sciences
1994 American Society for Investigative Pathology Merit Award
Residency: 1993 Arthur Purdy Stout Fellowship (Studied cardiovascular pathology with Dr. Margaret Billingham, Stanford University) Graduate School:
1987 Runner-Up, Upjohn Award (International Society for Heart Research Young Investigator Award)
1986 Winner, Sheard-Sanford Award (American Society of Clinical Pathologists award for outstanding student research)
Medical School: 1984-1985 Eugene Stead Fellow
1984-1985 Eugene Stead Fellow
1982-1983 Medical Alumni Scholarship
1982 Phi Beta Kappa
1982 Summa Cum Laude
1981 Ben Gustafson Scholarship for Outstanding Achievement in Chemistry
Stevens KR, Pabon L, Murry CE. Scaffold-free human cardiac tissue patch created from embryonic stem cells. Tissue Eng Part A. 2009 Jun;15(6):1211-22 [Epub Dec 8, 2008].
Moreno-Gonzalez A, Korte FS, Dai J, Chen K, Ho B, Reinecke H, Murry CE*, Regnier M*. Cell therapy enhances function of remote non-infarcted myocardium. J Mol Cell Cardiol. 2009 Nov;47(5):603-13. Epub 2009 Aug 14. *equal contributions
Stevens KR, Kreutziger K, Dupras S, Korte FS, Regnier MA, Muskheli V, Nourse M, Bendixen K, Reinecke H, Murry CE. Physiological Function and Transplantation of Scaffold-free and Vascularized Human Cardiac Muscle Tissue. Proc Natl Acad Sci USA 2009 Sep 29;106(39):16568-73. Epub 2009 Sep 17.
Nourse MB, Scatena M, Mortisen DJ, Hauch KD, Ratner BD, Pabon L, Murry CE. VEGF induces differentiation of endothelium from human embryonic stem cells: implications for tissue engineering. Arterioscler Thromb Vasc Biol. 2010 Jan;30(1):80-9. Epub 2009 Oct 29.
Madden LR, Mortisen DJ, Sussman EM, Dupra SK, Fugate JA, Cuy JL, Hauch KD, Laflamme MA, Murry CE, Ratner BD. Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proc Natl Acad Sci U S A. 2010 Aug;107(34):15211-16. Epub 2010 Aug 9.
Naumova AV, Reinecke H, Yarnykh V, Deem J, Yuan C, Murry CE. Ferritin overexpression for noninvasive magnetic resonance imaging-based tracking of stem cells transplanted into the heart. Mol Imaging. 2010 Aug;9(4):201-10.
Fernandes S, Naumova AV, Zhu WZ, Laflamme MA, Gold J, Murry CE. Human embryonic stem cell-derived cardiomyocytes engraft but do not alter cardiac remodeling after chronic infarction in rats. J Mol Cell Cardiol. 2010 Dec;49(6):941-9.
Garbern JC, Minami E, Stayton PS, Murry CE. Delivery of basic fibroblast growth factor with a pH-responsive, injectable hydrogel to improve angiogenesis in infarcted myocardium. Biomaterials. 2011 Mar;32(9):2407-16.
Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, Lynch C, Harness JV, Lee S, Barrero MJ, Ku S, Martynova M, Semechkin R, Galat V, Gottesfeld J, Izpisua Belmonte JC, Murry CE, Keirstead HS, Park HS, Schmidt U, Laslett AL, Muller FJ, Nievergelt CM, Shamir R, Loring JF. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell. 2011 Jan 7;8(1):106-18.
Kreutziger KL, Muskheli V, Johnson P, Braun K, Wight TN, Murry CE. Developing Vasculature and Stroma in Engineered Human Myocardium. Tissue Eng Part A. 2011 May;17(9-10):1219-28. Epub 2011 Feb 2.
Kreutziger KL, Murry CE. Engineered Human Cardiac Tissue. Pediatr Cardiol. 2011 Mar;32(3):334-41. Epub 2011 Feb 4.
Tulloch NL, Muskheli V, Razumova MV, Korte FS, Regnier M, Hauch KD, Pabon L, Reinecke H, Murry CE. Growth of engineered human myocardium with mechanical loading and vascular co-culture. Circ Res. 2011 Jun 24;109(1):47-59. Epub 2011 May 19.
Korte FS, Dai J, Buckley K, Feest ER, Adamek N, Geeves MA, Murry CE, Regnier M Upregulation of cardiomyocyte ribonucleotide reductase increases intracellular 2 deoxy-ATP, contractility, and relaxation. J Mol Cell Cardiol. 2011 Dec;51(6):894-901.Epub 2011 Sep 3.
Naumova AV, Yarnykh VL, Balu N, Reinecke H, Murry CE, Yuan C. Quantification of MRI Signal of Transgenic Grafts Overexpressing Ferritin in Murine Mycardioal Infarcts. NMR Biomed. 2012 Feb 24. Epub ahead of print.
Shiba Y*, Fernandes S*, Zhu WZ, Filice D, Muskheli V, Kim J, Palpant NJ, Gantz J, Moyes KW, Reinecke H, Van Biber B, Dardas T, Mignone JL, Izawa A, Hanna R, Viswanathan M, Gold JD, Kotlikoff MI, Sarvazyan N, Kay MW, Murry CE**, Laflamme MA**. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature. 2012 Sep 13;489(7415):322-5. *Co-first authors; **Co-corresponding authors. This paper was rated as one of 2012’s top 8 promising medical advances by the National Institutes of Health.
Paige SL, Thomas S, Stoick-Cooper CL, Wang H, Maves L, Sandstrom R, Pabon L, Reinecke H, Pratt G, Keller G, Moon RT, Stamatoyannopoulos J, Murry CE. A temporal chromatin signature in human embryonic stem cells identifies regulators of cardiac development. Cell. 2012 Sep 28;151(1):221-32. Epub 2012 Sep 11.