Also in this issue:

Saturated fatty acid–induced vascular calcification 7

A new model of Hirschsprung’s disease 8

Epigenetic-mediated drug resistance 10

Identification of a muscle-specific autoantigen 12

Continuous regeneration of intestinal lacteals

p. 6

A summary of the current issue ofthe Journal of Clinical investigation

December 2015

jci.org/this-monthScan with your mobile device for the digital version of JCI This Month.

This Month

Alejandro Aballay

Abul K. Abbas

Domenico Accili

Rexford S. Ahima

Qais Al-Awqati

Kari Alitalo

James Allison

Dario C. Altieri

Masayuki Amagai

Mark E. Anderson

Brian H. Annex

Alan Attie

Jane E. Aubin

Steven P. Balk

Michael F. Beers

John A. Belperio

Nina Bhardwaj

Morris J. Birnbaum

Joyce Bischoff

Mina J. Bissell

Craig Blackstone

Bruce R. Blazar

William A. Boisvert

Nancy Bonini

Brendan Boyce

Jonathan Bromberg

Frank C. Brosius

Hal E. Broxmeyer

Andrew Butler

Michael J. Caplan

Ruben D. Carrasco

Diego H. Castrillon

Harold Chapman

Ajay Chawla

Benjamin K. Chen

Benny J. Chen

Ju Chen

Marie-Françoise Chesselet

Vivian G. Cheung

Yongwon Choi

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Marco Colonna

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Ted Dawson

Sudhansu Dey

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Gianpietro Dotti

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Jack A. Elias

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Adrian Erlebacher

Joel D. Ernst

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Robert V. Farese Jr.

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Ciro Indolfi

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William G. Kaelin Jr.

Klaus Kaestner

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Sundeep Khosla

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Terri Laufer

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Stanley M. Lemon

Jon D. Levine

Ross L. Levine

Klaus Ley

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Jeffrey Pollard

Kornelia Polyak

Catherine Postic

Josef Prchal

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Anil Rustgi

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Gregg L. Semenza

John Seykora

Steven D. Shapiro

Mari Shinohara

Steven E. Shoelson

Gerald I. Shulman

Roy L. Silverstein

M. Celeste Simon

Mihaela Skobe

Lois Smith

Journal of Clinical Investigation Consulting Editors

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

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Marcel R.M. van den Brink

Luc Van Kaer

Matthias von Herrath

Yisong Y. Wan

Hong Wang

David Weinstock

Jeffrey Weiser

Stephen J. Weiss

Bart O. Williams

Joseph C. Wu

Thomas A. Wynn

Rudolf Zechner

Kang Zhang

Len 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 / t h i s - m o n t h d e c e m b e r 2 0 1 5 1

This MonthDecember 2015

editorHoward A. Rockman

Deputy editorsGarnett Kelsoe, Bryan L. Roth

Associate editorsSoman N. Abraham, Vann Bennett,Gerard C. Blobe, Kathleen M. Caron,Marc G. Caron, John P. Chute,Thomas M. Coffman, Anna Mae Diehl,Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Yiping Yang

Clinical Medicine Associate editorsMichael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy

Asia editorDavid M. Virshup

Chair, executive CouncilRobert J. Lefkowitz

BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen

BioethicistArthur L. Caplan

senior science editorSarah C. Jackson

science editorsJillian Hurst, Corinne Williams

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.

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Top Read Articles, 2015Of Note

Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxineJoao Pedro Werneck de Castro, Tatiana L. Fonseca, Cintia B. Ueta, Elizabeth A. McAninch, Sherine Abdalla, Gabor Wittmann, Ronald M. Lechan, Balazs Gereben, and Antonio C. Bianco http://jci.me/77588Research — Published January 2, 2015 — 21,210 views

neuroepithelial circuit formed by innervation of sensory enteroendocrine cellsDiego V. Bohórquez, Rafiq A. Shahid, Alan Erdmann, Alex M. Kreger, Yu Wang, Nicole Calakos, Fan Wang, and Rodger A. Liddle http://jci.me/78361Brief Report — Published January 2, 2015 — 12,598 views

Metabolically normal obese people are protected from adverse effects following weight gainElisa Fabbrini, Jun Yoshino, Mihoko Yoshino, Faidon Magkos, Courtney Tiemann Luecking, Dmitri Samovski, Gemma Fraterrigo, Adewole L. Okunade, Bruce W. Patterson, and Samuel Klein http://jci.me/78425Clinical Medicine — Published January 2, 2015 — 22,522 views

F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous mannerKanae Yumimoto, Sayuri Akiyoshi, Hiroki Ueo, Yasuaki Sagara, Ichiro Onoyama, Hiroaki Ueo, Shinji Ohno, Masaki Mori, Koshi Mimori, and Keiichi I. Nakayama http://jci.me/78782Research — Published January 2, 2015 — 17,686 views

oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver diseaseGéraldine Gentric, Vanessa Maillet, Valérie Paradis, Dominique Couton, Antoine L’Hermitte, Ganna Panasyuk, Bernard Fromenty, Séverine Celton-Morizur, and Chantal Desdouets http://jci.me/73957Research — Published January 26, 2015 — 13,629 views

Calcium release channel RyR2 regulates insulin release and glucose homeostasisGaetano Santulli, Gennaro Pagano, Celestino Sardu, Wenjun Xie, Steven Reiken, Salvatore Luca D’Ascia, Michele Cannone, Nicola Marziliano, Bruno Trimarco, Theresa A. Guise, Alain Lacampagne, and Andrew R. Marks http://jci.me/79273Research — Published April 6, 2015 — 14,598 views

Quantification of mutant huntingtin protein in cerebrospinal fluid from huntington’s disease patientsEdward J. Wild, Roberto Boggio, Douglas Langbehn, Nicola Robertson, Salman Haider, James R.C. Miller, Henrik Zetterberg, Blair R. Leavitt, Rainer Kuhn, Sarah J. Tabrizi, Douglas Macdonald, and Andreas Weiss http://jci.me/80743Clinical Medicine — Published April 6, 2015 — 12,800 views

hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivoShannon L. Macauley, Molly Stanley, Emily E. Caesar, Steven A. Yamada, Marcus E. Raichle, Ronaldo Perez, Thomas E. Mahan, Courtney L. Sutphen, and David M. Holtzman http://jci.me/79742Brief Report — Published May 4, 2015 — 13,900 views

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AgingAging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitorsCurtis J. Henry, Matias Casás-Selves, Jihye Kim, Vadym Zaberezhnyy, Leila Aghili, Ashley E. Daniel, Linda Jimenez, Tania Azam, Eoin N. McNamee, Eric T. Clambey, Jelena Klawitter, Natalie J. Serkova, Aik Choon Tan, Charles A. Dinarello, and James DeGregori http://jci.me/83024

More, p. 12

AIDS/HIVInterleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaquesLuca Micci, Emily S. Ryan, Rémi Fromentin, Steven E. Bosinger, Justin L. Harper, Tianyu He, Sara Paganini, Kirk A. Easley, Ann Chahroudi, Clarisse Benne, Sanjeev Gumber, Colleen S. McGary, Kenneth A. Rogers, Claire Deleage, Carissa Lucero, Siddappa N. Byrareddy, Cristian Apetrei, Jacob D. Estes, Jeffrey D. Lifson, Michael Piatak Jr., Nicolas Chomont, Francois Villinger, Guido Silvestri, Jason M. Brenchley, and Mirko Paiardini http://jci.me/81400

More, p. 11

EndocrinologyFGF21 and the late adaptive response to starvation in humansPouneh K. Fazeli, Mingyue Lun, Soo M. Kim, Miriam A. Bredella, Spenser Wright, Yang Zhang, Hang Lee, Ciprian Catana, Anne Klibanski, Parth Patwari, and Matthew L. Steinhauser http://jci.me/83349

GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activationMakoto Shigeto, Reshma Ramracheya, Andrei I. Tarasov, Chae Young Cha, Margarita V. Chibalina, Benoit Hastoy, Koenraad Philippaert, Thomas Reinbothe, Nils Rorsman, Albert Salehi, William R. Sones, Elisa Vergari, Cathryn Weston, Julia Gorelik, Masashi Katsura, Viacheslav O. Nikolaev, Rudi Vennekens, Manuela Zaccolo, Antony Galione, Paul R.V. Johnson, Kohei Kaku, Graham Ladds, and Patrik Rorsman http://jci.me/81975

With related Commentary by Jelena Kolic and Patrick E. MacDonaldMore, p. 12

GastroenterologyA collagen VI-dependent pathogenic mechanism for Hirschsprung’s diseaseRodolphe Soret, Mathilde Mennetrey, Karl F. Bergeron, Anne Dariel, Michel Neunlist, Franziska Grunder, Christophe Faure, David W. Silversides, and Nicolas Pilon for the Ente-Hirsch study group http://jci.me/83178

With related Commentary by Robert O. HeuckerothMore, p. 8

HematologyCoordinate expression of heme and globin is essential for effective erythropoiesisRaymond T. Doty, Susan R. Phelps, Christina Shadle, Marilyn Sanchez-Bonilla, Siobán B. Keel, and Janis L. Abkowitz http://jci.me/83054

Research articles in the current issue of the JCI

Brown adipose tissue after fasting

Collagen in developing bowel

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Research articles in the current issue of the JCI

Inflammation drives thrombosis after Salmonella infection via CLEC-2 on plateletsJessica R. Hitchcock, Charlotte N. Cook, Saeeda Bobat, Ewan A. Ross, Adriana Flores-Langarica, Kate L. Lowe, Mahmood Khan, C. Coral Dominguez-Medina, Sian Lax, Manuela Carvalho-Gaspar, Stefan Hubscher, G. Ed Rainger, Mark Cobbold, Christopher D. Buckley, Tim J. Mitchell, Andrea Mitchell, Nick D. Jones, N. Van Rooijen, Daniel Kirchhofer, Ian R. Henderson, David H. Adams, Steve P. Watson, and Adam F. Cunningham http://jci.me/79070

Platelet-derived HMGB1 is a critical mediator of thrombosisSebastian Vogel, Rebecca Bodenstein, Qiwei Chen, Susanne Feil, Robert Feil, Johannes Rheinlaender, Tilman E. Schäffer, Erwin Bohn, Julia-Stefanie Frick, Oliver Borst, Patrick Münzer, Britta Walker, Justin Markel, Gabor Csanyi, Patrick J. Pagano, Patricia Loughran, Morgan E. Jessup, Simon C. Watkins, Grant C. Bullock, Jason L. Sperry, Brian S. Zuckerbraun, Timothy R. Billiar, Michael T. Lotze, Meinrad Gawaz, and Matthew D. Neal http://jci.me/81660

The C-terminal CGHC motif of protein disulfide isomerase supports thrombosisJunsong Zhou, Yi Wu, Lu Wang, Lubica Rauova, Vincent M. Hayes, Mortimer Poncz, and David W. Essex http://jci.me/80319

ImmunologyHelminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosisLeticia Monin, Kristin L. Griffiths, Wing Y. Lam, Radha Gopal, Dongwan D. Kang, Mushtaq Ahmed, Anuradha Rajamanickam, Alfredo Cruz-Lagunas, Joaquín Zúñiga, Subash Babu, Jay K. Kolls, Makedonka Mitreva, Bruce A. Rosa, Rosalio Ramos-Payan, Thomas E. Morrison, Peter J. Murray, Javier Rangel-Moreno, Edward J. Pearce, and Shabaana A. Khader http://jci.me/77378

Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathiesInka Albrecht, Cecilia Wick, Åsa Hallgren, Anna Tjärnlund, Kanneboyina Nagaraju, Felipe Andrade, Kathryn Thompson, William Coley, Aditi Phadke, Lina-Marcela Diaz-Gallo, Matteo Bottai, Inger Nennesmo, Karine Chemin, Jessica Herrath, Karin Johansson, Anders Wikberg, A. Jimmy Ytterberg, Roman A. Zubarev, Olof Danielsson, Olga Krystufkova, Jiri Vencovsky, Nils Landegren, Marie Wahren-Herlenius, Leonid Padyukov, Olle Kämpe, and Ingrid E. Lundberg http://jci.me/81031

More, p. 12

MetabolismMitochondrial metabolism mediates oxidative stress and inflammation in fatty liverSanthosh Satapati, Blanka Kucejova, Joao A.G. Duarte, Justin A. Fletcher, Lacy Reynolds, Nishanth E. Sunny, Tianteng He, L. Arya Nair, Kenneth Livingston, Xiaorong Fu, Matthew E. Merritt, A. Dean Sherry, Craig R. Malloy, John M. Shelton, Jennifer Lambert, Elizabeth J. Parks, Ian Corbin, Mark A. Magnuson, Jeffrey D. Browning, and Shawn C. Burgess http://jci.me/82204

Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjectsJavier Traba, Miriam Kwarteng-Siaw, Tracy C. Okoli, Jessica Li, Rebecca D. Huffstutler, Amanda Bray, Myron A. Waclawiw, Kim Han, Martin Pelletier, Anthony A. Sauve, Richard M. Siegel, and Michael N. Sack http://jci.me/83260

More, p. 8

Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptinGregory J. Morton, Thomas H. Meek, Miles E. Matsen, and Michael W. Schwartz http://jci.me/82723

More, p. 8

Platelet aggregates

Pulmonary inflammation

Hepatic ROS

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Muscle biologyMesodermal iPSC-derived progenitor cells functionally regenerate cardiac and skeletal muscleMattia Quattrocelli, Melissa Swinnen, Giorgia Giacomazzi, Jordi Camps, Ines Barthélemy, Gabriele Ceccarelli, Ellen Caluwé, Hanne Grosemans, Lieven Thorrez, Gloria Pelizzo, Manja Muijtjens, Catherine M. Verfaillie, Stephane Blot, Stefan Janssens, and Maurilio Sampaolesi http://jci.me/82735

With related Commentary by Marco SandriMore, p. 9

NephrologySDF1 induction by acidosis from principal cells regulates intercalated cell subtype distributionGeorge J. Schwartz, XiaoBo Gao, Shuichi Tsuruoka, Jeffrey M. Purkerson, Hu Peng, Vivette D’Agati, Nicolas Picard, Dominique Eladari, and Qais Al-Awqati http://jci.me/80225

OncologyMyo9b is a key player in SLIT/ROBO-mediated lung tumor suppressionRuirui Kong, Fengshuang Yi, Pushuai Wen, Jianghong Liu, Xiaoping Chen, Jinqi Ren, Xiaofei Li, Yulong Shang, Yongzhan Nie, Kaichun Wu, Daiming Fan, Li Zhu, Wei Feng, and Jane Y. Wu http://jci.me/81673

Motif mimetic of epsin perturbs tumor growth and metastasisYunzhou Dong, Hao Wu, H.N. Ashiqur Rahman, Yanjun Liu, Satish Pasula, Kandice L. Tessneer, Xiaofeng Cai, Xiaolei Liu, Baojun Chang, John McManus, Scott Hahn, Jiali Dong, Megan L. Brophy, Lili Yu, Kai Song, Robert Silasi-Mansat, Debra Saunders, Charity Njoku, Hoogeun Song, Padmaja Mehta-D’Souza,

Rheal Towner, Florea Lupu, Rodger P. McEver, Lijun Xia, Derek Boerboom, R. Sathish Srinivasan, and Hong Chen http://jci.me/80349

More, p. 10

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myelomaJiro Kikuchi, Daisuke Koyama, Taeko Wada, Tohru Izumi, Peter O. Hofgaard, Bjarne Bogen, and Yusuke Furukawa http://jci.me/80325

More, p. 10

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab responseHsin-Wei Liao, Jung-Mao Hsu, Weiya Xia, Hung-Ling Wang, Ying-Nai Wang, Wei-Chao Chang, Stefan T. Arold, Chao-Kai Chou, Pei-Hsiang Tsou, Hirohito Yamaguchi, Yueh-Fu Fang, Hong-Jen Lee, Heng-Huan Lee, Shyh-Kuan Tai, Mhu-Hwa Yang, Maria P. Morelli, Malabika Sen, John E. Ladbury, Chung-Hsuan Chen, Jennifer R. Grandis, Scott Kopetz, and Mien-Chie Hung http://jci.me/82826

With related Commentary by David M. Epstein and Elizabeth BuckMore, p. 11

Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphomaRebecca L. Goldstein, Shao Ning Yang, Tony Taldone, Betty Chang, John Gerecitano, Kojo Elenitoba-Johnson, Rita Shaknovich, Wayne Tam, John P. Leonard, Gabriela Chiosis, Leandro Cerchietti, and Ari Melnick http://jci.me/80714

Research articles in the current issue of the JCI

Skeletal myofibers

EGFR methylation

Myo9b in human lung cancer

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Research articles in the current issue of the JCI

Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancerBeatrice Rondinelli, Dalia Rosano, Elena Antonini, Michela Frenquelli, Laura Montanini, DaChuan Huang, Simona Segalla, Kosuke Yoshihara, Samir B. Amin, Dejan Lazarevic, Bin Tean The, Roel G.W. Verhaak, P. Andrew Futreal, Luciano Di Croce, Lynda Chin, Davide Cittaro, and Giovanni Tonon http://jci.me/81040

TransplantationRabbit antithymocyte globulin–induced serum sickness disease and human kidney graft survivalGrégoire Couvrat-Desvergnes, Apolline Salama, Ludmilla Le Berre, Gwénaëlle Evanno, Ondrej Viklicky, Petra Hruba, Pavel Vesely, Pierrick Guerif, Thomas Dejoie, Juliette Rousse, Arnaud Nicot, Jean-Marie Bach, Evelyn Ang, Yohann Foucher, Sophie Brouard, Stéphanie Castagnet, Magali Giral, Jean Harb, Hélène Perreault, Béatrice Charreau, Marine Lorent, and Jean-Paul Soulillou http://jci.me/82267

Vascular biologyMicroRNA-33–dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosisMireille Ouimet, Hasini N. Ediriweera, U. Mahesh Gundra, Frederick J. Sheedy, Bhama Ramkhelawon, Susan B. Hutchinson, Kaitlyn Rinehold, Coen van Solingen, Morgan D. Fullerton, Katharine Cecchini, Katey J. Rayner, Gregory R. Steinberg, Phillip D. Zamore, Edward A. Fisher, P’ng Loke, and Kathryn J. Moore http://jci.me/81676

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transportJeremiah Bernier-Latmani, Christophe Cisarovsky, Cansaran Saygili Demir, Marine Bruand, Muriel Jaquet, Suzel Davanture, Simone Ragusa, Stefanie Siegert, Olivier Dormond, Rui Benedito, Freddy Radtke, Sanjiv A. Luther, and Tatiana V. Petrova http://jci.me/82045

More, p. 6

Endothelial-to-mesenchymal transition drives atherosclerosis progressionPei-Yu Chen, Lingfeng Qin, Nicolas Baeyens, Guangxin Li, Titilayo Afolabi, Madhusudhan Budatha, George Tellides, Martin A. Schwartz, and Michael Simons http://jci.me/82719

More, p. 7

Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicity

Masashi Masuda, Shinobu Miyazaki-Anzai, Audrey L. Keenan, Kayo Okamura, Jessica Kendrick, Michel Chonchol, Stefan Offermanns, James M. Ntambi, Makoto Kuro-o, and Makoto Miyazaki http://jci.me/82871

More, p. 7

VirologyBlood kinetics of Ebola virus in survivors and nonsurvivorsSimone Lanini, Gina Portella, Francesco Vairo, Gary P. Kobinger, Antonio Pesenti, Martin Langer, Soccoh Kabia, Giorgio Brogiato, Jackson Amone, Concetta Castilletti, Rossella Miccio, Alimuddin Zumla, Maria Rosaria Capobianchi, Antonino Di Caro, Gino Strada, Giuseppe Ippolito, and INMI-EMERGENCY EBOV Sierra Leone Study group http://jci.me/83111

More, p. 9

Ebola viral load at diagnosis associates with patient outcome and outbreak evolutionMarc-Antoine de La Vega, Grazia Caleo, Jonathan Audet, Xiangguo Qiu, Robert A. Kozak, James I. Brook, Steven Kern, Anja Wolz, Armand Sprecher, Jane Greig, Kamalini Lokuge, David K. Kargbo, Brima Kargbo, Antonino Di Caro, Allen Grolla, Darwyn Kobasa, James E. Strong, Giuseppe Ippolito, Michel Van Herp, and Gary P. Kobinger http://jci.me/83162

More, p. 9

miR-33 in plaque macrophages

Aortic NOTCH3

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The intestinal vasculature is responsible for the absorption of nutrients that pass through the gastroenterological tract. While the majority of nutrients are taken up by blood capillaries, spe-cialized lymphatic capillaries, called lacteals, absorb dietary fats and fat-soluble vitamins. In this month’s issue of the JCI, the Petrova lab exten-sively characterized intestinal stroma and showed using whole-mount staining that, unlike other adult vessels, intestinal lacteals have characteris-tics of embryonic lymphatics, such as increased proliferation and filopodia. The research team found that inducible deletion of the Notch ligand DLL4 specifically in lymphatic vessels in adult mice decreased the size of lacteals in the intestine but did not affect lymphatic vessels in other tis-sues, such as skin. In animals that were mosaic for DLL4 expression, they demonstrated that DLL4 promoted lymphatic endothelial tip cell forma-tion, survival, and migration in intestinal lacteals. Further, using blocking antibodies for VEGFR2 and VEGFR3, Petrova and colleagues found that VEGFC signaling was required to induce DLL4 expression in lacteals. Functionally, they showed that loss of DLL4 resulted in impaired dietary fat uptake, which was associated with a change in the junctional organization of lymphatic endothelial cells within the lacteals. Overall, these studies sup-port a requirement for continuous DLL4-driven regeneration to maintain lacteal function in adult animals. The accompanying image shows the orga-nization of stromal cells in adult intestinal villus by whole-mount immunostaining of macrophages (green, F4/80), villus smooth muscle cells (cyan, α–smooth muscle actin), and a lacteal (red, LYVE1). Image credit: Jeremiah Bernier-Latmani.

Continuous DLL4 signaling maintains adult intestinal lacteals

Editor’s picksResearch

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transportJeremiah Bernier-Latmani, Christophe Cisarovsky, Cansaran Saygili Demir, Marine Bruand, Muriel Jaquet, Suzel Davanture, Simone Ragusa, Stefanie Siegert, Olivier Dormond, Rui Benedito, Freddy Radtke, Sanjiv A. Luther, and Tatiana V. Petrova http://jci.me/82045

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Saturated fatty acid–induced lipotoxicity underlies vascular calcification

Research | Editor’s picks

vascular biology

Endothelial cells flip the mesenchymal switch to drive atherosclerosisAtherosclerosis is strongly associated with both systemic and vessel wall inflammation; however, antiinflammatory therapies have been unsuccessful in clinical trials. Because endothelial-to-mesenchymal transition (EndMT) is a common feature of inflammation-associated pathologies, Pei-Yu Chen and colleagues examined the role of EndMT and its key regulator FGFR1 in atherosclerosis. Using cultured human endothelial cells, Chen and colleagues demonstrated that both inflammatory cytokines and oscillatory shear stress reduce endothelial FGFR1 expression, thereby activating TGF-β signaling. In a murine model of atherosclerosis, disruption of endothelial FGF signaling led to earlier development of atherosclerosis and a much greater plaque burden compared with those in mice with intact FGF signaling (see the accompanying image) as well as elevated EndMT, matrix deposition, and neointima formation. In patient samples, the extent of coronary atherosclerosis strongly correlated with loss of endothelial FGFR1 expression, activation of TGF-β signaling, and expression of EndMT markers, indicating that EndMT drives atherosclerosis progression.

Endothelial-to-mesenchymal transition drives atherosclerosis progressionPei-Yu Chen, Lingfeng Qin, Nicolas Baeyens, Guangxin Li, Titilayo Afolabi, Madhusudhan Budatha, George Tellides, Martin A. Schwartz, and Michael Simons http://jci.me/82719

Vascular calcification is a common complication in chronic kidney disease (CKD), diabetes, and aging and is associated with the accumulation of saturated fatty acids (SFAs) in vascular smooth muscle cells (VSMCs). Masashi Masuda and colleagues found that expression of the stearoyl-CoA desaturase enzymes (SCD1/2), which regulates the intracellular balance of SFAs and unsaturated fatty acids (UFAs), was reduced in a murine model of vascular calcification. Moreover, mice with SMC-specific deletion of Scd1 and Scd2 exhibited severe calcification (see the accompanying image), osteogenic differentiation, and increased ER stress. An shRNA screen and lipidomic studies demonstrated

that the acyltransferases GPAT4, AGPAT3, and AGPAT5 mediate the conversion of SFAs to saturated phosphatidic acids (PAs), which induce vascular calcification via ER stress.

Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicityMasashi Masuda, Shinobu Miyazaki-Anzai, Audrey L. Keenan, Kayo Okamura, Jessica Kendrick, Michel Chonchol, Stefan Offermanns, James M. Ntambi, Makoto Kuro-o, and Makoto Miyazaki http://jci.me/82871

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Research | Editor’s picks

Investigating the HPA axis in leptin-mediated blood glucose loweringthe mechanism by which leptin reverses hyperglycemia in animal models of poorly controlled diabetes has been reported to be mediated by suppression of the hypothalamic-pituitary-adrenal (HPA) axis. In this issue, Gregory J. Morton and colleagues investigated the contribution of HPA axis suppression to leptin-mediated glucose lowering in a rat model of uncontrolled insulin-deficient diabetes mellitus. After confirming that leptin normalized glucocorticoid levels, they demonstrated that, in contrast to previous work, neither adrenalectomy nor pharmacological blockade of glucocorticoid receptors lowered blood glucose levels. Additionally, the glucose-lowering effects of leptin were not affected by maintaining circulating corticosteroids at the high levels characteristic of uncontrolled diabetes. Taken together, these data indicate that leptin’s effects on HPA axis activity do not explain leptin’s glucose-lowering action.

Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptinGregory J. Morton, Thomas H. Meek, Miles E. Matsen, and Michael W. Schwartz http://jci.me/82723

metabolism

Fasting blunts inflammasome activation in humans via SIRT3obesity-associated inflammation is partially mediated by the NLRP3 inflammasome, which is upregulated by multiple obesity- and diabetes-associated triggers, including mitochondrial alterations. Intermittent fasting has previously been shown to reduce inflammation, leading Javier Traba and colleagues to examine NLRP3 inflammasome activation in peripheral blood mononuclear cells and monocytes extracted from blood drawn after a 24-hour fast and refeeding in 19 healthy volunteers. They observed less NLRP3 inflammasome activation in the fasted state but greater activation under refed conditions. Mechanistically, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation and mitochondrial ROS, while pharmacologic or genetic activation of SIRT3 decreased NLRP3 inflammasome activation and enhanced mitochondrial function.

Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjectsJavier Traba, Miriam Kwarteng-Siaw, Tracy C. Okoli, Jessica Li, Rebecca D. Huffstutler, Amanda Bray, Myron A. Waclawiw, Kim Han, Martin Pelletier, Anthony A. Sauve, Richard M. Siegel, and Michael N. Sack http://jci.me/83260

Increased collagen deposition underlies Hirschsprung’s diseasethe enteric nervous system arises from the enteric neural crest cells (eNCCs), which migrate from the neural crest to colonize the bowel during development. Incomplete colonization causes Hirschsprung’s disease (HSCR), a congenital anomaly characterized by functional intestinal obstruction and megacolon. In this issue, Rodolphe Soret and colleagues report the generation and characterization of a murine model of HSCR, in which insertional mutagenesis upstream of collagen-6α4 (Col6a4) causes cell-autonomous overexpression of collagen VI by eNCCs. The increased collagen deposition around the mutant eNCCs inhibited migration (see the accompanying image), resulting in an aganglionic megacolon reminiscent of HSCR. Soret and colleagues found that the myenteric ganglia of human patients with HSCR are surrounded by abundant collagen VI myofibrils. This alteration was even more pronounced in patients with HSCR with Down syndrome, likely due to extra copies of genes that mediate collagen VI assembly, which are located on chromosome 21. In the accompanying Commentary, Robert Heuckeroth discusses how these findings suggest a mechanism for the increased prevalence of HSCR in children with Down syndrome.

A collagen VI–dependent pathogenic mechanism for Hirschsprung’s diseaseRodolphe Soret, Mathilde Mennetrey, Karl F. Bergeron, Anne Dariel, Michel Neunlist, Franziska Grunder, Christophe Faure, David W. Silversides, and Nicolas Pilon for the Ente-Hirsch study group http://jci.me/83178

Related CommentaryHirschsprung’s disease, Down syndrome, and missing heritability: too much collagen slows migrationRobert O. Heuckeroth http://jci.me/85003

gastroenterology

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Research | Editor’s picks

Induced pluripotent stem cell origins influence intrinsic myogenic potentialMuscular dystrophies (MDs) frequently involve the degeneration of both cardiac and skeletal muscle, and induced pluripotent stem cell–based (iPSC-based) regenerative therapies will need to correct both muscle types. Mattia Quattrocelli and colleagues generated murine iPSCs from fibroblasts (f-iPSCs) and mesoan-gioblasts (MAB-iPSCs). Interestingly, MAB-iPSCs exhibited greater myogenic differentiation than did f-iPSCs in vitro and in vivo. In a murine MD model, mesodermal iPSC-derived progenitors (MiPs) from f-iPSCs (f-MiPs) and MAB-iPSCs (MAB-MiPs) contributed equally to cardiac muscle regeneration, but MAB-MiPs made a greater contribution to skeletal muscle regeneration than did f-MiPs (see the accompanying image). Quattrocelli and colleagues injected immunodeficient MD mice with WT or TALEN-corrected canine MD MAB-MiPs and found that they induced comparable improvements in recipient striated muscles. Epigenetic analysis revealed that f-MiPs and MAB-MiPs exhibited different patterns of epigenetic marks. In the accompanying Commentary, Marco Sandri discusses the implications of these findings for regenerative medicine.

Identification of prognostic factors in Ebola virus infectionin this issue, researchers led by Giuseppe ippolito and Gary P. Kobinger identified factors that correlate with outcome in patients infected with ebola virus (eBoV). Ippolito and colleagues quantified viremia in 84 EBOV patients between 2 and 13 days after the onset of symptoms. They found that patients who survived reached peak viremia levels earlier, had lower average peak viremia levels, and exhibited faster decay in viremia than those who did not survive. Kobinger and colleagues analyzed the temporal changes in viremia levels in 632 patients who were diagnosed with EBOV from July to December 2014. They found that patients who did not survive had higher viral loads at the time of hospital admission compared to survivors. Moreover, at the population level, patient viral loads decreased between July and December, correlating with an increase in circulating EBOV-specific IgG antibodies in individuals who did not test positive for the virus. These studies indicate that initial viral load is a prognostic factor in patients infected with EBOV.

muscle biology

virology

Mesodermal iPSC-derived progenitor cells functionally regenerate cardiac and skeletal muscleMattia Quattrocelli, Melissa Swinnen, Giorgia Giacomazzi, Jordi Camps, Ines Barthélemy, Gabriele Ceccarelli, Ellen Caluwé, Hanne Grosemans, Lieven Thorrez, Gloria Pelizzo, Manja Muijtjens, Catherine M. Verfaillie, Stephane Blot, Stefan Janssens, and Maurilio Sampaolesi http://jci.me/82735

Related CommentaryMemory or amnesia: the dilemma of stem cell therapy in muscle dystrophiesMarco Sandri http://jci.me/85002

Related ResearchBlood kinetics of Ebola virus in survivors and nonsurvivorsSimone Lanini, Gina Portella, Francesco Vairo, Gary P. Kobinger, Antonio Pesenti, Martin Langer, Soccoh Kabia, Giorgio Brogiato, Jackson Amone, Concetta Castilletti, Rossella Miccio, Alimuddin Zumla, Maria Rosaria Capobianchi, Antonino Di Caro, Gino Strada, Giuseppe Ippolito, and INMI-EMERGENCY EBOV Sierra Leone Study group http://jci.me/83111

Ebola viral load at diagnosis associates with patient outcome and outbreak evolutionMarc-Antoine de La Vega, Grazia Caleo, Jonathan Audet, Xiangguo Qiu, Robert A. Kozak, James I. Brook, Steven Kern, Anja Wolz, Armand Sprecher, Jane Greig, Kamalini Lokuge, David K. Kargbo, Brima Kargbo, Antonino Di Caro, Allen Grolla, Darwyn Kobasa, James E. Strong, Giuseppe Ippolito, Michel Van Herp, and Gary P. Kobinger http://jci.me/83162

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Research | Editor’s picks

Epsin peptide mimetic modulates VEGF signaling to impair tumor growthtumor angiogenesis is critical for tumor growth and is primarily mediated by VEGFR2. Previous studies demonstrated that loss of endothelial epsin prevents VEGFR2 degradation and results in uncontrolled angiogenesis and dysfunc-tional tumor vasculature. Yunzhou Dong and colleagues developed an epsin peptide mimetic (UPI) that competitively binds activated VEGFR2 in the tumor endothelium and prevents its degradation, thereby prolonging proangiogenic signaling. In murine tumor xenograft models, UPI treatment impaired functional tumor angiogenesis, tumor growth, and metastasis (see the accompanying image) and enhanced survival. Moreover, UPI administration enhanced the effects of cytotoxic therapeutics such as doxorubicin and Taxol.

Epigenetic alterations underlie cell adhesion–mediated chemoresistance in multiple myelomaMultiple myeloma (MM) cells frequently infiltrate the bone marrow (BM), where cell adhesion interactions with BM stromal cells render them less sensitive to chemotherapy, a phenomenon known as cell adhesion–mediated drug resistance (CAM-DR). Jiro Kikuchi and colleagues found that stromal adhesion of MM cells inactivated the histone methyltransferase EZH2, thereby reducing methylation of histone 3–lysine 27 (H3K27). This epigenetic alteration sustained expression of the antiapoptotic genes IGF1, BCL2, and HIF1A to enhance cell survival. In murine MM models, pharmacological or genetic inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by inducing dephosphorylation

of EZH2, which resulted in increased EZH2 activity, hypermethylation of H3K27, and resensitization to chemotherapy (see the accompanying image). These studies identify an epigenetic mechanism underlying CAM-DR and suggest potential therapeutic interventions to enhance chemotherapy sensitivity in MM.

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myelomaJiro Kikuchi, Daisuke Koyama, Taeko Wada, Tohru Izumi, Peter O. Hofgaard, Bjarne Bogen, and Yusuke Furukawa http://jci.me/80325

oncology

Motif mimetic of epsin perturbs tumor growth and metastasisYunzhou Dong, Hao Wu, H.N. Ashiqur Rahman, Yanjun Liu, Satish Pasula, Kandice L. Tessneer, Xiaofeng Cai, Xiaolei Liu, Baojun Chang, John McManus, Scott Hahn, Jiali Dong, Megan L. Brophy, Lili Yu, Kai Song, Robert Silasi-Mansat, Debra Saunders, Charity Njoku, Hoogeun Song, Padmaja Mehta-D’Souza, Rheal Towner, Florea Lupu, Rodger P. McEver, Lijun Xia, Derek Boerboom, R. Sathish Srinivasan, and Hong Chen http://jci.me/80349

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Research | Editor’s picks

EGFR methylation impairs cetuximab response in colorectal cancerintracellular posttranslational modifications influence the signaling behavior of EGFR, but little is known about the impact of modifications to the extracellular portion of the receptor. Hsin-Wei Liao and colleagues report that protein arginine methyltransferase 1–mediated methylation of two extracel-lular arginine residues in EGFR enhances binding to EGF, receptor dimerization, and signaling activation. Expression of a methylation-defective EGFR reduced tumor growth in a murine orthotopic model of colorectal cancer. Moreover, EGFR methylation sustained signaling activity and cell proliferation even in the presence of cetuximab, an EGFR monoclonal antibody that is currently used to treat metastatic colorectal cancer. In human colorectal cancer patients, EGFR methylation level was correlated with a higher recurrence rate after cetuximab treatment and poor overall survival. In the accompanying Commentary, David Epstein and Elizabeth Buck discuss how these findings could aid in the development of improved antibody-based therapeutics.

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab responseHsin-Wei Liao, Jung-Mao Hsu, Weiya Xia, Hung-Ling Wang, Ying-Nai Wang, Wei-Chao Chang, Stefan T. Arold, Chao-Kai Chou, Pei-Hsiang Tsou, Hirohito Yamaguchi, Yueh-Fu Fang, Hong-Jen Lee, Heng-Huan Lee, Shyh-Kuan Tai, Mhu-Hwa Yang, Maria P. Morelli, Malabika Sen, John E. Ladbury, Chung-Hsuan Chen, Jennifer R. Grandis, Scott Kopetz, and Mien-Chie Hung http://jci.me/82826

Related CommentaryOld dog, new tricks: extracellular domain arginine methylation regulates EGFR functionDavid M. Epstein and Elizabeth Buck http://jci.me/85001

aids/hiv

oncology

IL-21 reduces immune dysfunction and viral persistence in SIV-infected macaquesWhile antiretroviral therapy (ARt) effectively suppresses viremia, many HIV-infected individuals still exhibit residual inflammation that is associated with non–AIDS-related morbidity and mortality and may contribute to viral persistence. Luca Micci, Emily Ryan, and colleagues investi-gated the effects of the cytokine IL-21 on inflammation and viral persistence in ART-treated, SIV-infected rhesus macaques (RMs). Compared with RMs receiving ART alone, RMs treated with both ART and IL-21 exhibited improved mucosal immunity (see the accompanying image), decreased residual CD4+ and CD8+ T cell activation, as well as reduced residual plasma viremia and SIV DNA content. Importantly, IL-21 supplementation reduced immune activation and viral replication following ART interruption. These studies support a link between residual inflammation and immune activation and the pathogenesis of ART-suppressed HIV.

Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaquesLuca Micci, Emily S. Ryan, Rémi Fromentin, Steven E. Bosinger, Justin L. Harper, Tianyu He, Sara Paganini, Kirk A. Easley, Ann Chahroudi, Clarisse Benne, Sanjeev Gumber, Colleen S. McGary, Kenneth A. Rogers, Claire Deleage, Carissa Lucero, Siddappa N. Byrareddy, Cristian Apetrei, Jacob D. Estes, Jeffrey D. Lifson, Michael Piatak Jr., Nicolas Chomont, Francois Villinger, Guido Silvestri, Jason M. Brenchley, and Mirko Paiardini http://jci.me/81400

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Research | Editor’s picks

A muscle-specific autoantigen in idiopathic inflammatory myopathiesidiopathic inflammatory myopathies (iiMs) are a group of rare systemic autoimmune diseases that cause progressive muscle weakness. Several IIMs are known to be associated with the development of autoantibodies against ubiquitously expressed intracellular proteins. Inka Albrecht and colleagues report that 25% of IIM patients have autoantibodies targeting the muscle-specific protein four-and-a-half LIM domain 1 (FHL1), as well as altered cellular distribution of FHL1 (see the accompanying image). Moreover, anti-FHL1 activity was predictive for muscle fiber damage, vasculitis, muscle atrophy, and dysphagia. In myositis-prone mice, injection of FHL1 exacerbated muscle weakness and increased mortality. Taken together, these data demonstrate a role for FHL1 in IIM pathogenesis and suggest that FHL1 autoantibodies could serve as a disease biomarker.

Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathiesInka Albrecht, Cecilia Wick, Åsa Hallgren, Anna Tjärnlund, Kanneboyina Nagaraju, Felipe Andrade, Kathryn Thompson, William Coley, Aditi Phadke, Lina-Marcela Diaz-Gallo, Matteo Bottai, Inger Nennesmo, Karine Chemin, Jessica Herrath, Karin Johansson, Anders Wikberg, A. Jimmy Ytterberg, Roman A. Zubarev, Olof Danielsson, Olga Krystufkova, Jiri Vencovsky, Nils Landegren, Marie Wahren-Herlenius, Leonid Padyukov, Olle Kämpe, and Ingrid E. Lundberg http://jci.me/81031

immunology

endocrinology

aging

Mapping out glucagon-like peptide 1–stimulated insulin secretion

Age-associated inflammation selects for oncogenic B cell progenitorsAging is a major risk factor for the development of leukemia, leading Curtis Henry and colleagues to examine the intrinsic and extrinsic factors that promote B cell development and oncogenesis during aging. They observed that B cell progenitors in aged mice exhibit reduced cellular fitness. Notably, expression of the oncogenes BCR-ABL, NRASV12, or Myc corrected age-associated defects and increased leukemogenesis in aged mice. However, transplantation of oncogene-expressing, aged B cells into young mice did not induce leukemia, suggesting that age-associated extrinsic factors such as increased inflammation influence oncogenesis. Increasing inflammation in young mice resulted in B cell progenitor defects similar to those seen in aged mice, while reducing inflammation in aged mice preserved B cell progenitor fitness and reduced selection of oncogene-expressing progenitors, preventing leukemogenesis. These data indicate that age-associated inflammation contributes to cancer incidence through the selection of cells harboring oncogenic mutations.

Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitorsCurtis J. Henry, Matias Casás-Selves, Jihye Kim, Vadym Zaberezhnyy, Leila Aghili, Ashley E. Daniel, Linda Jimenez, Tania Azam, Eoin N. McNamee, Eric T. Clambey, Jelena Klawitter, Natalie J. Serkova, Aik Choon Tan, Charles A. Dinarello, and James DeGregori http://jci.me/83024

type 2 diabetes is caused by a combination of impairments in insulin secretion and action, and recent therapeutic strategies have targeted glucagon-like peptide 1 (GLP-1), which mediates glucose-stimulated insulin secretion in islets. In this issue, Makoto Shigeto and colleagues investigated the molecular mechanisms underlying GLP-1 activity in murine and human islets. They found that physiological concentrations of GLP-1 (1 pM) activate PLC to increase diacylglycerol and activate PKC. PKC activation mobilizes intracellular calcium, activating the sodium-permeable cation channels TRPM4 and TRPM5 to depolarize the membrane, thereby triggering insulin release. Importantly, GLP-1–stimulated insulin secretion was disrupted by pharmacologic or genetic inhibition of these pathway components. In the accompanying Commentary, Jelena Kolic and Patrick MacDonald discuss how these data contradict those in previous studies using nanomolar concentrations of GLP-1 that identified a cAMP/PKA-dependent mechanism.

GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activationMakoto Shigeto, Reshma Ramracheya, Andrei I. Tarasov, Chae Young Cha, Margarita V. Chibalina, Benoit Hastoy, Koenraad Philippaert, Thomas Reinbothe, Nils Rorsman, Albert Salehi, William R. Sones, Elisa Vergari, Cathryn Weston, Julia Gorelik, Masashi Katsura, Viacheslav O. Nikolaev, Rudi Vennekens, Manuela Zaccolo, Antony Galione, Paul R.V. Johnson, Kohei Kaku, Graham Ladds, and Patrik Rorsman http://jci.me/81975

Related CommentarycAMP-independent effects of GLP-1 on β cellsJelena Kolic and Patrick E. MacDonald http://jci.me/85004

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Features

Cuts to Canadian clinician-scientist training program jeopardize future advances

perspective

this summer, the Canadian institutes of health Research (CihR) announced that funding support for MD/PhD programs would be discontinued following the 2015–2016 academic year. This abrupt change of course has stunned the Canadian physician-scientist community and sent shock waves through the institutions that host medical student training programs. In this month’s issue of the JCI, a group of MD/PhD trainees from the University of British Columbia provide their perspective on how cuts by the CIHR will impact the next generation of physician-scientists, and the long-term ramifications for translational research in Canada. The accompanying figure highlights the small percentage of the total CIHR budget devoted to MD/PhD program funding. David Twa et al. believe that the repercussions of cutting program funding far outweigh the potential savings and urge renewed commitment to support students who will lead future clinical and translational research efforts.

The Canadian clinician-scientist training program must be reinstatedDavid D.W. Twa, Jordan W. Squair, Michael A. Skinnider, and Jennifer X. Ji http://jci.me/85194

The Journal of Clinical Investigation

All JCI review series: jci.org/review_series

Recent Review Series

AutoimmunityEdited by Antonio La Cava Published June 2015

Autoimmune disease encompasses a diverse group of over 80 chronic disorders. Each of these diseases has distinct clinical manifestations that are due to the differences in the cells and organ systems involved; however, these diseases are universally characterized by a loss of self tolerance, resulting in autoreactive immune cells, autoantibodies, and elevated levels of inflammatory cytokines. Reviews in this series examine mechanisms underlying autoimmunity, including failure of B cell tolerance checkpoints, the generation of autoantibodies, cytokine dysregulation, aberrant T cell signaling, and the loss of immune-suppressive cells and functions. They also explore the influence of genetic background, environment, microRNAs, and sex-specific factors on the loss of immune homeostasis. jci.org/review_series/90

Cancer immunotherapyEdited by Yiping Yang Published September 2015

In the mid-1800s, Rudolf Virchow noted the presence of surfeit inflammatory cells in many tumors. Roughly 50 years later, Paul Ehrlich postulated that the immune system both recognizes and protects against cancer. Since then, researchers have been trying to elucidate the relationship between cancer, inflammation, and the innate and adaptive immune systems, starting with the theory of immunosurveillance introduced by Lewis Thomas and further developed by Sir MacFarlane Burnet. We now know that tumor cells display antigens that are recognized by immune cells but that antitumor immunity can be circumvented directly by tumor cells themselves via a variety of escape mechanisms. The goal of cancer immunotherapy is to mount an effective antitumor immune response by

repairing, stimulating, or enhancing the immune system’s response to cancer cells. Reviews in this series detail progress in cancer immunoediting, immunosuppressive cells in the tumor microenvironment, cancer-associated inflammation, therapeutic cancer vaccines, genomic approaches in immunotherapy, adoptive transfer of genetically engineered T cells, and checkpoint blockade therapy. jci.org/review_series/91