the journal of clinical investigation • jci.org/impact • march 2013 Impact jci.org/impact MARCH 2013 ALSO IN THIS ISSUE: Visualizing cerebrospinal fluid dynamics 8 Cigarette smoke represses miR-487b 8 Reprogramming pancreatic islet cells 9 Altered tissue biomechanics in fibrosis 9 Review series: Aging edited by Christopher B. Newgard and Norman E. Sharpless 10 Features 13 A summary of this month’s Journal of Clinical Investigation Generating enteric neurons from transplanted cells p. 6
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t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n • j c i . o r g / i m p a c t • m a r c h 2 0 1 3
Impact
jci.org/impactMARCH 2013
Also in this issue:
Visualizing cerebrospinal fluid dynamics 8
Cigarette smoke represses miR-487b 8
Reprogramming pancreatic islet cells 9
Altered tissue biomechanics in fibrosis 9
Review series: Aging edited by Christopher B. Newgard and Norman E. Sharpless 10
Features 13
A summary of this month’s Journal of Clinical investigation
Generating enteric neurons from transplanted cellsp. 6
Journal of Clinical Investigation Consulting Editors
Lois Smith
Steven R. Smith
Susan S. Smyth
Weihong Song
Ashley L. St. John
Herman F. Staats
Jonathan S. Stamler
John R. Stanley
Colin L. Stewart
Doris Stoffers
Warren Strober
Maureen A. Su
Katalin Susztak
Catharina Svanborg
Ira Tabas
Alan R. Tall
Sakae Tanaka
Victor J. Thannickal
David L. Thomas
Andrei Thomas-Tikhonenko
Georgia D. Tomaras
Peter Tontonoz
Laurence A. Turka
Raphael H. Valdivia
Marcel R.M. van den Brink
Luc Van Kaer
Matthias von Herrath
Hong Wang
David Weinstock
Jeffrey Weiser
Stephen J. Weiss
Bart O. Williams
Joseph C. Wu
Thomas A. Wynn
Rudolf Zechner
Kang Zhang
Leonard Zon
Ming-Hui Zou
Weiping Zou
t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n • j c i . o r g / i m p a c t • m a r c h 2 0 1 3 1
Tempus fugitFrom the Editor
editorHoward A. Rockman
Deputy editors Garnett Kelsoe, Norman Sharpless
Associate editorsSoman N. Abraham, Vann Bennett,Gerard Blobe, Kathleen M. Caron,Marc G. Caron, John P. Chute,Thomas M. Coffman, Anna Mae Diehl,Ronald J. Falk, Daniel P. Kelly,Mary E. Klotman, Rodger A. Liddle,Nigel Mackman, Douglas A. Marchuk,Larry G. Moss, Christopher B. Newgard,Paul W. Noble, Cam Patterson, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Bryan Roth, Yiping Yang
Clinical Medicine Associate editorsBruce Burnett, Vance G. Fowler Jr.,Michael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy
Asia editorsScott A. Summers, David M. Virshup
Chair, executive CouncilRobert J. Lefkowitz
BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen
BioethicistArthur J. Caplan
science editorsKathryn Claiborn, Sarah C. Jackson
Assistant science editorJillian Hurst
editor at largeUshma S. Neill
issn 2324-7703 (print)issn 2325-4556 (online)
The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.
ImpactMarch 2013
Contact the JCiThe Journal of Clinical Investigation15 Research DriveAnn Arbor, Michigan 48103, USAPhone: 734.222.6050E-mail: [email protected]
Full articles online,jci.me/123/3
It is now one year into our stewardship of the JCI, and in an Editorial in this-month’s issue (jci.me/69370), I have looked back on the privileges enjoyed, responsibilities undertaken, challenges faced, and initiatives announced since March 2012. Overseeing the evaluation of manu-scripts submitted across the biomedical spectrum has been a career highlight. I have the honor of collaborating with Editorial Board members who possess both in-depth knowledge of their scientific areas and a passion for
science and new discovery. We have benefited from the gifts of authors who share with us their most treasured findings and creativity every day.
In the past year, the Board has received about 3,700 original submissions and 800 revisions, with the challenge of selecting papers adhering to the JCI’s tradition of publishing work that is not only scientifically rigorous, but reveals insights into the disease mechanism. Over 4,400 reviews were submitted, by almost 2,500 reviewers, an authoritative group of scientists whose efforts I gratefully acknowledge.
A number of initiatives announced at the beginning of my tenure have come to fruition: Our video series Conversations with Giants in Medicine started in April 2012 with Harold Varmus; this month’s interview is with Paul Greengard (see p. 13). In another video effort, Author’s Take, authors briefly present the work in their JCI articles (jci.org/kiosk/authors_take). We are publishing two new series: the Attending Physician, discussing the therapeutic advance demonstrated by a research article published in the Journal (p. 9); and Hindsight, probing the JCI archives for landmark publications that have changed a scientific field (p. 13)
The JCI now considers submissions in a new category, Clinical Medicine (jci.me/clin-med): phase I/II research with the potential to change the practice of medi-cine; we expect to publish our first article in the coming months. We’ll also be pub-lishing Clinical Medicine Reviews, focusing on specific areas with broad relevance.
Our deepest appreciation goes to those authors who entrust their work to us and who make the JCI the standout journal that it is. I, and the rest of the Board, look forward to continuing to fill the Journal with your exciting results. And, as always, I welcome your feedback ([email protected]).
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Research articles in the current issue of the JCI
Cardiovascular diseaseDepletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosisRoland Klingenberg, Norbert Gerdes, Robert M. Badeau, Anton Gisterå, Daniela Strodthoff, Daniel F.J. Ketelhuth, Anna M. Lundberg, Mats Rudling, Stefan K. Nilsson, Gunilla Olivecrona, Stefan Zoller, Christine Lohmann, Thomas F. Lüscher, Matti Jauhiainen, Tim Sparwasser, and Göran K. Hansson jci.me/63891
CXCL5 limits macrophage foam cell formation in atherosclerosisAnthony Rousselle, Fatimunnisa Qadri, Lisa Leukel, Rüstem Yilmaz, Jean-Fred Fontaine, Gabin Sihn, Michael Bader, Amrita Ahluwalia, and Johan Duchene jci.me/66580
HDAC4 controls histone methylation in response to elevated cardiac loadMathias Hohl, Michael Wagner, Jan-Christian Reil, Sarah-Anne Müller, Marcus Tauchnitz, Angela M. Zimmer, Lorenz H. Lehmann, Gerald Thiel, Michael Böhm, Johannes Backs, and Christoph Maack jci.me/61084
Diabetes increases mortality after myocardial infarction by oxidizing CaMKIIMin Luo, Xiaoqun Guan, Elizabeth D. Luczak, Di Lang, William Kutschke, Zhan Gao, Jinying Yang, Patric Glynn, Samuel Sossalla, Paari D. Swaminathan, Robert M. Weiss, Baoli Yang, Adam G. Rokita, Lars S. Maier, Igor Efimov, Thomas J. Hund, and Mark E. Anderson jci.me/65268
More, p. 7Parthenogenetic stem cells for tissue-engineered heart repairMichael Didié, Peter Christalla, Michael Rubart, Vijayakumar Muppala, Stephan Döker, Bernhard Unsöld, Ali El-Armouche, Thomas Rau, Thomas Eschenhagen, Alexander P. Schwoerer, Heimo Ehmke, Udo Schumacher, Sigrid Fuchs, Claudia Lange, Alexander Becker, Wen Tao, John A. Scherschel, Mark H. Soonpaa, Tao Yang, Qiong Lin, Martin Zenke, Dong-Wook Han, Hans R. Schöler, Cornelia Rudolph, Doris Steinemann, Brigitte Schlegelberger, Steve Kattman, Alec Witty, Gordon Keller, Loren J. Field, and Wolfram-Hubertus Zimmermann jci.me/66854
With related Commentary by Sara J. McSweeney and Michael D. Schneider More, p. 7
GastroenterologyTransplanted progenitors generate functional enteric neurons in the postnatal colonRyo Hotta, Lincon A. Stamp, Jaime P.P. Foong, Sophie N. McConnell, Annette J. Bergner, Richard B. Anderson, Hideki Enomoto, Donald F. Newgreen, Florian Obermayr, John B. Furness, and Heather M. Young jci.me/65963
More, p. 6
Gene therapy Adeno-associated virus capsid antigen presentation is dependent on endosomal escapeChengwen Li, Yi He, Sarah Nicolson, Matt Hirsch, Marc S. Weinberg, Ping Zhang, Tal Kafri, and R. Jude Samulski jci.me/66611
ImmunologyIL-6 trans-signaling promotes pancreatitis-associated lung injury and lethalityHong Zhang, Patrick Neuhöfer, Liang Song, Björn Rabe, Marina Lesina, Magdalena U. Kurkowski, Matthias Treiber, Thomas Wartmann, Sara Regnér, Henrik Thorlacius, Dieter Saur, Gregor Weirich, Akihiko Yoshimura, Walter Halangk, Joseph P. Mizgerd, Roland M. Schmid, Stefan Rose-John, and Hana Algül jci.me/64931
MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injuryNicolas Deroide, Xuan Li, Dominique Lerouet, Emily Van Vré, Lauren Baker, James Harrison, Marine Poittevin, Leanne Masters, Lina Nih, Isabelle Margaill, Yoichiro Iwakura, Bernhard Ryffel, Marc Pocard, Alain Tedgui, Nathalie Kubis, and Ziad Mallat jci.me/65167
Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cellsJianmei W. Leavenworth, Xiaolei Tang, Hye-Jung Kim, Xiaoyang Wang, and Harvey Cantor jci.me/66938
SHP-1 phosphatase activity counteracts increased T cell receptor affinityMichael Hebeisen, Lukas Baitsch, Danilo Presotto, Petra Baumgaertner, Pedro Romero, Olivier Michielin, Daniel E. Speiser, and Nathalie Rufer jci.me/65325
PAR-1 contributes to the innate immune response during viral infectionSilvio Antoniak, A. Phillip Owens III, Martin Baunacke, Julie C. Williams, Rebecca D. Lee, Alice Weithäuser, Patricia A. Sheridan, Ronny Malz, James P. Luyendyk, Denise A. Esserman, JoAnn Trejo, Daniel Kirchhofer, Burns C. Blaxall, Rafal Pawlinski, Melinda A. Beck, Ursula Rauch, and Nigel Mackman jci.me/66125
Lymphatic systemEndothelial ERK signaling controls lymphatic fate specificationYong Deng, Deepak Atri, Anne Eichmann, and Michael Simons jci.me/63034
More, p. 8
MetabolismMuscle lipogenesis balances insulin sensitivity and strength through calcium signalingKatsuhiko Funai, Haowei Song, Li Yin, Irfan J. Lodhi, Xiaochao Wei, Jun Yoshino, Trey Coleman, and Clay F. Semenkovich jci.me/65726
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Research articles in the current issue of the JCI
MetabolismEpigenomic plasticity enables human pancreatic a to β cell reprogrammingNuria C. Bramswig, Logan J. Everett, Jonathan Schug, Craig Dorrell, Chengyang Liu, Yanping Luo, Philip R. Streeter, Ali Naji, Markus Grompe, and Klaus H. Kaestner jci.me/66514
With related Commentary by Larry G. Moss More, p. 9
NeurobiologyBrain-wide pathway for waste clearance captured by contrast-enhanced MRIJeffrey J. Iliff, Hedok Lee, Mei Yu, Tian Feng, Jean Logan, Maiken Nedergaard, and Helene Benveniste jci.me/67677
With related Commentary by Warren J. Strittmatter More, p. 8
Oncology IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liverChunsheng Liu, Daniel D. Billadeau, Haitham Abdelhakim, Edward Leof, Kozo Kaibuchi, Carmelo Bernabeu, George S. Bloom, Liu Yang, Lisa Boardman, Vijay H. Shah, and Ningling Kang jci.me/63836
Virus-induced hepatocellular carcinomas cause antigen-specific local toleranceGerald Willimsky, Karin Schmidt, Christoph Loddenkemper, Johanna Gellermann, and Thomas Blankenstein jci.me/64742
TGF-β inhibition enhances chemotherapy action against triple-negative breast cancerNeil E. Bhola, Justin M. Balko, Teresa C. Dugger, María Gabriela Kuba, Violeta Sánchez, Melinda Sanders, Jamie Stanford, Rebecca S. Cook, and Carlos L. Arteaga jci.me/65416
Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progressionAntonio F. Santidrian, Akemi Matsuno-Yagi, Melissa Ritland, Byoung B. Seo, Sarah E. LeBoeuf, Laurie J. Gay, Takao Yagi, and Brunhilde Felding-Habermann jci.me/64264
Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis
Sichuan Xi, Hong Xu, Jigui Shan, Yongguang Tao, Julie A. Hong, Suzanne Inchauste, Mary Zhang, Tricia F. Kunst, Leandro Mercedes, and David S. Schrump jci.me/61271
More, p. 8Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesisZhen Chen, Tsung-Ching Lai, Yi-Hua Jan, Feng-Mao Lin, Wei-Chi Wang, Han Xiao, Yun-Ting Wang, Wei Sun, Xiaopei Cui, Ying-Shiuan Li, Tzan Fang, Hongwei Zhao, Chellappan Padmanabhan, Ruobai Sun, Danny Ling Wang, Hailing Jin, Gar-Yang Chau, Hsien-Da Huang, Michael Hsiao, and John Y-J. Shyy jci.me/65344
Angiopoietin-like protein 1 suppresses SLUG to inhibit cancer cell motilityTsang-Chih Kuo, Ching-Ting Tan, Yi-Wen Chang, Chih-Chen Hong, Wei-Jiunn Lee, Min-Wei Chen, Yung-Ming Jeng, Jean Chiou, Pei Yu, Pai-Sheng Chen, Ming-Yang Wang, Michael Hsiao, Jen-Liang Su, and Min-Liang Kuo jci.me/64044
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Research articles in the current issue of the JCI
Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progressionRachana Patel, Meiling Gao, Imran Ahmad, Janis Fleming, Lukram B. Singh, Taranjit Singh Rai, Arthur B. McKie, Morag Seywright, Robert J. Barnetson, Joanne Edwards, Owen J. Sansom, and Hing Y. Leung jci.me/63672
Host immunity contributes to the anti-melanoma activity of BRAF inhibitorsDeborah A. Knight, Shin Foong Ngiow, Ming Li, Tiffany Parmenter, Stephen Mok, Ashley Cass, Nicole M. Haynes, Kathryn Kinross, Hideo Yagita, Richard C. Koya, Thomas G. Graeber, Antoni Ribas, Grant A. McArthur, and Mark J. Smyth jci.me/66236
ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancerChangmeng Cai, Hongyun Wang, Housheng Hansen He, Sen Chen, Lingfeng He, Fen Ma, Lorelei Mucci, Qianben Wang, Christopher Fiore, Adam G. Sowalsky, Massimo Loda, X. Shirley Liu, Myles Brown, Steven P. Balk, and Xin Yuan jci.me/66666
Pulmonology Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosisYong Zhou, Xiangwei Huang, Louise Hecker, Deepali Kurundkar, Ashish Kurundkar, Hui Liu, Tong-Huan Jin, Leena Desai, Karen Bernard, and Victor J. Thannickal jci.me/66700
With related Attending Physician by Dean Sheppard More, p. 9
Modified Foxp3 mRNA protects against asthma through an IL-10–dependent mechanismLauren E. Mays, Susanne Ammon-Treiber, Benedikt Mothes, Mohammed Alkhaled, Jennifer Rottenberger, Eva Sophie Müller-Hermelink, Melanie Grimm, Markus Mezger, Sandra Beer-Hammer, Esther von Stebut, Nikolaus Rieber, Bernd Nürnberg, Matthias Schwab, Rupert Handgretinger, Marco Idzko, Dominik Hartl, and Michael S.D. Kormann jci.me/65351
Technical advancep53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotesAndrea Prodosmo, Andrea De Amicis, Cecilia Nisticò, Mario Gabriele, Giuliana Di Rocco, Laura Monteonofrio, Maria Piane, Enrico Cundari, Luciana Chessa, and Silvia Soddu jci.me/67289
2-Photon imaging of phagocyte-mediated T cell activation in the CNSMarija Pesic, Ingo Bartholomäus, Nikolaos I. Kyratsous, Vigo Heissmeyer, Hartmut Wekerle, and Naoto Kawakami jci.me/67233
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Proper function of the digestive system requires coordinated contraction of the muscle in the wall of the intestinal tract, regulated by the enteric nervous system. Damage to or inherited absence of these neurons can result in motility disorders that are currently poorly managed medically. In principle, disorders of the enteric nervous system could be treated by cell therapy, but it was previously unknown whether transplanted stem cells could migrate and differentiate correctly to innervate the bowel. In this article, Ryo Hotta and colleagues isolated neural crest stem cells from embryonic and postnatal mice, cultured them to promote the formation of neurospheres, and implanted them into colonic muscles of recipient mice. Hotta et al. found that these cells were able to migrate away from the transplantation site and differentiate into neurons that incorporated into the neural circuitry and the glial cells that support them. These findings suggest that the transplantation of neural stem cells is a promising therapeutic avenue for the treatment of gastrointestinal motility disorders.
In the accompanying image, enteric neural crest–derived neurospheres were characterized in vitro by expression of Kikume (green) and staining for Sox10 (blue) and Tuj1(red).
Transplanted progenitors generate functional enteric neurons in the postnatal colonRyo Hotta, Lincon A. Stamp, Jaime P.P. Foong, Sophie N. McConnell, Annette J. Bergner, Richard B. Anderson, Hideki Enomoto, Donald F. Newgreen, Florian Obermayr, John B. Furness, and Heather M. Young jci.me/65963
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Oxidized CaMKII is a “diabetic factor” in myocardial infarction–related mortalityDiabetic patients are more than twice as likely to die from a myocardial infarction (MI) as nondiabetic patients, but the mechanisms that underlie increased MI-related mortality in diabetic patients are unknown. High levels of oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) have been linked to increased risk of sudden death after heart attack, and hearts from diabetic patients have significantly greater ox-CaMKII compared with hearts from nondiabetic patients. To determine whether ox-CaMKII was an essential component of the molecular pathway that increased MI-related mortality in diabetic patients, Min Luo and colleagues developed a mouse that expresses an oxidation-resistant form of CaMKII (MM-VV) in the myocar-
dium. Diabetic mice expressing the MM-VV CaMKII isoform were protected from increased mortality after MI, suggesting that ox-CaMKII may also increase mortality after MI in diabetic patients. The image shows ox-CaMKII expression in the sinoatrial node.
Diabetes increases mortality after myocardial infarction by oxidizing CaMKIIMin Luo, Xiaoqun Guan, Elizabeth D. Luczak, Di Lang, William Kutschke, Zhan Gao, Jinying Yang, Patric Glynn, Samuel Sossalla, Paari D. Swamina-than, Robert M. Weiss, Baoli Yang, Adam G. Rokita, Lars S. Maier, Igor R. Efimov, Thomas J. Hund, and Mark E. Anderson jci.me/65268
cardiovascular disease
Research | Editor’s Picks
Although new surgical techniques have dramatically improved survival rates, one of the major complications of myocardial infarction — mas-sive death of cardiomyocytes — is not addressed by current therapies. One approach that might speed recovery is cell therapy using direct replacement of the injured cells with cardiomyocytes or their stem cell–derived precursors. However, substantial barriers include the ethical complications of using stem cells and their products, as well as the potential for immune system rejection after implantation. In this article, Michael Didié, Peter Christalla, and colleagues circumvent both of these roadblocks by generating parthenogenetic stem cells (PSCs) from mouse oocytes. These unfertilized cells harbor two copies of the maternal genome, and are thus more likely to be homozygous for histocompatibility markers, which should greatly reduce the number of cell lines required to create a tissue bank capable of matching most of the population. The PSCs were able to differentiate into cardiomyocytes, survive after transplantation, and improve heart function after infarction if implanted as engineered heart muscle.
In the accompanying Commentary, Sara McSweeney and Michael Schneider explain the possible benefits
Virgin cells mending broken heartsof this approach and the potential for cell-based therapy to treat heart disease and other disorders.
The figure shows PSC-derived cardiomyocytes (green) engrafted into the mouse heart.
Parthenogenetic stem cells for tissue-engineered heart repairMichael Didié, Peter Christalla, Michael Rubart, Vijayakumar Muppala, Stephan Döker, Bernhard Unsöld, Ali El-Armouche, Thomas Rau, Thomas Eschenhagen, Alexander P. Schwoerer, Heimo Ehmke, Udo Schumacher, Sigrid Fuchs, Claudia Lange, Alexander Becker, Wen Tao, John A. Scherschel, Mark H. Soonpaa, Tao Yang, Qiong Lin, Martin Zenke, Dong-Wook Han, Hans R. Schöler, Cornelia Rudolph, Doris Steinemann, Brigitte Schlegelberger, Steve Kattman, Alec Witty, Gordon Keller, Loren J. Field, and Wolfram-Hubertus Zimmermann jci.me/66854
Related CommentaryVirgin birth: engineered heart muscle from parthenogenetic stem cells Sara J. McSweeney and Michael D. Schneiderjci.me/67961
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Research | Editor’s Picks
neurobiology lymphatic system
Brain imaging reveals waste removal pathway
Most cells in the body are surrounded by intersti-tial fluid, which is required to supply nutrients and to wash away waste by draining into lymphatic vessels. The brain, by contrast, does not have classical lymphatic vessels like other organs but is surrounded by cerebrospinal fluid (CSF), which has long been thought not to mix with other extracellular fluids. Recent research has revealed, however, that CSF filters through the brain and exchanges with the interstitial fluid via a newly defined brain-wide glymphatic pathway. In this issue, Jeffrey Iliff and colleagues used contrast-enhanced dynamic MRI to visualize paramagnetic tracer molecules moving through the glymphatic system. Because some neurological pathologies,
such as Alzheimer’s disease and chronic traumatic encephalopathy, are associated with the accumu-lation of large extracellular aggregates, the au-thors hope that this advanced imaging technique may be useful in monitoring waste clearance and assessing disease susceptibility.
In the accompanying Commentary, Warren Strittmatter describes the anatomy of this newly discovered glymphatic system and how the ability to monitor changes in the rate of flow and aggregate clearance could become an important diagnostic tool.
The image shows fluorescent CSF tracer influx into the brain.
Brain-wide pathway for waste clearance captured by contrast-enhanced MRIJeffrey J. Iliff, Hedok Lee, Mei Yu, Tian Feng, Jean Logan, Maiken Nedergaard, and Helene Benveniste jci.me/67677
Related CommentaryBathing the brainWarren J. Strittmatter jci.me/68241
Excess ERK signaling underlies RASopathy- associated lymphatic disordershuman diseases associated with gain-of-function mutations in the RAS/RAF signaling cascade (RASopathies) are frequently accompanied by lymphangiectasia, a pathological enlargement of the lymphatic sacs. To determine how RAS/RAF signaling impacts the development of the lymphatic system, Yong Deng and colleagues gen-erated transgenic mice with endothelial-specific expression of a Noonan syndrome–associated RAF mutant (RAF1S259A). Expression of RAF1S259A enhanced expression of the lymphangiogenic transcription factors SOX18 and PROX1 in an ERK-dependent manner and increased lymphatic fate specification. The mutant mice also exhibited lymphangiectasia, which could be rescued by inhibition of ERK signaling. These findings sug-gest that excessive ERK activation underlies the lymphangiectasia and indicate that ERK inhibition could be a useful therapeutic strategy in the treat-ment of RASopathies. The accompanying image shows increased lymphangiogenesis in mutant embryos (S259A).
Endothelial ERK signaling controls lymphatic fate specificationYong Deng, Deepak Atri, Anne Eichmann, and Michael Simons jci.me/63034
A smoking gun in lung cancer epigeneticsRecent studies have identified correlations between cigarette smoke–induced microRNA (miRNA) expression and different aspects of lung cancer; however, it is unclear how miRNA expression directly contributes to carcinogenesis. Sichuan Xi and colleagues measured miRNA expression in normal human respiratory epithelial cells exposed to cigarette smoke condensate (CSC) and lung cancer cells derived from smokers and nonsmokers. They found that CSC exposure represses miR-487b, resulting in upregulation of the oncogenes WNT5A, KRAS, MYC, SUZ12, and BMI1 and subsequent enhancement of proliferation, invasion, tumorigenicity, and metastatic capacity. Downregulation of miR-487b and concomitant upregulation of the five oncogenes was also observed in primary lung cancer specimens. These results reveal a direct mechanism by which cigarette smoke–induced miRNA alterations promote lung carcinogenesis.
Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesisSichuan Xi, Hong Xu, Jigui Shan, Yongguang Tao, Julie A. Hong, Suzanne Inchauste, Mary Zhang, Tricia F. Kunst, Leandro Mercedes, and David S. Schrump jci.me/61271
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Research | Editor’s Picks
in differentiated cells, a stable phenotype is maintained in part by chromatin alterations, referred to as epigenetic marks, which determine the relative transcriptional activity of cell type–specific genes. In this issue, Nuria Bramswig and colleagues analyzed the
epigenetic state of human pancreatic cells and found that, in glucagon-producing a cells, many genes related to the β cell program were simul-taneously marked by activating and repressing modifications. Bramswig et al. further found that treating human or mouse islets with chromatin-modifying compounds induced the expression of β cell genes in a cells. These findings suggest that treating islets with chromatin remodelers may be a method to drive transdifferentiation of a cells toward a β cell phenotype. As Larry Moss explains in the accompanying Commentary, scientists may one day be able to capitalize on this inherent plasticity of a cells to create a new source of β cells for diabetes therapy.
The figure shows coexpression of β and a cell markers in human islet cells after treatment with chromatin modifiers.
Epigenomic plasticity enables human pancreatic a to β cell reprogrammingNuria C. Bramswig, Logan J. Everett, Jonathan Schug, Craig Dorrell, Chengyang Liu, Yanping Luo, Philip R. Streeter, Ali Naji, Markus Grompe, and Klaus H. Kaestner jci.me/66514
Related CommentaryCreating new β cells: cellular transmutation by genomic alchemyLarry G. Moss jci.me/68348
Reprogramming a cells to treat diabetes
metabolismpulmonology
Myofibroblasts are highly contractile cells that function to pull the edges of an injured tissue together during wound healing, forming a scar. After healing is complete, myofibroblasts disap-pear. In pulmonary fibrosis, myofibroblasts fail to undergo apoptosis and continue to form scars in the lung, leading to stiff, fibrotic lung tissue that has decreased oxygen diffusion capacity. Using
an experimental mouse model of lung fibrosis, Yong Zhou and colleagues defined a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cyto-skeletal remodeling, and the transcription factor megakaryoblastic leukemia 1 that regulates myofibroblast differentiation and survival. These findings reveal a positive feedback loop whereby fibrosis-mediated stiffening of lung tissue promotes the survival of myofibroblasts, leading to more fibrosis. Pharmacological disruption of this signaling pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis, which indicates that therapeutic interventions targeting mechanosensi-tive signaling could be effectively used to treat fibrotic disease. In an accompanying Attending Physician article, Dean Sheppard discusses the potential use of ROCK inhibitors for the treatment of pulmonary fibrosis. The confocal microscopy image shows actin polymerization in myofibroblasts cultured on a stiff matrix.
Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosisYong Zhou, Xiangwei Huang, Louise Hecker, Deepali Kurundkar, Ashish Kurundkar, Hui Liu, Tong-Huan Jin, Leena Desai, Karen Bernard, and Victor J. Thannickal jci.me/66700
Under pressure: mechanosensitive signaling promotes pulmonary fibrosis
hematology
Cellular traffic jam predisposes mice to hematologic malignancysMAP1, a GtPase-activating protein (GAP) that mediates clathrin-dependent endocytosis, is frequently mutated in colon cancer; however, it is unclear whether and how SMAP1 is involved in other types of malignancy. Shunsuke Kon and colleagues generated Smap1-deficient mice to examine the func-tion of SMAP1 in clathrin-dependent trafficking and cell growth and differentiation. Though Smap1-defi-cient mice appeared healthy, loss of Smap1 resulted
in the intracellular accumulation of the oncogenic cytokine receptor c-KIT in hematopoietic progenitors and mast cells. This accumulation was accompanied by enhanced ERK activation and increased cell growth. As the mice aged, nearly half developed hematological abnormalities that were reminiscent of human myelodysplastic syndrome. Thus, deregulation of clathrin-dependent endocytosis likely triggers that development of hematologic malignancies.
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The role of mitochondria in agingAna Bratic and Nils-Göran Larsson
Causes, consequences, and reversal of immune system agingEncarnacion Montecino-Rodriguez, Beata Berent-Maoz, and Kenneth Dorshkind
Cellular senescence and the senescent secretory phenotype: therapeutic opportunitiesTamara Tchkonia, Yi Zhu, Jan van Deursen, Judith Campisi, and James L. Kirkland
Series Editors: Christopher B. newgard and norman e. sharpless
The biology of aging and opportunities for therapeutic intervention
Review Series
Aging is an inevitable part of life. However, emerging research on the mo-lecular pathways underlying aging suggests that it may someday be possible to therapeutically target the aging process to slow or delay age-related diseases. The Aging Series in this month’s issue of the JCI focuses on selected cellular mechanisms of aging and their contribution to clinical conditions. In their overview, series editors Christopher Newgard and Norman Sharpless discuss areas of aging research with a strong potential for therapeutic intervention and critically examine uncertainties in the field. The series includes reviews explor-ing many aspects of aging, including cellular senescence and the senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, the role of sirtuins in metabolism and aging-associated diseases, the mTOR signaling pathway, telomeric dysfunction, immune system decline with age, and aging-associated changes to pancreatic islet β cells.
Coming of age: molecular drivers of aging and therapeutic opportunitiesChristopher B. Newgard and Norman E. Sharpless jci.me/68833
The sirtuin family’s role in aging and age-associated pathologiesJessica A. Hall, John E. Dominy, Yoonjin Lee, and Pere Puigserver
Rapalogs and mTOR inhibitors as anti-aging therapeutics Dudley W. Lamming, Lan Ye, David M. Sabatini, and Joseph A. Baur
The role of aging upon β cell turnoverJake A. Kushner
Telomeres and age-related disease: how telomere biology informs clinical paradigmsMary Armanios
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Review Series | aging
As we age, our immune systems gradually decline, resulting in decreased produc-tion of lymphocytes and diminished function of mature B cells and T cells. These impairments result in a decreased capacity of the immune system to respond to pathogens in the elderly. Kenneth Dorshkind and colleagues examine the molecular and cellular changes that cause immune system aging, the effects of immune system aging, and strategies that might be used to stimulate im-munity in the elderly. Their review emphasizes the aging-associated decline in the adaptive immune system, including depletion of lymphoid hematopoietic
Aging-associated immune system declinestem cells and intracellular pathways contributing to compromised lymphocyte function, as well as opportunities to design therapeutic strategies to reverse immune system deterioration in the elderly population. The accompanying image shows how multiple age-related changes can affect the lymphocyte populations, resulting in diminished immune function with age.
Causes, consequences, and reversal of immune system agingEncarnacion Montecino-Rodriguez, Beata Berent-Maoz, and Kenneth Dorshkind jci.me/64096
Sirtuins in aging and diseasethe sirtuin family of proteins has been implicated in stress-resistance pathways activated by caloric restriction and more broadly in the aging process. The seven members of the mammalian sirtuin family have unique roles and are induced by a wide variety of cellular stressors. Pere Puigserver and colleagues review the data on the role of each of the sirtuins in several age-associated diseases, including metabolic syndrome, cardiovascular disease, neurodegeneration, and cancer. They discuss controversies in the field surrounding the concept that the activation of sirtuin proteins could provide a therapeutic target for slowing age-related decline and suggest challenges that must be addressed before further exploring the development of clinically useful sirtuin activators.
The sirtuin family’s role in aging and age-associated pathologiesJessica A. Hall, John E. Dominy, Yoonjin Lee, and Pere Puigserver jci.me/64094
Mitochondrial dysfunction in agingimpairments in mitochondrial function, including defects in respiratory chain function and mitochondrial energy metabolism, have long been associated with aging. Ana Bratic and Nils-Göran Larsson review the evidence support-ing a role for mitochondria in the aging process, including data from genetic models indicating that increased mitochondrial DNA (mtDNA) mutation levels play a causative role in aging pathology. Further, they discuss emerging studies suggesting that aging-associated mtDNA mutations are due to an expansion of mtDNA replication errors generated during development. Their review also explores caveats of the mitochondrial free radical theory of aging and high-lights how other mechanisms, such as insulin/IGF1 signaling and the mTOR pathway, might underlie the key role of mitochondria in aging.
The role of mitochondria in agingAna Bratic and Nils-Göran Larsson jci.me/64125
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Review Series | aging
the mtoR pathway is critical for regulating cell growth and has been implicated in increased longevity due to caloric restriction. Joseph Baur and colleagues review the experimental evidence supporting the efficacy of the mTOR inhibitor rapamycin in increasing life span in genetic model systems and consider possible mechanisms of action of rapamycin, including changes in the regulation of translation, autophagy, and stem cell maintenance as well as its influence on inflammation and cancer. Their review also highlights the difficulties of using rapamycin therapeutically due to undesirable side effects and the prospects for developing safer therapies based on analogs of rapamycin or other approaches that target mTOR signaling to combat aging.
Rapalogs and mTOR inhibitors as anti-aging therapeuticsDudley W. Lamming, Lan Ye, David M. Sabatini, and Joseph A. Baur jci.me/64099
Exploring mTOR inhibitors as anti-aging therapeutics
Much research effort has been dedicated to the concept of developing therapies for diabetes that preserve and regenerate β cell endocrine function to restore insulin secretion. Jake Kushner summarizes evidence from model systems on β cell regeneration and explores emerging work that suggests that aging fundamentally restricts the ability of β cells to reenter the cell cycle and regenerate. These studies have important implications that might limit the potential of β cell regenera-tion therapies. In his review, Kushner discusses the molecular mechanisms behind age-dependent changes in β cell regeneration capacity, including epigenetic changes in genes regulating the cell cycle. In this image, a proposed model of how β cell regeneration capacity changes with age is shown.
The role of aging upon β cell turnoverJake A. Kushner jci.me/64095
Decreased β cell function in diabetes and aging
Cellular senescence and the senescence-associated secretory phenotypeGenetic studies over the last decade have provided intriguing links between cellular senescence and organismal aging. In their fascinating review, Tamara Tchkonia and colleagues discuss how cellular senes-cence can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). The authors review the mechanisms that induce senescence and the SASP, such as mitogenic signals, short telomeres, DNA damage, protein aggregation, and increased reactive oxygen species, as well as how the SASP alters tissue microenvironments, attracts immune cells, and induces senescence in neighboring cells. Additionally, their article suggests therapeutic opportunities based on targeting senescent cells and the SASP, and identifies age-related disorders for which such clinical interventions might be beneficial.
Cellular senescence and the senescent secretory phenotype: therapeutic opportunitiesTamara Tchkonia, Yi Zhu, Jan van Deursen, Judith Campisi, and James L. Kirkland jci.me/64098
telomeres are specialized structures that protect the ends of linear chromosomes, and a shortening of telomeres is associated with organismal aging and cellular senescence. Mary Armanios provides a clinical perspective on how telomere biology influences a variety of aging-associated degenerative diseases, such as idio-pathic pulmonary fibrosis, bone marrow failure,
and liver cirrhosis. She suggests how defective telomeres might explain the genetics of some age-related conditions and examines the clinical evidence indicating that telomere shortening might drive age-related changes. Armanios also critically examines the complexities of interpret-ing telomere length in clinical studies. Important-ly, her review explores the clinical implications
of telomere biology in pathophysiology and in informing individualized therapy options.
Telomeres and age-related disease: how telomere biology informs clinical paradigmsMary Armanios jci.me/66370
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Features
Linking insulin resistance to endothelial dysfunctionobesity and type 2 diabetes are major risk factors for the development of cardiovascular disease. Insulin resistance is a primary fea-ture of these metabolic syndromes and is now recognized as a critical driver of atherosclerosis. In 1996, Alain Baron, Helmut Steinberg, and colleagues demonstrated that insulin resistance mediates endothelial dysfunction by reducing antithrombotic NO production and enhancing prothrombotic endothelin release. In this article, the authors discuss how these initial observations have prompted further study of the role of insulin and other fuel hormones, such as fatty acids, in vascular function and disease.
Insulin resistance in the vasculatureKieran J. Mather, Helmut O. Steinberg, and Alain D. Baron jci.me/67166
conversations with giants in medicine
Paul GreengardDuring his distinguished career, Nobel laureate Paul Greengard has laid the foundation for our un-derstanding of the nervous system. Working both in the pharmaceutical industry and in academia, Greengard was among the first to recognize the parallels between endocrine hormones and neurotransmitters. His research group has made incredible strides in uncovering the mechanisms of that underlie depression, Alzheimer’s disease, schizophrenia, and other disorders. Following his receipt of the Nobel Prize, Greengard used his honorarium to establish the Pearl Meister Green-gard award for women in science, named in honor of his mother. Greengard recently sat down with JCI Editor at Large Ushma Neill to discuss the early influences in his career path, and how his experi-ences have shaped his experimental approaches.
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hindsight
Self regulating: Tregs and the immune systemthe t cells of the immune system are a key part of the inflammatory response to infection and injury; however, uncontrolled inflammation can result in tissue damage. A subset of T cells, Tregs, actually sup-press inflammation and can limit the extent of the immune response. In this article, Ashutosh Chaudhry and Alexander Rudensky review our current understanding of these cells, their role in inflammatory condi-tions such as obesity, and their ability to integrate signals in the environment to mediate immune responses. Tregs are now known to be critical in promoting toler-ance and preventing the development of autoimmunity, and further understanding of the signals and transcriptional programs that drive them may inform the develop-ment of immune-based therapies. The accompanying schematic illustrates the importance of optimal Stat signaling levels in Tregs in maintaining proper immune homeostasis.
Control of inflammation by integration of environmental cues by regulatory T cellsAshutosh Chaudhry and Alexander Y. Rudensky jci.me/57175
