Gary K. Owens

Education

  • BS, Pennsylvania State University
  • MS, Pennsylvania State University
  • PhD, Pennsylvania State University
  • Postdoc, University of Washington, Seattle

Primary Appointment

  • Professor, Molecular Physiology and Biological Physics

Contact

Research Interest(s)

Epigenetic Control of Perivascular and Stem Cell Plasticity/Trans-Differentiation during Injury-Repair and in Disease

Research Description

There is clear evidence that altered control of the differentiated state of vascular smooth muscle cells (SMC), or SMC phenotypic switching, plays a critical role in development of a number of major human diseases including atherosclerosis, hypertension, asthma, and cancer. However, the mechanisms and factors that regulate SMC phenotypic switching in these diseases are poorly understood. A major long-term goal of our laboratory has been to elucidate cellular and molecular mechanisms that control the growth and differentiation of SMC during normal vascular development, and to determine how these control processes are altered during vascular injury or in disease states [see review by Alexander et al.1]. For example, a major focus of previous studies has been to identify molecular mechanisms that control the coordinate expression of genes such as smooth muscle a–actin (SM ?-actin), SM22?, and smooth muscle myosin heavy chains (SM MHC) that are required for the differentiated function of the SMC. Studies involve use of a wide repertoire of molecular-genetic techniques and include identification of cis elements and trans regulatory factors that regulate cell-type specific expression of SMC differentiation marker genes both in cultured cell systems and in vivo in transgenic mice. In addition, we use a variety of gene knockout, mouse chimeric, and gene over-expression approaches to investigate the role of specific transcription factors and local environmental cues (e.g. growth factors, mechanical factors, cell-cell and cell-matrix interactions, hypoxia, inflammatory cytokines, etc.) in regulation of SMC differentiation in vivo during vascular development, as well as following vascular injury, or with cardiovascular disease 2, 3.

A particularly exciting recent development is that we have employed SMC specific promoters originally cloned and characterized in our laboratory to create mice in which we can target conditional knockout (or over-expression) of genes of interest specifically to SMCs and also perform rigorous SMC-pericyte lineage tracing experiments to define mechanisms that control phenotypic transitions of these cells during injury-repair and in diseases such as atherosclerosis. Remarkably, using these model systems, we have recently shown that SMC-pericytes de-differentiate, give rise to mesenchymal stem cell (MSC)-like cells, and trans-differentiate into alternative cell types during development of experimental atherosclerosis, as well as in models of myocardial infarction, lung injury, skin wounding, and partial hepatectomy. Moreover, we have shown that the phenotypic transitions of SMC-pericytes in these models is regulated by activation of stem cell pluripotency genes, including Oct4 (manuscript in review), and Klf43, 4, factors also shown to be involved in reprogramming of somatic cells into induced pluripotential stem (iPS) cells.

Our lab has also pioneered studies of the role of epigenetic mechanisms in control of SMC differentiation and phenotypic switching5, as well as lineage determination of multiple specialized cell types from embryonic stem cells (ESC)6. Of major interest, we have shown that lineage determination of SMC, as well as other specialized cells from ESC, involves acquisition of locus- and cell-type selective histone modifications that influence chromatin structure and permissiveness of genes for transcriptional activation. Moreover, we have demonstrated that phenotypic switching of SMC into alternative cell types involves reversal of a subset of these histone modifications and transcriptional silencing of SMC marker genes. However, these cells retain certain histone modifications that we hypothesize serve as a mechanism for “cell lineage memory” during reversible phenotypic switching. That is, a mechanism that allows a SMC to undergo transient transitions to alternative phenotypes necessary for vascular repair, but which biases the cell into re-differentiating into a SMC once the repair is complete. Of major significance, we have recently developed a powerful new assay that allows assessment of specific histone modifications within single cells within fixed tissue specimens (i.e. a single cell chromatin immunoprecipitation assay) to further test this hypothesis within our various in vivo model systems.

Finally, a major long term emphasis of the lab is to translate results of our basic science studies into advancing clinical practice. Current projects in this area include testing how inhibition of IL-1? signaling may help promote increased stability of atherosclerotic plaques thus reducing the probability of a heart attack or stroke. In addition, we are investigating ways to therapeutically augment the stem cell like properties of SMC-pericytes as a means to treat a wide range of major human diseases.

Reference List

(1) Alexander MR, Owens GK. Epigenetic Control of Smooth Muscle Cell Differentiation and Phenotypic Switchingin Vascular Development and Disease. Annu Rev Physiol 2012 February 15;74:13-40. (2) Wamhoff BR, Hoofnagle MH, Burns A, Sinha S, McDonald OG, Owens GK. A G/C Element Mediates Repression of the SM22a Promoter Within Phenotypically Modulated Smooth Muscle Cells in Experimental Atherosclerosis. Circ Res 2004 November 12;95(10):981-8. (3) Yoshida T, Kaestner KH, Owens GK. Conditional Deletion of Kruppel-Like Factor 4 Delays Downregulation of Smooth Muscle Cell Differentiation Markers but Accelerates Neointimal Formation Following Vascular Injury. Circ Res 2008 June 20;102(12):1548-57. (4) Salmon M, Gomez D, Greene E, Shankman L, Owens GK. Cooperative Binding of KLF4, pELK-1, and HDAC2 to a G/C Repressor Element in the SM22alpha Promoter Mediates Transcriptional Silencing During SMC Phenotypic Switching In Vivo. Circ Res 2012 August 31;111(6):685-96. (5) McDonald OG, Wamhoff BR, Hoofnagle MH, Owens GK. Control of SRF binding to CARG-box chromatin regulates smooth muscle gene expression in vivo. J Clin Invest 2006;116:36-48. (6) Gan Q, Yoshida T, McDonald OG, Owens GK. Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells. Stem Cells 2007 January;25(1):2-9.

Selected Publications

  • Alexander M, Murgai M, Moehle C, Owens G. Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms. Physiological genomics. 2012;44(7): 417-29. PMID: 22318995 | PMCID: PMC3339851
  • Gomez D, Owens G. Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovascular research. 2012;95(2): 156-64. PMID: 22406749 | PMCID: PMC3388816
  • Nguyen A, Gomez D, Bell R, Campbell J, Clowes A, Gabbiani G, Giachelli C, Parmacek M, Raines E, Rusch N, Speer M, Sturek M, Thyberg J, Towler D, Weiser-Evans M, Yan C, Miano J, Owens G. Smooth Muscle Cell Plasticity: Fact or Fiction? Circulation research. 2012. PMID: 23093573
  • Salmon M, Gomez D, Greene E, Shankman L, Owens G. Cooperative binding of KLF4, pELK-1, and HDAC2 to a G/C repressor element in the SM22α promoter mediates transcriptional silencing during SMC phenotypic switching in vivo. Circulation research. 2012;111(6): 685-96. PMID: 22811558 | PMCID: NIHMS401822
  • Alexander M, Moehle C, Johnson J, Yang Z, Lee J, Jackson C, Owens G. Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. The Journal of clinical investigation. 2011;122(1): 70-9. PMID: 22201681 | PMCID: PMC3248279
  • Alexander M, Owens G. Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annual review of physiology. 2011;74 13-40. PMID: 22017177
  • Gan Q, Thiébaud P, Thézé N, Jin L, Xu G, Grant P, Owens G. WD repeat-containing protein 5, a ubiquitously expressed histone methyltransferase adaptor protein, regulates smooth muscle cell-selective gene activation through interaction with pituitary homeobox 2. The Journal of biological chemistry. 2011;286(24): 21853-64. PMID: 21531708 | PMCID: PMC3122240
  • Hoofnagle M, Neppl R, Berzin E, Teg Pipes G, Olson E, Wamhoff B, Somlyo A, Owens G. Myocardin is differentially required for the development of smooth muscle cells and cardiomyocytes. American journal of physiology. Heart and circulatory physiology. 2011;300(5): H1707-21. PMID: 21357509 | PMCID: PMC3094091
  • Moehle C, Bhamidipati C, Alexander M, Mehta G, Irvine J, Salmon M, Upchurch G, Kron I, Owens G, Ailawadi G. Bone marrow-derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation. The Journal of thoracic and cardiovascular surgery. 2011;142(6): 1567-74. PMID: 21996300
  • Jin L, Gan Q, Zieba B, Goicoechea S, Owens G, Otey C, Somlyo A. The actin associated protein palladin is important for the early smooth muscle cell differentiation. PloS one. 2010;5(9): e12823. PMID: 20877641 | PMCID: PMC2943901
  • Yoshida T, Gan Q, Franke A, Ho R, Zhang J, Chen Y, Hayashi M, Majesky M, Somlyo A, Owens G. Smooth and cardiac muscle-selective knock-out of Kruppel-like factor 4 causes postnatal death and growth retardation. The Journal of biological chemistry. 2010;285(27): 21175-84. PMID: 20439457 | PMCID: PMC2898332
  • Cherepanova O, Pidkovka N, Sarmento O, Yoshida T, Gan Q, Adiguzel E, Bendeck M, Berliner J, Leitinger N, Owens G. Oxidized phospholipids induce type VIII collagen expression and vascular smooth muscle cell migration. Circulation research. 2009;104(5): 609-18. PMID: 19168440 | PMCID: PMC2758767
  • Deaton R, Gan Q, Owens G. Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle. American journal of physiology. Heart and circulatory physiology. 2009;296(4): H1027-37. PMID: 19168719 | PMCID: PMC2670704
  • Nickerson M, Song J, Meisner J, Bajikar S, Burke C, Shuptrine C, Owens G, Skalak T, Price R. Bone marrow-derived cell-specific chemokine (C-C motif) receptor-2 expression is required for arteriolar remodeling. Arteriosclerosis, thrombosis, and vascular biology. 2009;29(11): 1794-801. PMID: 19734197 | PMCID: PMC2766019
  • Jin L, Yoshida T, Ho R, Owens G, Somlyo A. The actin-associated protein Palladin is required for development of normal contractile properties of smooth muscle cells derived from embryoid bodies. The Journal of biological chemistry. 2008;284(4): 2121-30. PMID: 19015263 | PMCID: PMC2629081
  • Shang Y, Yoshida T, Amendt B, Martin J, Owens G. Pitx2 is functionally important in the early stages of vascular smooth muscle cell differentiation. The Journal of cell biology. 2008;181(3): 461-73. PMID: 18458156 | PMCID: PMC2364692
  • Thomas J, Deaton R, Hastings N, Shang Y, Moehle C, Eriksson U, Topouzis S, Wamhoff B, Blackman B, Owens G. PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns. American journal of physiology. Heart and circulatory physiology. 2008;296(2): H442-52. PMID: 19028801 | PMCID: PMC2643880
  • Wamhoff B, Lynch K, Macdonald T, Owens G. Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(8): 1454-61. PMID: 18535287 | PMCID: PMC2605659
  • Yoshida T, Gan Q, Owens G. Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids. American journal of physiology. Cell physiology. 2008;295(5): C1175-82. PMID: 18768922 | PMCID: PMC2584997
  • Yoshida T, Kaestner K, Owens G. Conditional deletion of Krüppel-like factor 4 delays downregulation of smooth muscle cell differentiation markers but accelerates neointimal formation following vascular injury. Circulation research. 2008;102(12): 1548-57. PMID: 18483411 | PMCID: PMC2633447
  • Gan Q, Yoshida T, Li J, Owens G. Smooth muscle cells and myofibroblasts use distinct transcriptional mechanisms for smooth muscle alpha-actin expression. Circulation research. 2007;101(9): 883-92. PMID: 17823374
  • McDonald O, Owens G. Programming smooth muscle plasticity with chromatin dynamics. Circulation research. 2007;100(10): 1428-41. PMID: 17525382
  • Pidkovka N, Cherepanova O, Yoshida T, Alexander M, Deaton R, Thomas J, Leitinger N, Owens G. Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. Circulation research. 2007;101(8): 792-801. PMID: 17704209
  • Gan Q, Yoshida T, McDonald O, Owens G. Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells. Stem cells (Dayton, Ohio). 2006;25(1): 2-9. PMID: 17023513
  • Gorenne I, Jin L, Yoshida T, Sanders J, Sarembock I, Owens G, Somlyo A, Somlyo A. LPP expression during in vitro smooth muscle differentiation and stent-induced vascular injury. Circulation research. 2006;98(3): 378-85. PMID: 16397143
  • Kawai-Kowase K, Owens G. Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells. American journal of physiology. Cell physiology. 2006;292(1): C59-69. PMID: 16956962
  • Khromov A, Wang H, Choudhury N, McDuffie M, Herring B, Nakamoto R, Owens G, Somlyo A, Somlyo A. Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca2+ and decreased cGMP-induced relaxation. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(7): 2440-5. PMID: 16461919 | PMCID: PMC1413704
  • McDonald O, Wamhoff B, Hoofnagle M, Owens G. Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo. The Journal of clinical investigation. 2006;116(1): 36-48. PMID: 16395403 | PMCID: PMC1323266
  • Sinha S, Wamhoff B, Hoofnagle M, Thomas J, Neppl R, Deering T, Helmke B, Bowles D, Somlyo A, Owens G. Assessment of contractility of purified smooth muscle cells derived from embryonic stem cells. Stem cells (Dayton, Ohio). 2006;24(7): 1678-88. PMID: 16601077
  • Yoshida T, Gan Q, Shang Y, Owens G. Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters. American journal of physiology. Cell physiology. 2006;292(2): C886-95. PMID: 16987998