Roger R. Markwald
Medical University of South Carolina
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Featured researches published by Roger R. Markwald.
Circulation Research | 1995
Leonard M. Eisenberg; Roger R. Markwald
The majority of congenital heart defects arise from abnormal development of valvuloseptal tissue. The primordia of the valve leaflets and membranous septa of the heart are the cardiac cushions. Remodeling of the cushions is associated with a transitional extracellular matrix that includes sulfated proteoglycans and the microfibrillar proteins fibulin and fibrillin. Cushion formation is restricted to the AV canal and ventricular outflow tract regions of the primary heart tube. The proper placement of the cushions may be the result of the development of the primary heart tube as a segmented organ, as well as the subsequent looping of the heart. Segmentation of the heart tube may be demonstrated by the alternating molecular expression pattern along the longitudinal axis. In support of this hypothesis is the restricted expression of BMP-4 and msx-2 to the AV canal and ventricular outflow tract. The importance of looping for cushion positioning may imply that the iv and inv genes and retinoic acid are important for the proper patterning of the heart. The cells of the cushions evolve from endocardial cells that undergo an epithelial-to-mesenchymal transformation. This developmental event is regulated by the myocardium and is probably due to the production of protein complexes, present within the cardiac jelly of the cushion-forming regions, that consist of fibronectin and the ES proteins. Both the cushion mesenchyme and its endocardial cell antecedents express JB3, an ECM protein. JB3 expression is also featured within the heart-forming fields of the primary mesoderm, from which the endocardial progenitors of the cushion cells originate.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Cellular Biochemistry | 2007
Russell A. Norris; Brook Damon; Vladimir Mironov; Vladimir Kasyanov; Anand Ramamurthi; Ricardo A. Moreno-Rodriguez; Thomas C. Trusk; Jay D. Potts; Richard L. Goodwin; Jeffrey M. Davis; Stanley Hoffman; Xuejun Wen; Yukiko Sugi; Christine B. Kern; Corey H. Mjaatvedt; Debi Turner; Toru Oka; Simon J. Conway; Jeffery D. Molkentin; Gabor Forgacs; Roger R. Markwald
Periostin is predominantly expressed in collagen‐rich fibrous connective tissues that are subjected to constant mechanical stresses including: heart valves, tendons, perichondrium, cornea, and the periodontal ligament (PDL). Based on these data we hypothesize that periostin can regulate collagen I fibrillogenesis and thereby affect the biomechanical properties of connective tissues. Immunoprecipitation and immunogold transmission electron microscopy experiments demonstrate that periostin is capable of directly interacting with collagen I. To analyze the potential role of periostin in collagen I fibrillogenesis, gene targeted mice were generated. Transmission electron microscopy and morphometric analyses demonstrated reduced collagen fibril diameters in skin dermis of periostin knockout mice, an indication of aberrant collagen I fibrillogenesis. In addition, differential scanning calorimetry (DSC) demonstrated a lower collagen denaturing temperature in periostin knockout mice, reflecting a reduced level of collagen cross‐linking. Functional biomechanical properties of periostin null skin specimens and atrioventricular (AV) valve explant experiments provided direct evidence of the role that periostin plays in regulating the viscoelastic properties of connective tissues. Collectively, these data demonstrate for the first time that periostin can regulate collagen I fibrillogenesis and thereby serves as an important mediator of the biomechanical properties of fibrous connective tissues. J. Cell. Biochem. 101: 695–711, 2007.
Circulation Research | 1997
M.C. DeRuiter; Robert E. Poelmann; J.C. Vanmunsteren; V. Mironov; Roger R. Markwald; A.C. Gittenberger-de Groot
All blood vessels are lined by endothelium and, except for the capillaries, surrounded by one or more layers of smooth muscle cells. The origin of the embryonic vascular smooth muscle cell has until now been described from neural crest and locally differentiating mesenchyme. In this study, we have substantial evidence that quail embryonic endothelial cells are competent in the dorsal aorta of the embryo to transdifferentiate into subendothelial mesenchymal cells expressing smooth muscle actins in vivo. At the onset of smooth muscle cell differentiation, QH1-positive endothelial cells were experimentally labeled with a wheat germ agglutinin-colloidal gold marker (WGA-Au). No labeled subendothelial cells were observed at this time. However, 19 hours after the endothelial cells had endocytosed, the WGA-Au-labeled subendothelial mesenchymal cells were observed in the aortic wall. Similarly, during the same time period, subendothelial cells that coexpressed the QH1 endothelial marker and a mesenchymal marker, alpha-smooth muscle actin, were present. In such cells, QH1 expression was reduced to a cell membrane localization. A similar antigen switch was also observed during endocardial-mesenchymal transformation in vitro. Our results are the first direct in vivo evidence that embryonic endothelial cells may transdifferentiate into candidate vascular smooth muscle cells. These data arouse new interpretations of the origin and differentiation of the cells of the vascular wall in normal and diseased vessels.
Journal of Clinical Investigation | 2010
Polakit Teekakirikul; Seda Eminaga; Okan Toka; Ronny Alcalai; Libin Wang; Hiroko Wakimoto; Matthew Nayor; Tetsuo Konno; Joshua M. Gorham; Cordula M. Wolf; Jae B. Kim; Joachim P. Schmitt; Jefferey D. Molkentin; Russell A. Norris; Andrew M. Tager; Stanley Hoffman; Roger R. Markwald; Christine E. Seidman; Jonathan G. Seidman
Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophy-negative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce non-myocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.
Tissue Engineering Part A | 2008
Karoly Jakab; Cyrille Norotte; Brook Damon; Francoise Marga; Adrian Neagu; Cynthia L. Besch-Williford; Anatoly Kachurin; Kenneth H. Church; Hyoungshin Park; Vladimir Mironov; Roger R. Markwald; Gordana Vunjak-Novakovic; Gabor Forgacs
Understanding the principles of biological self-assembly is indispensable for developing efficient strategies to build living tissues and organs. We exploit the self-organizing capacity of cells and tissues to construct functional living structures of prescribed shape. In our technology, multicellular spheroids (bio-ink particles) are placed into biocompatible environment (bio-paper) by the use of a three-dimensional delivery device (bio-printer). Our approach mimics early morphogenesis and is based on the realization that the genetic control of developmental patterning through self-assembly involves physical mechanisms. Three-dimensional tissue structures are formed through the postprinting fusion of the bio-ink particles, in analogy with early structure-forming processes in the embryo that utilize the apparent liquid-like behavior of tissues composed of motile and adhesive cells. We modeled the process of self-assembly by fusion of bio-ink particles, and employed this novel technology to print extended cellular structures of various shapes. Functionality was tested on cardiac constructs built from embryonic cardiac and endothelial cells. The postprinting self-assembly of bio-ink particles resulted in synchronously beating solid tissue blocks, showing signs of early vascularization, with the endothelial cells organized into vessel-like conduits.
Circulation Research | 2008
Paige Snider; Robert B. Hinton; Ricardo A. Moreno-Rodriguez; Jian Wang; Rhonda Rogers; Andrew Lindsley; Fang Li; David A. Ingram; Donald R. Menick; Loren J. Field; Anthony B. Firulli; Jeffery D. Molkentin; Roger R. Markwald; Simon J. Conway
The secreted periostin protein, which marks mesenchymal cells in endocardial cushions following epithelial–mesenchymal transformation and in mature valves following remodeling, is a putative valvulogenesis target molecule. Indeed, periostin is expressed throughout cardiovascular morphogenesis and in all 4 adult mice valves (annulus and leaflets). Additionally, periostin is expressed throughout the fibrous cardiac skeleton and endocardial cushions in the developing heart but is absent from both normal and/or pathological mouse cardiomyocytes. Periostin (perilacZ) knockout mice exhibit viable valve disease, with neonatal lethality in a minority and latent disease with leaflet abnormalities in the viable majority. Surviving perilacZ-null leaflets are truncated, contain ectopic cardiomyocytes and smooth muscle, misexpress the cartilage proteoglycan aggrecan, demonstrate disorganized matrix stratification, and exhibit reduced transforming growth factor-&bgr; signaling. Neonatal perilacZ nulls that die (14%) display additional defects, including leaflet discontinuities, delamination defects, and deposition of acellular extracellular matrix. Assessment of collagen production, 3D lattice formation ability, and transforming growth factor-&bgr; responsiveness indicate periostin-deficient fibroblasts are unable to support normal valvular remodeling and establishment of a mature cardiac skeleton. Furthermore, pediatric stenotic bicuspid aortic valves that have lost normal extracellular matrix trilaminar stratification have greatly reduced periostin. This suggests that loss of periostin results in inappropriate differentiation of mesenchymal cushion cells and valvular abnormalities via a transforming growth factor-&bgr;–dependent pathway during establishment of the mature heart. Thus, perilacZ knockouts provide a new model of viable latent valve disease.
Developmental Biology | 1975
Roger R. Markwald; Timothy P. Fitzharris; William N.Adams Smith
Abstract Embryonic hearts 8–40 somites (10.0–13.5 days) where subjected to transmission and scanning ultrastructural and histological examination to monitor pathways of endocardial differentiation. Primitive endocardium (day 10.0 or 8 somites) consisted of closely packed cells with smooth luminal surfaces except for cilia at cellular interfaces. Internally these cells possessed minimal secretory potential as indicated by undilated rough-surfaced endoplasmic reticulum (RER) and undeveloped Golgi complexes. The latter had nondistended lamellae and a low population of small (100-nm) bristle-coated and uncoated vesicles. Cytodifferentiation of the primitive endocardium was biphasic. In the outflow tract and AV canal, areas of future cushion tissue (cardiac mesenchyme) formation, endocardium was transformed by day 11.5 (16–18 somites) into cells with amplified secretory potential as evidenced by dilation of RER cisternae, hypertrophy of Golgi lamellae and augmented formation of Golgi vesicles consisting primarily of larger (150–200 nm) uncoated types. The luminal surfaces in these areas became convoluted and flattened while the extracellular (cardiac jelly) surface developed blebs and was studded with globular and fibrillar strands of matrical material. Surface topography and serial sectioning of the initial sites of cushion tissue formation suggested the latter was actually a derivative of endocardium having augmented secretory potential. Conversely, endocardium approached by invaginating myocardial trabeculae (atrium and ventricle) appeared to lose secretory potential as indicated by its (1) progressive attenuation of the cytoplasm, (2) reduction or complete loss of surface projections and associated globular and fibrillar material, (3) regression of RER and Golgi complexes, and (4) acquisition of cystic foci in otherwise nondilated RER. Results therefore indicated that both endocardial surface and internal features could be related to developmental changes in microenvironment and function.
FEBS Journal | 2011
Suniti Misra; Paraskevi Heldin; Vincent C. Hascall; Nikos K. Karamanos; Spyros S. Skandalis; Roger R. Markwald; Shibnath Ghatak
It is becoming increasingly clear that signals generated in tumor microenvironments are crucial to tumor cell behavior, such as survival, progression and metastasis. The establishment of these malignant behaviors requires that tumor cells acquire novel adhesion and migration properties to detach from their original sites and to localize to distant organs. CD44, an adhesion/homing molecule, is a major receptor for the glycosaminoglycan hyaluronan, which is one of the major components of the tumor extracellular matrix. CD44, a multistructural and multifunctional molecule, detects changes in extracellular matrix components, and thus is well positioned to provide appropriate responses to changes in the microenvironment, i.e. engagement in cell–cell and cell–extracellular matrix interactions, cell trafficking, lymph node homing and the presentation of growth factors/cytokines/chemokines to co‐ordinate signaling events that enable the cell responses that change in the tissue environment. The potential involvement of CD44 variants (CD44v), especially CD44v4–v7 and CD44v6–v9, in tumor progression has been confirmed for many tumor types in numerous clinical studies. The downregulation of the standard CD44 isoform (CD44s) in colon cancer is postulated to result in increased tumorigenicity. CD44v‐specific functions could be caused by their higher binding affinity than CD44s for hyaluronan. Alternatively, CD44v‐specific functions could be caused by differences in associating molecules, which may bind selectively to the CD44v exon. This minireview summarizes how the interaction between hyaluronan and CD44v can serve as a potential target for cancer therapy, in particular how silencing CD44v can target multiple metastatic tumors.
Current Opinion in Biotechnology | 2011
Vladimir Mironov; Vladimir Kasyanov; Roger R. Markwald
Organ printing, or the layer by layer additive robotic biofabrication of functional three-dimensional tissue and organ constructs using self-assembling tissue spheroid building blocks, is a rapidly emerging technology that promises to transform tissue engineering into a commercially successful biomedical industry. It is increasingly obvious that similar well-established industries implement automated robotic systems on the path to commercial translation and economic success. The use of robotic bioprinters alone however is not sufficient for the development of large industrial scale organ biofabrication. The design and development of a fully integrated organ biofabrication line is imperative for the commercial translation of organ printing technology. This paper presents recent progress and challenges in the development of the essential components of an organ biofabrication line.
Mechanisms of Development | 2001
Agnieszka Kruzynska-Frejtag; Michal Machnicki; Rhonda Rogers; Roger R. Markwald; Simon J. Conway
Periostin was originally isolated as a osteoblast-specific factor that functions as a cell adhesion molecule for preosteoblasts and is thought to be involved in osteoblast recruitment, attachment and spreading. Additionally, periostin expression has previously been shown to be significantly increased by both transforming growth factor beta-1(TGFbeta1) and bone morphogenetic protein (BMP)-2. Likewise the endocardial cushions that form within embryonic heart tube (embryonic day (E)10-13) are formed by the recruitment, attachment and spreading of endocardial cells into the overlying extracellular matrix, in response to secreted growth factors of the TGFbeta and BMP families. In order to determine whether periostin is similarly involved in heart morphogenesis, in situ hybridization and reverse transcription-polymerase chain reaction were used to detect periostin mRNA expression in the developing mouse heart. We show for the first time that periostin mRNA is expressed in the developing mouse embryonic and fetal heart, and that it is localized to the endocardial cushions that ultimately divide the primitive heart tube into a four-chambered heart.