DOCSLIB.ORG

Role of Akt in Myofibroblast Differentiation Leading to Pulmonary

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Role of Akt in Myofibroblast Differentiation Leading to Pulmonary ROLE OF AKT IN MYOFIBROBLAST DIFFERENTIATION LEADING TO PULMONARY VASCULAR REMODELING AND IDIOPATHIC PULMONARY FIBROSIS by MAHA MAHMOUD ABDALLA (Under the Direction of Somanath P.R. Shenoy) ABSTRACT Idiopathic pulmonary fibrosis (IPF) is an incurable, chronic and progressive lung disease with severely poor prognosis. The presence of pulmonary hypertension (PH) secondary to IPF is an independent risk factor for increased mortality. Alarmingly, there are no effective pharmacologic treatments for IPF, and lung transplantation remains the only effective option. Therefore, identification of novel therapeutic targets is critical in the hopes of devising new treatments. Persistent myofibroblasts (MFs) differentiation and excess extracellular matrix (ECM) accumulation are hallmark features of IPF. Recently, it has been shown that Akt is upregulated in IPF patients; however whether Akt is necessary for MFs remains unclear. This dissertation sought to 1) identify the role of Akt in MF differentiation leading to IPF, and 2) investigate the safety and efficacy of triciribine (TCBN), a selective Akt inhibitor, as a potential therapeutic option for IPF. The work presented in this thesis has been conducted using a combined approach of pharmacological, genetics, and functional assays. We first identified that Akt is a critical determinant of pathological MF differentiation and ECM expression as evident by loss- and gain- of function studies, both in vitro and in vivo. Mechanistically, we found that Akt1 transcriptionally regulates αSMA synthesis, independent of mTOR. Furthermore, TCBN reversed TGFβ (pro-fibrotic cytokine) - and hypoxia-induced pulmonary fibrosis and vascular remodeling, compared to placebo and rapamycin. In contrast, rapamycin, which targets mTOR downstream of Akt, exacerbated fibrosis and vascular remodeling as evident by worsening interstitial fibrosis, micro-hemorrhage, and increased peripheral vascular rarefaction. Collectively, research efforts associated with this thesis 1) identified Akt as a novel target as it is crucial for MFs - central orchestrators of IPF; 2) determined novel anti-fibrotic and anti-remodeling properties of Triciribine; and 3) determined that rapamycin activates Akt via feedback mechanisms, which sheds light on the observed detrimental effects of everolimus, a rapamycin derivative, in IPF patients. In conclusion, our study is the first to determine the crucial role of Akt1 in IPF and associated vascular remodeling. Thus, selective Akt inhibition, not mTOR, may serve as a favorable therapeutic strategy in IPF. INDEX WORDS: Idiopathic pulmonary fibrosis, vascular remodeling, myofibroblast, extracellular matrix, Akt, mTOR, triciribine, rapamycin, chronic hypoxia, TGFβ ROLE OF AKT IN MYOFIBROBLAST DIFFERENTIATION LEADING TO PULMONARY VASCULAR REMODELING AND IDIOPATHIC PULMONARY FIBROSIS by MAHA MAHMOUD ABDALLA Pharm.D, MCPHS University, 2010 A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2014 © 2014 Maha Mahmoud Abdalla All Rights Reserved ROLE OF AKT IN MYOFIBROBLAST DIFFERENTIATION LEADING TO PULMONARY VASCULAR REMODELING AND IDIOPATHIC PULMONARY FIBROSIS by MAHA MAHMOUD ABDALLA Major Professor: Somanath P.R. Shenoy Committee: Susan C. Fagan Adviye Ergul Lakshman Segar Aaron Beedle Electronic Version Approved: Julie Coffield Interim Dean of the Graduate School The University of Georgia August 2014 DEDICATION I dedicate this thesis to the Almighty God, my father, Mahmoud Abdalla, my mother, Magda Hussein, and my brothers, Mohamed and Mostafa, for being my pillars of support, my source of refuge, and my guiding light. My parents have always been my foremost role models. They have instilled in us that, no matter the obstacles and challenges, persistence is the key to achieve your dreams and aspirations. They lead by example. Not succumbing to “what’s meant to be,” at the age of 6, my father was a young entrepreneur. In his early twenties, he traveled abroad and combined his business knowledge with his background as an agriculture engineer to design innovative farming techniques, which catapulted him to be a consultant. Determined to break cultural norm at a time where girls did not continue their education and marry at a young age, my mother fought through social and cultural challenges. Rain or shine, she was determined to attend every class. Ultimately, she went to college and became a lawyer. They have taught us that so long as you tried, took risks, embraced your failures and turned them into success, and did not settle for “what’s meant to be,” you will reach your dreams and live life with no regrets. They have sacrificed so much to secure our future. They’ve taught us the meaning of family, discipline, independence, integrity, and ingenuity. They push us to look past any challenges that we may face as there is always a solution. “You just have to use your brain, and keep at it!” In essence, this is not just my Ph.D., but my family’s Ph.D. “If you can imagine it, you can dream it. Dream it and you can become it.” iv ACKNOWLEDGEMENTS The accomplishment of this dissertation is the result of approximately four years of work whereby I have been supported by many people. First, I sincerely thank my advisor, Dr. Somanath Shenoy, for guiding my development as a researcher, honing in my critical thinking skills, and for providing me with ample support and encouragement to grow as we developed and established new fields of study (pulmonary fibrosis and pulmonary vascular remodeling) in his laboratory. Thank you for giving me the opportunity to be part of your team, I have learned so much and I look forward to future collaborations. I would like to extend my appreciation to the members of the Shenoy Lab, especially Alanna Pruitt for her assistance and support. I also would like to especially thank Dr. Anna Goc for guiding and training me during my rotation in Dr. Shenoy’s lab, and for being an exceptional colleague and a collaborator over the course of my Ph.D. I am grateful to my committee members, Drs. Susan Fagan, Adviye Ergul, Lakshman Segar, and Aaron Beedle for their tremendous support and systematic guidance, excellent technical support, constructive criticism, and invaluable advice and encouragement throughout the course of my graduate career. I would like to thank the members of their labs for teaching me unique vascular assessment techniques, especially Dr. Roshini Prakash, Ma Handong, Dr. Mohammed Abdelsaid, and Dr. Rajkumar Pyla. I would like to acknowledge my deep sense of gratitude and indebtedness to Drs. Carroll-Ann Goldsmith, Keith Foster, Abir Kanaan, Paul Belliveau, Susan Fagan, and v Azza El-Remessy for their invaluable mentorship and their “you can do it” attitude and encouragements; exemplary role models. Their dedication and passion for their work and students are qualities that I truly admire and hope to emulate as I progress in my career. I would like to acknowledge my pharmacy students whom I have had the privilege of mentoring (LeeAnn, Erin, Samantha, Jessica, Bobby, Uvette, and Brian). Working with them was one of the most enjoyable experiences during my graduate studies, they have helped me become a better teacher and a mentor, and I was truly proud of them and to see the fruit of their labor as they presented posters at conferences including ACCP. I thank Dr. Ahmed Alhusban for his continued support and motivation and invaluable advice. Through our scientific discussions, we constantly challenge each other to think outside the box and excel; it is a privilege to call him a friend. I would like to thank my family and my extended family (Dolores, John, Heather, and Dayana), friends, and the MCPHS University and CET family for their support. vi TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ............................................................................................... v LIST OF FIGURES ....................................................................................................... viii LIST OF ABBREVIATIONS ............................................................................................. x CHAPTER 1. INTRODUCTION AND LITERATURE REVIEW ........................................ 1 CHAPTER 2. AKT1 MEDIATES ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION AND MYOFIBROBLAST DIFFERENTIATION VIA MYOCARDIN AND SERUM RESPONSE FACTOR ............................................................... 37 CHAPTER 3. TRICIRIBINE, A SELECTIVE AKT INHIBITOR, AMELIORATES TGFβ- AND HYPOXIA INDUCED PULMONARY FIBROSIS AND VASCULAR REMODELING ......................................................................................... 81 CHAPTER 4. INTEGRATED DISCUSSION ............................................................... 129 CHAPTER 5. SUMMARY AND CLINICAL SIGNIFICANCE ........................................ 140 APPENDICES ............................................................................................................. 145 vii LIST OF FIGURES Page 1-1 Akt1 mediated pathways .................................................................................... 18 1-2 A schematic representation of our hypothesis .................................................... 19 2-1 Akt1 is critical for αSMA expression in response to TGFβ .................................. 63 2-2 Akt1 is differentially utilized by TGFβ and bFGF in fibroblast to MF differentiation. ..........................................................................................................................
Load more

Recommended publications
  • Extracellular Matrix Grafts: from Preparation to Application (Review)
    INTERNATIONAL JOURNAL OF MOleCular meDICine 47: 463-474, 2021 Extracellular matrix grafts: From preparation to application (Review) YONGSHENG JIANG1*, RUI LI1,2*, CHUNCHAN HAN1 and LIJIANG HUANG1 1Science and Education Management Center, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang 315700; 2School of Chemistry, Sun Yat-sen University, Guangzhou, Guangdong 510275, P.R. China Received July 30, 2020; Accepted December 3, 2020 DOI: 10.3892/ijmm.2020.4818 Abstract. Recently, the increasing emergency of traffic acci- Contents dents and the unsatisfactory outcome of surgical intervention are driving research to seek a novel technology to repair trau- 1. Introduction matic soft tissue injury. From this perspective, decellularized 2. ECM-G characterization matrix grafts (ECM-G) including natural ECM materials, and 3. Methods of decellularization treatments their prepared hydrogels and bioscaffolds, have emerged as 4. Removal of residual cellular components and chemicals possible alternatives for tissue engineering and regenerative 5. Application of ECM-P in regenerative medicine medicine. Over the past decades, several physical and chemical 6. Challenges and future outlook on ECM-P decellularization methods have been used extensively to deal 7. Conclusions with different tissues/organs in an attempt to carefully remove cellular antigens while maintaining the non-immunogenic ECM components. It is anticipated that when the decellular- 1. Introduction ized biomaterials are seeded with cells in vitro or incorporated into irregularly shaped defects in vivo, they can provide the The extracellular matrix (ECM) derived from organs/tissues is appropriate biomechanical and biochemical conditions for a complex, highly organized assembly of macromolecules with directing cell behavior and tissue remodeling.
    [Show full text]
  • Extracellular Matrix Degradation and Remodeling in Development and Disease
    Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Extracellular Matrix Degradation and Remodeling in Development and Disease Pengfei Lu1,2, Ken Takai2, Valerie M. Weaver3, and Zena Werb2 1Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research and Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M20 4BX, United Kingdom 2Department of Anatomy and Program in Developmental Biology, University of California, San Francisco, California 94143-0452 3Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143 Correspondence: [email protected] The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branch- ing morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnor- mal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic inter- ventions for diseases and novel strategies for tissue engineering and regenerative medicine. he extracellular matrix (ECM) forms a milieu versatile and performs many functions in addi- Tsurrounding cells that reciprocally influ- tion to its structural role.
    [Show full text]
  • Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases
    cells Review Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases Ping Song * , Junqing An and Ming-Hui Zou Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA; [email protected] (J.A.); [email protected] (M.-H.Z.) * Correspondence: [email protected]; Tel.: +1-404-413-6636 Received: 29 January 2020; Accepted: 5 March 2020; Published: 10 March 2020 Abstract: Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan. Keywords: cellular senescence; senescence immunotherapy; ageing; chronic disease; ageing markers 1.
    [Show full text]
  • A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: to Target Or Not to Target?
    International Journal of Molecular Sciences Review A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target? Machteld Sillen and Paul J. Declerck * Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, B-3000 Leuven, Belgium; [email protected] * Correspondence: [email protected] Abstract: Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction with biological ligands such as vitronectin and cell-surface receptors, the function of PAI-1 extends to pericellular proteolysis, tissue remodeling and other processes including cell migration. This review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics. Keywords: plasminogen activator inhibitor-1; PAI-1; fibrinolysis; cardiovascular disease; cancer; inflammation; fibrosis; aging Citation: Sillen, M.; Declerck, P.J. 1. Introduction A Narrative Review on Plasminogen Plasminogen activator inhibitor-1 (PAI-1) belongs to the family of serine protease Activator Inhibitor-1 and Its inhibitors (serpins) and is an important regulator of the plasminogen/plasmin system (Patho)Physiological Role: To Target (Figure1)[ 1]. This system revolves around the conversion of the zymogen plasmino- or Not to Target?. Int. J. Mol. Sci. 2021, gen into the active enzyme plasmin through proteolytic cleavage that is mediated by 22, 2721.
    [Show full text]
  • 2011: Macrophage Phenotype As a Determinant of Remodeling Outcome with the Use of Biologic Scaffolds
    Macrophage Phenotype as a Determinant of Remodeling Outcome with the use of Biologic Scaffolds Stephen F. Badylak1, Kathryn A. Kukla1,3, Li Zhang1, Neill J. Turner1, Bryan N. Brown1,2 Corresponding Author: Stephen F. Badylak 1McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 2Department of Biomedical Engineering, Cornell University, Ithaca, NY; and 3Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA Statement of Purpose: The ultimate determination of deposition of dense and disorganized connective tissue clinical success for an implanted biomaterial is the consistent with encapsulation. Remodeling of the response of the host tissue following implantation. The autograft was characterized by necrosis of the muscular innate immune mechanisms that participate in and component of the tissue and deposition of dense mature modulate the host response include effector cells such as connective tissue and adipose tissue consistent with macrophages. Macrophages have been classified as scarring. having either an M1 or an M2 phenotype, depending upon gene expression, effector molecule production, and cell Despite differences in the tissue remodeling outcome, a function. To date, the causes and the effects of morphologically indistinguishable population of macrophage polarization towards an M1 or M2 phenotype macrophages was observed following implantation of have been studied largely in the context of the host each scaffold material. However, immunolabeling response to pathogens and in cancer biology. Recently, techniques showed that scaffolds which resulted in M1 and M2 macrophages have been shown to play constructive remodeling (i.e., UBM) were associated with distinct roles in the remodeling process following tissue a predominant M2 (regulatory, pro-wound healing) injury and the host response to biologic scaffold materials macrophage population, while scaffolds which resulted in (1).
    [Show full text]
  • Apoptosis During Embryonic Tissue Remodeling Is Accompanied by Cell Senescence
    www.impactaging.com AGING, November 2015, Vol 7 N 11 Research Paper Apoptosis during embryonic tissue remodeling is accompanied by cell senescence Carlos I. Lorda‐Diez1, Beatriz Garcia‐Riart1, Juan A. Montero 1, Joaquín Rodriguez‐León2, Juan A 1 1 Garcia‐Porrero , and Juan M. Hurle 1 Departamento de Anatomía y Biología Celular and IDIVAL, Universidad de Cantabria, Santander 39011, Spain; 2 Departamento de Anatomía y Biología Celular,Universidad de Extremadura, Badajoz 07006, Spain. , s , v l p n , , n l , AS , Key words: programmed cell death sene cence limb de e o me t β‐galactosidase sy dacty y S P INZ Received: 07/01/15; Accepted: 11/02/15; Published: 11/14/15 Correspondence to: Juan M. Hurlé, PhD; E‐mail: [email protected] Copyright: Lorda‐Diez et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Abstract This study re‐examined the dying process in the interdigital tissue during the formation of free digits in the developing limbs. We demonstrated that the interdigital dying process was associated with cell senescence, as deduced by induction of β‐gal activity, mitotic arrest, and transcriptional up‐regulation of p21 together with many components of the senescence ‐associated secretory phenotype. We also found overlapping domains of expression of members of the Btg/Tob gene family of antiproliferative factors in the regressing interdigits. Notably, Btg2 was up‐regulated during interdigit remodeling in species with free digits but not in the webbed foot of the duck.
    [Show full text]
  • The Myofibroblast in Wound Healing and Fibrosis
    F1000Research 2016, 5(F1000 Faculty Rev):752 Last updated: 17 JUL 2019 REVIEW The myofibroblast in wound healing and fibrosis: answered and unanswered questions [version 1; peer review: 2 approved] Marie-Luce Bochaton-Piallat1, Giulio Gabbiani1, Boris Hinz2 1Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland 2Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Canada First published: 26 Apr 2016, 5(F1000 Faculty Rev):752 ( Open Peer Review v1 https://doi.org/10.12688/f1000research.8190.1) Latest published: 26 Apr 2016, 5(F1000 Faculty Rev):752 ( https://doi.org/10.12688/f1000research.8190.1) Reviewer Status Abstract Invited Reviewers The discovery of the myofibroblast has allowed definition of the cell 1 2 responsible for wound contraction and for the development of fibrotic changes. This review summarizes the main features of the myofibroblast version 1 and the mechanisms of myofibroblast generation. Myofibroblasts originate published from a variety of cells according to the organ and the type of lesion. The 26 Apr 2016 mechanisms of myofibroblast contraction, which appear clearly different to those of smooth muscle cell contraction, are described. Finally, we summarize the possible strategies in order to reduce myofibroblast F1000 Faculty Reviews are written by members of activities and thus influence several pathologies, such as hypertrophic the prestigious F1000 Faculty. They are scars and organ fibrosis. commissioned and are peer reviewed before Keywords publication to ensure that the final, published version Myofibroblast , mechanotransduction , myofibroblast generation , is comprehensive and accessible. The reviewers myofibroblast contraction , hypertrophic scars , organ fibroses who approved the final version are listed with their names and affiliations.
    [Show full text]
  • Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications Katherine J
    ORIGINAL ARTICLE Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications Katherine J. Strissel, Zlatina Stancheva, Hideaki Miyoshi, James W. Perfield, II, Jason DeFuria, Zoe Jick, Andrew S. Greenberg, and Martin S. Obin OBJECTIVE—We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications. dipose tissue (AT) macrophages (ATM⌽s) pro- mote obesity-associated AT inflammation and RESEARCH DESIGN AND METHODS—Male C57BL/6 mice insulin resistance (1–5). Infiltrating ATM⌽s se- were fed a high-fat diet for 20 weeks to induce obesity. Every 4 crete proinflammatory mediators that are ele- weeks, insulin resistance was assessed by intraperitoneal insulin A tolerance tests, and epididymal (eAT) and inguinal subcutaneous vated in AT of obese mice and humans and are implicated AT (iAT) and livers were harvested for histological, immunohis- in the development of insulin resistance, including tumor tochemical, and gene expression analyses. necrosis factor (TNF)-␣, interleukin (IL)-6, and monocyte chemotactic protein (MCP)-1 (5–9). In obese mice and RESULTS—Frequency of adipocyte death in eAT increased humans, M⌽s infiltrate AT as circulating monocytes in from Ͻ0.1% at baseline to 16% at week 12, coincident with response to AT secretion of MCP-1, which recruits mono- increases in 1) depot weight; 2) AT macrophages (ATM⌽s) cytes expressing the C-C chemokine receptor (CCR)2 expressing F4/80 and CD11c; 3) mRNA for tumor necrosis factor (1,2,10–12,13). CCR2ϩ M⌽s expressing the M⌽ differen- (TNF)-␣, monocyte chemotactic protein (MCP)-1, and interleu- ⌽ tiation marker F4/80 and CD11c, a dendritic cell (DC) kin (IL)-10; and 4) insulin resistance.
    [Show full text]
  • Sex Differences in Adipose Tissue Remodeling: Mechanisms and Role in Disease Risk Associated with Obesity AFFINITY RESEARCH COLLABORA TIVE Susan K
    Sex differences in adipose tissue remodeling: mechanisms and role in disease risk associated with obesity AFFINITY RESEARCH COLLABORA TIVE Susan K. Fried, pre-ARC Director If you are interested in joining this ARC please contact [email protected]. The amount and anatomical location of stored fat differs in females and males. Females store more fat in peripheral depots (hips and thighs) and are typically ‘pear-shaped’, while males store most of their fat in central (abdominal) depots (both subcutaneously and in visceral depots) and develop an apple shape with age/obesity. The amount of abdominal fat, particularly the amount of visceral fat, varies within each sex and this variation is in large part genetically determined. Fat distribution is of medical importance because it is tightly correlated with risk of chronic disease, including type 2 diabetes, cardiovascular disease, infertility and cancer. In association with their lower body fat distribution, females are at overall lower risk for metabolic disease than males. Data from recent epidemiological and clinical studies and animal models indicate that the amount of gluteal-femoral fat exerts a protective effect on disease risk that is independent of total body fat, through unknown mechanisms. The adipose organ serves two main functions that are critical for survival: 1) a highly regulated fuel reservoir that stores food energy in highly specialized cells (adipocytes) when available and releases it when needed, and 2) an endocrine tissue that synthesizes and secretes hormones (most notably leptin and adiponectin) that regulate virtually every physiological system, including reproduction, immunity, and metabolism (systemic fuel homeostasis). Adipose tissues located in different anatomical regions are functionally distinct and differ in cellular composition, blood flow and innervation.
    [Show full text]
  • Connective Tissue Breakdown
    Murad H, J Gerontol Geriatr Med 2019, 5: 038 DOI: 10.24966/GGM-8662/100038 HSOA Journal of Gerontology & Geriatric Medicine Research Article Introduction Connective Tissue Breakdown: Research on aging including therapies for external, internal, and emotional concerns will continue to expand to accommodate for the Remodeling, Repair, and Pre- demands of baby boomers who are seeking to stay young as old as possible. The youngest baby boomers turned 55 this year and while vention Using an Inclusive many of them are looking forward to retirement, you can be assured that none are looking forward to aging. With intrinsic and extrinsic Method of Treatment aging, certain deteriorations may occur giving rise to disorders and illnesses such as arteriosclerosis and cardiovascular disease, ocular disorders, skin laxity, cellulite, arthritis, and joint problems, to name Howard Murad MD FAAD1,2* a few. These conditions have one thing in common: connective tis- 1Inclusive Health Medical Group, USA sue. Because connective tissue deterioration in the body can have 2Department of Medicine, University of California, Los Angeles, California, far-reaching, systemic effects, much research has been devoted to de- USA coding its mechanisms. Studies on connective tissue have produced valuable data, which have stimulated the creation of treatments for preventive and reju- Abstract venative health care. Treatments have focused on external therapies such as skin care and esthetic medicine; others concentrate on internal Because new methods that prevent connective tissue-deteriorat- solutions, delving into nutrition, medication, diets, and supplements; ing processes are desirable to delay aging, stave off disease, and lastly, a small number of programs have examined patient psyche to improve wound healing, the study of the Extracellular Matrix (ECM) find methods of reducing emotional stress and anxiety.
    [Show full text]
  • The Apoptotic Program Promotes Tissue Remodeling and Fibrosis
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector letter to the editor The apoptotic program promotes The Authors reply: In their letter, Pallet and He´bert1 tissue remodeling and fibrosis astutely observe that renal cell injury including apoptosis potentially aggravates renal fibrosis, inflammation, and To the Editor: Havasi and Borkan1 discussed recent chronic organ injury. The specific messengers that precipitate observations that link apoptosis to cell deletion and loss of fibrosis and alterations in extracellular matrix proteins are organ function after acute kidney injury. Although the major debated and include chemotactic factors, profibrogenic consequence of apoptosis is cell death, emerging evidence cytokines such as epidermal growth factor and transforming suggests that apoptosis is involved in tissue remodeling and growth factor b, proinflammatory caspases, and cathepsin. In fibrogenesis. addition, it is now accepted that acute kidney injury often The molecular machinery regulating the effector phase of leaves subtle tubular and vascular defects associated with apoptosis favors the extracellular translocation of a highly renal fibrosis and increases the risk of end-stage renal regulated set of mediators of importance in leukocyte disease.2,3 In addition to the above ‘messengers of injury’, trafficking and tissue remodeling. This molecular legacy recent evidence suggests that many cell types are capable of mounts a communication network with surrounding cells
    [Show full text]
  • The Extracellular Matrix at a Glance Introduction the Extracellular Matrix (ECM) Is the Non- Christian Frantz1, Kathleen M
    Cell Science at a Glance 4195 The extracellular matrix at a glance Introduction The extracellular matrix (ECM) is the non- Christian Frantz1, Kathleen M. Stewart1 and Valerie M. Weaver1,2,* cellular component present within all tissues and 1Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California San organs, and provides not only essential physical Francisco, San Francisco, CA 94143, USA scaffolding for the cellular constituents but also 2 Department of Anatomy, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad initiates crucial biochemical and biomechanical Center of Regeneration Medicine and Stem Cell Research at UCSF, UCSF Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA cues that are required for tissue morphogenesis, *Author for correspondence ([email protected]) differentiation and homeostasis. The importance Journal of Cell Science 123, 4195-4200 of the ECM is vividly illustrated by the wide © 2010. Published by The Company of Biologists Ltd range of syndromes, which can be anything doi:10.1242/jcs.023820 from minor to severe, that arise from genetic abnormalities in ECM proteins (Jarvelainen et al., 2009). Although, fundamentally, the ECM is composed of water, proteins and The Extracellular Matrix at a Glance polysaccharides, each tissue has an ECM with Christian Frantz, Kathleen M. Stewart and Valerie M. Weaver a unique composition and topology that is 1 ECM macromolecules generated during tissue development through Examples of proteoglycans Fibrous proteins a dynamic and reciprocal, biochemical Glycosaminoglycan hydrogel Modular PGs SLRPs Cell-surface PGs Syndecan Glypican and biophysical dialogue between the Fibrous collagens Core protein Decorin Lumican Fibronectin Tenascin Elastins Laminin Glycosamino- Cell membrane various cellular components (e.g.
    [Show full text]