jci.org/impactJuly 2014
Also in this issue:
The epigenetics of atherosclerosis 7
Modeling primary dystonia 8
Oncogenic alternative splicing 10
Kisspeptin regulates metabolism 12
A summary of this month’s Journal of Clinical investigation
Guiding arterial innervation p. 6
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editorHoward A. Rockman
Deputy editor Garnett Kelsoe, Bryan L. Roth
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, 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, Cam Patterson, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Bryan Roth, Jonathan S. Serody, Norman Sharpless, Yiping Yang
Clinical Medicine Associate editorsMichael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy
Asia editorsDavid M. Virshup
Chair, executive CouncilRobert J. Lefkowitz
BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen
BioethicistArthur L. Caplan
senior science editorSarah C. Jackson
Assistant 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.
ImpactJuly 2014
Contact the JCiThe Journal of Clinical Investigation2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: [email protected]
Full articles online,jci.me/124/7
The JCI’s Editorial Board is composed of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the board meets weekly to discuss the manuscripts undergoing review.
Featured Editor
Daniel P. Kelly, M.D., Associate Editor, is the Scientific Director of the Sanford-Burnham Medical Research Institute in Florida. As a junior physician-scientist at Washington University in St. Louis, Dr. Kelly defined the genetic basis for a common inborn error in mitochondrial fatty acid oxidation that causes sudden death, work that led to the development of practical screening tests for newborns. Thereafter, he became interested in how similar derangements in cardiac energy metabolism may contribute to heart
failure and sudden death in common acquired forms of mitochondrial diseases caused by hypertension, ischemic injury, and diabetes. His work has defined a transcriptional regulatory axis involved in the control of cardiac and skeletal muscle fuel and energy metabolism through pioneering fundamental studies on nuclear receptors including the PPARs, estrogen-related receptors, and the inducible transcriptional coactivator PGC-1. The Kelly laboratory has identified molecular “switches” in this regulatory pathway that potentially define distinct forms of heart failure, an important step toward identifying therapeutic targets for phenotype-specific treatment of heart failure.
Publication highlights
Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk G, Kelly DP. The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002;109(1):121–130.
Lai L, Leone TC, Zechner C, Schaeffer PJ, Kelly SM, Flanagan DP, Medeiros DM, Kovacs A, Kelly DP. Transcriptional coactivators PGC-1α and PGC-1β control overlapping programs required for perinatal maturation of the heart. Genes Dev. 2008;22(14):1948–1961.
Gan Z, Rumsey J, Hazen BC, Lai L, Leone TC, Vega RB, Xie H, Conley KE, Auwerx J, Smith SR, Olson EN, Kralli A, Kelly DP. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism. J Clin Invest. 2013;123(6):2564–2575.
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AgingPhosphatase WIP1 regulates adult neurogenesis and WNT signaling during agingYunhua Zhu, Oleg N. Demidov, Amanda M. Goh, David M. Virshup, David P. Lane, and Dmitry V. Bulavin http://jci.me/73015
AIDS/HIVAbnormal B cell memory subsets dominate HIV-specific responses in infected individualsLela Kardava, Susan Moir, Naisha Shah, Wei Wang, Richard Wilson, Clarisa M. Buckner, Brian H. Santich, Leo J.Y. Kim, Emily E. Spurlin, Amy K. Nelson, Adam K. Wheatley, Christopher J. Harvey, Adrian B. McDermott, Kai W. Wucherpfennig, Tae-Wook Chun, John S. Tsang, Yuxing Li, and Anthony S. Fauci http://jci.me/74351
Bone biologyNOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κBHengwei Zhang, Matthew J. Hilton, Jennifer H. Anolik, Stephen L. Welle, Chen Zhao, Zhenqiang Yao, Xing Li, Zhiyu Wang, Brendan F. Boyce, and Lianping Xing http://jci.me/68901
Vitamin B12–dependent taurine synthesis regulates growth and bone massPablo Roman-Garcia, Isabel Quiros-Gonzalez, Lynda Mottram, Liesbet Lieben, Kunal Sharan, Arporn Wangwiwatsin, Jose Tubio, Kirsty Lewis, Debbie Wilkinson, Balaji Santhanam, Nazan Sarper, Simon Clare, George S. Vassiliou, Vidya R. Velagapudi, Gordon Dougan, and Vijay K. Yadav http://jci.me/72606
More, p. 12
GastroenterologyMyosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion diseaseByron C. Knowles, Joseph T. Roland, Moorthy Krishnan, Matthew J. Tyska, Lynne A. Lapierre, Paul S. Dickman, James R. Goldenring, and Mitchell D. Shub http://jci.me/71651
GeneticsHypomorphic PCNA mutation underlies a human DNA repair disorderEmma L. Baple, Helen Chambers, Harold E. Cross, Heather Fawcett, Yuka Nakazawa, Barry A. Chioza, Gaurav V. Harlalka, Sahar Mansour, Ajith Sreekantan-Nair, Michael A. Patton, Martina Muggenthaler, Phillip Rich, Karin Wagner, Roselyn Coblentz, Constance K. Stein, James I. Last, A. Malcolm R. Taylor, Andrew P. Jackson, Tomoo Ogi, Alan R. Lehmann, Catherine M. Green, and Andrew H. Crosby http://jci.me/74593
Research articles in the current issue of the JCI
Microvillus inclusion disease
Osteogenic precursors in arthritis
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Research articles in the current issue of the JCI
Hematologyumbilical cord blood expansion with nicotinamide provides long-term multilineage engraftmentMitchell E. Horwitz, Nelson J. Chao, David A. Rizzieri, Gwynn D. Long, Keith M. Sullivan, Cristina Gasparetto, John P. Chute, Ashley Morris, Carolyn McDonald, Barbara Waters-Pick, Patrick Stiff, Steven Wease, Amnon Peled, David Snyder, Einat Galamidi Cohen, Hadas Shoham, Efrat Landau, Etty Friend, Iddo Peleg, Dorit Aschengrau, Dima Yackoubov, Joanne Kurtzberg, and Tony Peled http://jci.me/74556 More, p. 9
Purinergic P2y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescenceJoonseok Cho, Rushdia Yusuf, Sungho Kook, Eyal Attar, Dongjun Lee, Baehang Park, Tao Cheng, David T. Scadden, and Byeong Chel Lee http://jci.me/61636With related Commentary by Brian S. Garrison and Derrick J. Rossi More, p. 9
HepatologySplicing regulator Slu7 is essential for maintaining liver homeostasisMaría Elizalde, Raquel Urtasun, María Azkona, María U. Latasa, Saioa Goñi, Oihane García-Irigoyen, Iker Uriarte, Victor Segura, María Collantes, Mariana Di Scala, Amaia Lujambio, Jesús Prieto, Matías A. Ávila, and Carmen Berasain http://jci.me/74382
ImmunologyImmune activation alters cellular and humoral responses to yellow fever 17D vaccineEnoch Muyanja, Aloysius Ssemaganda, Pearline NGauv, Rafael Cubas, Helene Perrin, Divya Srinivasan, Glenda Canderan, Benton Lawson, Jakub Kopycinski, Amanda S. Graham, Dawne K. Rowe, Michaela J. Smith, Sharon Isern, Scott Michael, Guido Silvestri, Thomas H. Vanderford, Erika Castro, Giuseppe Pantaleo, Joel Singer, Jill Gillmour, Noah Kiwanuka, Annet Nanvubya, Claudia Schmidt, Josephine Birungi, Josephine Cox, Elias K. Haddad, Pontiano Kaleebu, Patricia Fast, Rafick-Pierre Sekaly, and Lydie Trautmann http://jci.me/75429
Characterization of pandemic influenza immune memory signature after vaccination or infectionOlivia Bonduelle, Fabrice Carrat, Charles-Edouard Luyt, Catherine Leport, Anne Mosnier, Nora Benhabiles, Anne Krivine, Flore Rozenberg, Nora Yahia, Assia Samri, Dominique Rousset, Sylvie van der Werf, Brigitte Autran, and Behazine Combadiere http://jci.me/74565 More, p. 11
MetabolismImpaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesityKristen P. Tolson, Christian Garcia, Stephanie Yen, Stephanie Simonds, Aneta Stefanidis, Alison Lawrence, Jeremy T. Smith, and Alexander S. Kauffman http://jci.me/71075With related Commentary by Stephanie B. Seminara More, p. 12
Nephrologyα-Intercalated cells defend the urinary system from bacterial infectionNeal Paragas, Ritwij Kulkarni, Max Werth, Kai M. Schmidt-Ott, Catherine Forster, Rong Deng, Qingyin Zhang, Eugenia Singer, Alexander D. Klose, Tian Huai Shen, Kevin P. Francis, Sunetra Ray, Soundarapandian Vijayakumar, Samuel Seward, Mary E. Bovino, Katherine Xu, Yared Takabe, Fábio E. Amaral, Sumit Mohan, Rebecca Wax, Kaitlyn Corbin, Simone Sanna-Cherchi, Kiyoshi Mori, Lynne Johnson, Thomas Nickolas, Vivette D’Agati,
Chyuan-Sheng Lin, Andong Qiu, Qais Al-Awqati, Adam J. Ratner, and Jonathan Barasch http://jci.me/71630With related Commentary by yuxuan Miao and Soman N. Abraham More, p. 11
Hepatic SLU7 following fasting
LCN2 in bladder uroepithelia
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Research articles in the current issue of the JCI
NeuroscienceAldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulationGuoxiang Liu, Jia Yu, Jinhui Ding, Chengson Xie, Lixin Sun, Iadov Rudenko, Wang Zheng, Namratha Sastry, Jing Luo, Gay Rudow, Juan C. Troncoso, and Huaibin Cai http://jci.me/72176
Remote control of induced dopaminergic neurons in parkinsonian ratsMaria Teresa Dell’Anno, Massimiliano Caiazzo, Damiana Leo, Elena Dvoretskova, Lucian Medrihan, Gaia Colasante, Serena Giannelli, Ilda Theka, Giovanni Russo, Liudmila Mus, Gianni Pezzoli, Raul R. Gainetdinov, Fabio Benfenati, Stefano Taverna, Alexander Dityatev, and Vania Broccoli http://jci.me/74664
With related Commentary by Elena M. Vazey and Gary Aston-Jones More, p. 8
TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegenerationChun-Chi Liang, Lauren M. Tanabe, Stephanie Jou, Frank Chi, and William T. Dauer http://jci.me/72830
With related Commentary by Åsa Petersén and Deniz Kirik More, p. 8
Missense dopamine transporter mutations associate with adult parkinsonism and ADHDFreja H. Hansen, Tina Skjørringe, Saiqa Yasmeen, Natascha V. Arends, Michelle A. Sahai, Kevin Erreger, Thorvald F. Andreassen, Marion Holy, Peter J. Hamilton, Viruna Neergheen, Merete Karlsborg, Amy H. Newman, Simon Pope, Simon JR. Heales, Lars Friberg, Ian Law, Lars H. Pinborg, Harald H. Sitte, Claus Loland, Lei Shi, Harel Weinstein, Aurelio Galli, Lena E. Hjermind, Lisbeth B. Møller, and Ulrik Gether http://jci.me/73778
Oncologylineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progressionRoberto Ferrarese, Griffith R. Harsh IV, Ajay K. Yadav, Eva Bug, Daniel Maticzka, Wilfriend Reichardt, Stephen M. Dombrowski, Tyler E. Miller, Anie P. Masilamani, Fangping Dai, Hyunsoo Kim, Michael Hadler, Denise M. Scholtens, Irene L.Y. Yu, Jürgen Beck, Vinodh Srinivasasainagendra, Fabrizio Costa, Nicoleta Baxan, Dietmar Pfeifer, Dominik v. Elverfeldt, Rolf Backofen, Astrid Weyerbrock, Christine W. Duarte, Xiaolin He, Marco Prinz, James P. Chandler, Hannes Vogel, Arnab Chakravarti, Jeremy N. Rich, Maria S. Carro, and Markus Bredel http://jci.me/68836
More, p. 10
Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasisJason Boyang Wu, Chen Shao, Xiangyan Li, Qinlong Li, Peizhen Hu, Changhong Shi, Yang Li, Yi-Ting Chen, Fei Yin, Chun-Peng Liao, Bangyan L. Stiles, Haiyen E. Zhau, Jean C. Shih, and Leland W.K. Chung http://jci.me/70982
WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitorsJamie N. Anastas, Rima M. Kulikauskas, Tigist Tamir, Helen Rizos, Georgiana V. Long, Erika M. von Euw, Pei-Tzu Yang, Hsiao-Wang Chen, Lauren Haydu, Rachel A. Toroni, Olivia M. Lucero, Andy J. Chien, and Randall T. Moon http://jci.me/70156
Four individually druggable MET hotspots mediate HGF-driven tumor progressionCristina Basilico, Anna Hultberg, Christophe Blanchetot, Natalie de Jonge, Els Festjens, Valérie Hanssens, Sjudry-Ilona Osepa, Gitte De Boeck, Alessia Mira, Manuela Cazzanti, Virginia Morello, Torsten Dreier, Michael Saunders, Hans de Haard, and Paolo Michieli http://jci.me/72316
Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitorsMiwa Tanaka, Yukari Yamazaki, Yohei Kanno, Katsuhide Igarashi, Ken-ichi Aisaki, Jun Kanno, and Takuro Nakamura http://jci.me/72399 More, p. 11
CRIPTO1 expression in EGFR-mutant NSClC elicits intrinsic EGFR-inhibitor resistanceKang-Seo Park, Mark Raffeld, Yong Wha Moon, Liqiang Xi, Caterina Bianco, Trung Pham, Liam C. Lee, Tetsuya Mitsudomi, Yasushi Yatabe, Isamu Okamoto, Deepa Subramaniam, Tony Mok, Rafael Rosell, Ji Luo, David S. Salomon, Yisong Wang, and Giuseppe Giaccone http://jci.me/73048
Induced dopaminergic neurons
Prostate cancer pathogenesis
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Research articles in the current issue of the JCI
Biliary repair and carcinogenesis are mediated by Il-33–dependent cholangiocyte proliferationJun Li, Nataliya Razumilava, Gregory J. Gores, Stephanie Walters, Tatsuki Mizuochi, Reena Mourya, Kazuhiko Bessho, Yui-Hsi Wang, Shannon S. Glaser, Pranavkumar Shivakumar, and Jorge A. Bezerra http://jci.me/73742
CTlA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cellsAndreas Herrmann, Saul J. Priceman, Maciej Kujawski, Hong Xin, Gregory A. Cherryholmes, Wang Zhang, Chunyan Zhang,
Christoph Lahtz, Claudia Kowolik, Steve J. Forman, Marcin Kortylewski, and Hua Yu http://jci.me/73174 More, p. 10
Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growthErik H. Knelson, Angela L. Gaviglio, Jasmine C. Nee, Mark D. Starr, Andrew B. Nixon, Stephen G. Marcus, and Gerard C. Blobe http://jci.me/74270
MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis
Chi-Hong Chao, Chao-Ching Chang, Meng-Ju Wu, How-Wen Ko, Da Wang, Mien-Chie Hung, Jer-Yen Yang, and Chun-Ju Chang http://jci.me/73351
PulmonologyCystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressureAshley G. Henderson, Camille Ehre, Brian Button, Lubna H. Abdullah, Li-Heng Cai, Margaret W. Leigh, Genevieve C. DeMaria, Hiro Matsui, Scott H. Donaldson, C. William Davis, John K. Sheehan, Richard C. Boucher, and Mehmet Kesimer http://jci.me/73469
More, p. 9
Vascular biologyFlow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosisJessilyn Dunn, Haiwai Qiu, Soyeon Kim, Daudi Jjingo, Ryan Hoffman, Chan Woo Kim, Inhwan Jang, Dong Ju Son, Daniel Kim, Chenyi Pan, Yuhong Fan, I. King Jordan, and Hanjoong Jo http://jci.me/74792
More, p. 7
Resident fibroblast lineages mediate pressure overload–induced cardiac fibrosisThomas Moore-Morris, Nuno Guimarães-Camboa, Indroneal Banerjee, Alexander C. Zambon, Tatiana Kisseleva, Aurélie Velayoudon, William B. Stallcup, Yusu Gu, Nancy D. Dalton, Martha Cedenilla, Rafael Gomez-Amaro, Bin Zhou, David A. Brenner, Kirk L. Peterson, Ju Chen, and Sylvia M. Evans http://jci.me/74783
With related Commentary by Nenad Bursac More, p. 7
β2-Adrenergic agonists augment air pollution–induced Il-6 release and thrombosisSergio E. Chiarella, Saul Soberanes, Daniela Urich, Luisa Morales-Nebreda, Recep Nigdelioglu, David Green, James B. Young, Angel Gonzalez, Carmen Rosario, Alexander V. Misharin, Andrew J. Ghio, Richard G. Wunderink, Helen K. Donnelly, Kathryn A. Radigan, Harris Perlman, Navdeep S. Chandel, G.R. Scott Budinger, and Gökhan M. Mutlu http://jci.me/75157
Netrin-1 controls sympathetic arterial innervationIsabelle Brunet, Emma Gordon, Jinah Han, Brunella Cristofaro, Dong Broqueres-You, Chun Liu, Karine Bouvrée, Jiasheng Zhang, Raquel del Toro, Thomas Mathivet, Bruno Larrivée, Julia Jagu, Laurence Pibouin-Fragner, Luc Pardanaud, Maria J.C. Machado, Timothy E. Kennedy, Zhen Zhuang, Michael Simons, Bernard I. Levy, Marc Tessier-Lavigne, Almut Grenz, Holger Eltzschig, and Anne Eichmann http://jci.me/75181
With related Commentary by yoh-suke Mukouyama More, p. 6
Cholangiocyte proliferation
Resident fibroblasts in heart
Neuroblastoma stroma
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Vascular tone and blood flow are regulated in part by arterial innervation. The tone of ar-teries differs depending on the density of in-nervation, with less innervation in large elas-tic arteries and greater innervation in small resistance arteries. In this issue of the JCI, a research team led by Anne Eichmann pro-vides insights into the unique cues that guide axons toward arterial innervation rather than innervation of other tissues and organs. The researchers discovered that sympathetic arte-rial innervation requires production of the axon guidance cue netrin-1. Using a murine model system, they found that arterial inner-vation initiates after birth as the arterial wall matures. They showed that expression of netrin-1 was upregulated in innervated arteries compared with that in noninnervated arteries in neonatal mice. Moreover, condi-tional deletion of the gene encoding netrin-1 in arterial smooth muscle cells, or deletion of the gene encoding its cognate receptor deleted in colorectal cancer (DCC) in axons, revealed that the netrin-1/DCC signaling pathway is essential for arterial innervation. In addition, loss of netrin-1 in adult mice in-duced a reduction in sympathetic innervation in resistance arteries and defects in vasocon-striction. In his accompanying Commentary, Yoh-suke Mukouyama highlights how this study sheds new light on the mechanisms specifically regulating arterial innervation and blood flow. The accompanying image shows sympathetic neurons (immunostained for tyrosin hydroxylase; red) extending axo-nal bundles along an artery (PECAM stain-ing; blue), with sympathetic fibers surround-ing and innervating arterial smooth muscle cells (smooth muscle actin staining; green).
Of all the nerve: insights into the innervation of arteries
Editor’s picksResearch
Netrin-1 controls sympathetic arterial innervationIsabelle Brunet, Emma Gordon, Jinah Han, Brunella Cristofaro, Dong Broqueres-You, Chun Liu, Karine Bouvrée, Jiasheng Zhang, Raquel del Toro, Thomas Mathivet, Bruno Larrivée, Julia Jagu, Laurence Pibouin-Fragner, Luc Pardanaud, Maria J.C. Machado, Timothy E. Kennedy, Zhen Zhuang, Michael Simons, Bernard I. Levy, Marc Tessier-Lavigne, Almut Grenz, Holger Eltzschig, and Anne Eichmann http://jci.me/75181
Related CommentaryVessel-dependent recruitment of sympathetic axons: looking for innervation in all the right placesYoh-suke Mukouyama http://jci.me/76622
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Research | Editor’s picks
The origins of cardiac fibroblastsheart failure is characterized by the activation and accumulation of cardiac fibroblasts, leading to fibrosis and pathological alterations in the myocardium. Therapies that decrease the number of cardiac fibroblasts could potentially reduce fibrosis and improve heart function. Previous studies have suggested that cardiac fibroblasts are derived from hematopoietic stem cells in the circulation or endothelial cells that undergo endothelial-to-mesenchymal transition in response to cardiac injury. To pin down the origins of cardiac fibroblasts, Thomas Moore-Morris and colleagues used multiple murine Cre lines and a fibroblast-specific fluorescent reporter, collagen1a1-GFP, to perform genetic lineage tracing in a murine pressure overload model of heart failure. They found that fibroblasts did not originate from either of the previously identified sources but instead were derived from two resident fibroblast lineages of epicardial and endothelial origins in the heart (see the accompanying image). Importantly, pressure overload hypertrophy resulted in activation and proliferation of the two lineages. In the accompanying Commentary, Nenad Bursac discusses how these findings will affect the development of antifibrosis therapeutics for heart failure.
Resident fibroblast lineages mediate pressure overload–induced cardiac fibrosisThomas Moore-Morris, Nuno Guimarães-Camboa, Indroneal Banerjee, Alexander C. Zambon, Tatiana Kisseleva, Aurélie Velayoudon, William B. Stallcup, Yusu Gu, Nancy D. Dalton, Martha Cedenilla, Rafael Gomez-Amaro, Bin Zhou, David A. Brenner, Kirk L. Peterson, Ju Chen, and Sylvia M. Evans http://jci.me/74783
Related CommentaryCardiac fibroblasts in pressure overload hypertrophy: the enemy within?Nenad Bursac http://jci.me/76628
The endothelial epigenome goes with the flow in atherosclerosisArtherosclerotic plaques preferentially develop in arterial regions with disturbed blood flow; however, the molecular mechanisms underlying this pattern are unknown. Jessilyn Dunn and colleagues found that arterial flow alters genome-wide DNA methylation patterns in endothelial cells. Carotid ligation surgery in mice or oscillatory shear stress in cultured endothelial cells induced expression of DNA methyltransferase-1 (DNMT1). Genetic or pharmacologic
vascular biology
reduction of DNMT1 activity in either model decreased endothelial inflammation and reduced lesion formation in a murine atherosclerosis model (see the accompanying image). Genomic analysis revealed that flow disturbance resulted in hypermethylation of the promoters of 11 mechanosensitive genes in a DNMT-dependent manner. These results demonstrate that disturbed flow is an epigenetic regulator that contributes to atherosclerosis.
Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosisJessilyn Dunn, Haiwei Qiu, Soyeon Kim, Daudi Jjingo, Ryan Hoffman, Chan Woo Kim, Inhwan Jang, Dong Ju Son, Daniel Kim, Chenyi Pan, Yuhong Fan, I. King Jordan, and Hanjoong Jo http://jci.me/74792
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Research | Editor’s picks
Tunable dopaminergic neurons in parkinsonian rats
Primary dystonia model reveals molecular pathogenesisPrimary dystonias are a group of diseases that manifest as abnormal twisting movements, but the molecular and cellular substrates of these illnesses are poorly understood. To explore this disease pathogenesis, Chun-Chi Liang and colleagues developed a genetic model of primary dystonia in mice by manipulating Tor1a, the mouse homolog of the most common genetic form of the disease (see the accompanying image). Mice lacking CNS Tor1a or expressing a pathogenic Tor1a mutant displayed involuntary twisting movements similar to those that characterize the human disease. Additionally, a discrete set of sensorimotor circuits in these animals exhibited abnormal
perinuclear accumulation of ubiquitin and the neuron-specific ubiquitin ligase HRD1, followed by neurodegeneration that featured enhanced ER stress and caspase-3 activation. In the accompanying Commentary, Åsa Petersén and Deniz Kirik discuss the
importance of animal models in advancing our understanding of neurological disease.
TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegenerationChun-Chi Liang, Lauren M. Tanabe, Stephanie Jou, Frank Chi, and William T. Dauer http://jci.me/72830
Related CommentaryTwisting mice move the dystonia field forwardÅsa Petersén and Deniz Kirik http://jci.me/76624
neuroscience
Replacement of striatal dopaminergic (DA) neurons is a therapeutic goal in Parkinson’s disease. DA neurons have previously been generated and successfully transplanted into animal models of Parkinson’s disease; however, long-term survival and functional integration with existing neural circuits has not been demonstrated. Maria Teresa Dell’Anno and colleagues directly reprogrammed mouse fibroblasts to generate induced dopaminergic (iDA) neurons that express a specially engineered receptor construct, known as a designer receptor exclusively activated by designer drugs (DREADD). The drug clozapine N-oxide (CNO) specifically activates DREADD-expressing iDA neurons to modulate dopamine release. Dell’Anno and colleagues engrafted parkinsonian rats with iDA neurons and found that the neurons were successfully incorporated into striatal circuits (see the accompanying image), displayed appropriate physiological responses, and retained their neuronal phenotype even after long-term engraftment. Importantly, parkinsonian rats engrafted with iDA neurons exhibited behavioral recovery that could be
markedly enhanced by DREADD activation. In the accompanying Commentary, Elena M. Vazey and Gary Aston-Jones discuss how these findings could impact the development of neuronal replacement therapies.
Remote control of induced dopaminergic neurons in parkinsonian ratsMaria Teresa Dell’Anno, Massimiliano Caiazzo, Damiana Leo, Elena Dvoretskova, Lucian Medrihan, Gaia Colasante, Serena Giannelli, Ilda Theka, Giovanni Russo, Liudmila Mus, Gianni Pezzoli, Raul R. Gainetdinov, Fabio Benfenati, Stefano Taverna, Alexander Dityatev, and Vania Broccoli http://jci.me/74664
Related CommentaryDesigner receptors: therapeutic adjuncts to cell replacement therapy in Parkinson’s diseaseElena M. Vazey and Gary Aston-Jones http://jci.me/76833
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Research | Editor’s picks
Mucin concentration contributes to a sticky situation in cystic fibrosisCystic fibrosis (CF) in the lung is characterized by the accumulation of thick, sticky mucus that clogs the airways and leads to life-threatening lung infections. To gain a better understanding of mucus clearance in CF, Ashley Henderson and colleagues used size exclusion chromatography/differential refractometry techniques to measure the mucin concentration in sputum from normal and CF airways. They found that mucin concentrations and partial osmotic pressure were greater in CF secretions compared with those in normal secretions. Importantly, increased mucin concentration and partial osmotic pressure promoted mucus stasis, thereby contributing to lung infection and inflammation in CF. The accompanying immunohistological sections show mucin deposition in non-CF (top) and CF lung tissue (bottom).
Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressureAshley G. Henderson, Camille Ehre, Brian Button, Lubna H. Abdullah, Li-Heng Cai, Margaret W. Leigh, Genevieve C. DeMaria, Hiro Matsui, Scott H. Donaldson, C. William Davis, John K. Sheehan, Richard C. Boucher, and Mehmet Kesimer http://jci.me/73469
Ex vivo expansion of umbilical cord blood for transplantationumbilical cord blood (uCB) is a rich source of hematopoietic stem and progenitor cells (HSPCs) that can be used for bone marrow transplantation; however, UCB transplantation is hampered by low cell dose, which delays engraftment and immune reconstitution. Mitchell Horwitz and colleagues conducted a phase I clinical trial to test the long-term engraftment capability of UCB HSPCs that were expanded ex vivo for 21 days in the presence of nicotinamide and then combined with the noncultured T cell fraction of the UCB (NiCord). Eleven adults with hematological malignancies received 1 unit of NiCord and a second unit of unmanipulated UCB following myeloablative bone marrow conditioning. Eight patients exhibited complete or partial engraftment of the NiCord unit and achieved earlier hematopoietic recovery compared with historical controls (13 vs. 25 days). These results indicate that further clinical study of NiCord is warranted.
umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftmentMitchell E. Horwitz, Nelson J. Chao, David A. Rizzieri, Gwynn D. Long, Keith M. Sullivan, Cristina Gasparetto, John P. Chute, Ashley Morris, Carolyn McDonald, Barbara Waters-Pick, Patrick Stiff, Steven Wease, Amnon Peled, David Snyder, Einat Galamidi Cohen, Hadas Shoham, Efrat Landau, Etty Friend, Iddo Peleg, Dorit Aschengrau, Dima Yackoubov, Joanne Kurtzberg, and Tony Peled http://jci.me/74556
Purinergic receptor P2Y14 protects hematopoietic stem progenitor cells
pulmonologyhematology
organisms have evolved protective mechanisms that allow them to recover from exposure to stressors such as radiation, oxidation, and infection. Dysfunctional responses to stress are likely instigators of oncogenesis or degenerative disease. Stress-induced nucleotide accumulation in the extracellular space alerts cells to danger through activation of G protein–coupled purinergic receptors. Byeong Chel Lee and colleagues examined the role of the purinergic receptor P2Y14 in the hematopoietic stem progenitor cell (HSPC) stress response. They found that loss of P2Y14 in mice rendered HSPCs more susceptible to radiation-induced senescence and death. Additionally, P2Y14-deficient HSPCs were not able to repopulate bone marrow in irradiated mice as efficiently as WT HSPCs. Irradiated P2Y14-deficient HSPCs had increased ROS and enhanced expression of the cell-cycle inhibitors p16INK4a and hypophosphorylated Rb. Inhibition of stress-responsive kinases or ROS scavengers ameliorated these effects. These data indicate that P2Y14 helps prevent
stress-induced senescence of HPSCs, promoting recovery after radiation exposure. In the accompanying Commentary, Brian Garrison and Derrick Rossi discuss how these findings contribute to our understanding of the HSPC stress response.
Purinergic P2y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescenceJoonseok Cho, Rushdia Yusuf, Sungho Kook, Eyal Attar, Dongjun Lee, Baehang Park, Tao Cheng, David T. Scadden, and Byeong Chel Lee http://jci.me/61636
Related Commentaryloss of P2y14 results in an arresting response to hematological stressBrian S. Garrison and Derrick J. Rossi http://jci.me/76626
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Research | Editor’s picks
Lineage-specific splicing of a tumor suppressor acts oncogenic
Aptamer-guided targeting of tumor-associated T cells
Alternative splicing of pre-mRnAs increases protein diversity and function and contributes to the specification of tissue identity. In this issue, Roberto Ferrarese and colleagues show that lineage-specific splicing of a tumor suppressor acts oncogenic in glioblastoma multiforme (GBM). Full-length ANXA7 (ANXA7-I1) is a tumor suppressor and regulates oncogenic EGFR signaling. Ferrarese and colleagues found that alternatively spliced ANXA7 (ANXA7-I2) was enriched in neuronal and glial precursors and glioblastoma tissues. Expression of ANXA7-I2 disrupted endosomal targeting of EGFR, thereby enhancing EGFR signaling. Ribonucleoprotein PTBP1, which is highly expressed in GBM due to the loss of miR-124 and PTBP1 amplification, mediated exon splicing of ANXA7. Depletion of PTBP1 inhibited malignancy and angiogenesis in a murine GBM model (see the accompanying image); however, these effects were reversed by concurrent depletion of ANXA7-I1. Taken
oncology
together, these data indicate that oncogenic pathways can be activated by lineage-specific splicing of a tumor suppressor gene.
lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progressionRoberto Ferrarese, Griffith R. Harsh IV, Ajay K. Yadav, Eva Bug, Daniel Maticzka, Wilfried Reichardt, Stephen M. Dombrowski, Tyler E. Miller, Anie P. Masilamani, Fanping Dai, Hyunsoo Kim, Michael Hadler, Denise M. Scholtens, Irene L.Y. Yu, Jürgen Beck, Vinodh Srinivasasainagendra, Fabrizio Costa, Nicoleta Baxan, Dietmar Pfeifer, Dominik v. Elverfeldt, Rolf Backofen, Astrid Weyerbrock, Christine W. Duarte, Xiaolin He, Marco Prinz, James P. Chandler, Hannes Vogel, Arnab Chakravarti, Jeremy N. Rich, Maria S. Carro, and Markus Bredel http://jci.me/68836
stAt3, a mediator of tumor survival, proliferation, invasion, and immunosuppression, is persistently activated in tumor cells and tumor-associated immune cells. In CD8+ T cells, activation of STAT3 impairs antitumor responses, while loss of STAT3 promotes antitumor responses. Andreas Herrmann and colleagues describe the use of an aptamer-targeted STAT3 siRNA to inhibit STAT3 in tumor cells and tumor-associated immune cells in mice. An aptamer that binds the cell surface receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA), an inhibitor of the T cell antitumor response, was attached to STAT3 siRNA (CTLA4apt–STAT3 siRNA), allowing for targeted delivery to tumor-associated T cells, Tregs, or malignant T cells (see the accompanying image). Local or systemic administration of CTLA4apt–STAT3 siRNA in different murine tumor models decreased STAT3 expression in CTLA4-expressing T cells, reduced tumor-associated Tregs, and decreased tumor growth and metastasis. Importantly, CTLA4apt–STAT3 siRNA also inhibited tumor growth and promoted tumor cell apoptosis in mice bearing human T cell lymphoma.
CTlA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cellsAndreas Herrmann, Saul J. Priceman, Maciej Kujawski, Hong Xin, Gregory A. Cherryholmes, Wang Zhang, Chunyan Zhang, Christoph Lahtz, Claudia Kowolik, Steve J. Forman, Marcin Kortylewski, and Hua Yu http://jci.me/73174
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Research | Editor’s picks
immunology
A murine model of Ewing’s sarcoma reveals tumor origins
Assessing immune memory after infection or vaccinationthe magnitude and character of immune memory determines protection against future infection; thus, the type of immunological memory elicited by a vaccine determines its effectiveness. Olivia Bonduelle and colleagues characterized the humoral and cellular immune responses in individuals infected with or vaccinated against pandemic influenza A (H1N1) one year after antigen exposure. They found that severely ill subjects exhibited high levels of humoral and polyfunctional effector/memory CD4+ T cell responses. In contrast, mildly ill or vaccinated individuals exhibited strong cellular immunity, including elevated levels of degranulation and mucosal homing markers in influenza-specific T cells. These findings indicate that the context of initial immunization (i.e., level of infection or vaccination) determines the cellular signature of immunological memory.
Characterization of pandemic influenza immune memory signature after vaccination or infectionOlivia Bonduelle, Fabrice Carrat, Charles-Edouard Luyt, Catherine Leport, Anne Mosnier, Nora Benhabiles, Anne Krivine, Flore Rozenberg, Nora Yahia, Assia Samri, Dominique Rousset, Sylvie van der Werf, Brigitte Autran, and Behazine Combadiere http://jci.me/74565
oncology
α-Intercalated cells stand sentinel in the kidneythe urinary system constitutively synthesizes broad-specificity antimicrobial peptides (AMPs) to defend itself against infection, but less is known about the acute response to urinary tract infections (UTIs). In this issue, Neal Paragas and colleagues demonstrate that kidney α-intercalated cells (A-ICs) help protect the urinary system against infection. Using murine UTI models and human samples, they showed that A-IC binding of uropathogenic E. coli triggered urine acidification and the release of the antibacterial protein lipocalin 2 (LCN2). In human patient samples, LCN2 was upregulated 10-fold in patients with UTIs compared with uninfected patients. Importantly, loss of A-ICs in mice severely limited LCN2 secretion and bacterial clearance. In the accompanying Commentary, Yuxuan Miao and Soman Abraham discuss how these findings contribute to our understanding of the kidney’s role in immune defense.
α-Intercalated cells defend the urinary system from bacterial infectionNeal Paragas, Ritwij Kulkarni, Max Werth, Kai M. Schmidt-Ott, Catherine Forster, Rong Deng, Qingyin Zhang, Eugenia Singer, Alexander D. Klose, Tian Huai Shen, Kevin P. Francis, Sunetra Ray, Soundarapandian Vijayakumar, Samuel Seward, Mary E. Bovino, Katherine Xu, Yared Takabe, Fábio E. Amaral, Sumit Mohan, Rebecca Wax, Kaitlyn Corbin, Simone Sanna-Cherchi, Kiyoshi Mori, Lynne Johnson, Thomas Nickolas, Vivette D’Agati, Chyuan-Sheng Lin, Andong Qiu, Qais Al-Awqati, Adam J. Ratner, and Jonathan Barasch http://jci.me/71630
Related CommentaryKidney α–intercalated cells and lipocalin 2: defending the urinary tractYuxuan Miao and Soman N. Abraham http://jci.me/76630
nephrology
ewing’s sarcoma is a rare pediatric bone tumor that results from a genetic translocation that results in an EWS-ETS fusion. The tumor can have both mesodermal and ectodermal features, making it difficult to determine the cellular origin. In this issue, Miwa Tanaka and colleagues developed a murine model of Ewing’s sarcoma by introducing EWS-ETS fusion genes into a late gestational cell fraction enriched for osteochondrogenic progenitors from the embryonic superficial zone (eSZ) of the long bones (see the accompanying image). The model tumors shared a gene expression profile with human Ewing’s sarcoma, and both murine and human tumors exhibited upregulated WNT/β-catenin and EGF signaling. Finally, inhibitors of the WNT/β-catenin pathway attenuated murine tumor growth.
Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitorsMiwa Tanaka, Yukari Yamazaki, Yohei Kanno, Katsuhide Igarashi, Ken-ichi Aisaki, Jun Kanno, and Takuro Nakamura http://jci.me/72399
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Research | Editor’s picks
Maternal vitamin B12 deficiency alters growth and bone accrual in offspringthe maternal environment is known to have a substantial effect on the in utero development and postnatal physiology of the offspring. In this issue, Pablo Roman-Garcia, Isabel Quiros-Gonzalez, and colleagues detail the effects of maternal vitamin B12 (B12) deficiency on bone accrual in offspring. Using a murine genetic model of B12 deficiency, they found that the offspring of B12-deficient mothers exhibited growth retardation and osteoporosis (see the accompanying image) due to a loss of liver taurine biosynthesis that was associated with impairment of the growth hormone/IGF1 axis. Remarkably, a single injection of B12 or oral feeding of taurine rescued the phenotype by increasing liver IGF1 synthesis and action. These results demonstrate that B12 is essential for postnatal growth and bone accrual and suggest that B12/taurine supplementation could potentially be used to increase bone mass.
Kisspeptin signaling regulates energy balance and metabolism in mice
metabolism
bone biology
Vitamin B12–dependent taurine synthesis regulates growth and bone massPablo Roman-Garcia, Isabel Quiros-Gonzalez, Lynda Mottram, Liesbet Lieben, Kunal Sharan, Arporn Wangwiwatsin, Jose Tubio, Kirsty Lewis, Debbie Wilkinson, Balaji Santhanam, Nazan Sarper, Simon Clare, George S. Vassiliou, Vidya R. Velagapudi, Gordon Dougan, and Vijay K. Yadav http://jci.me/72606
Kisspeptin and its receptor, Kiss1R, regulate reproduction through stimulation of gonadotropin-releasing hormone (GnRH) neurons; however, KISS1R is also expressed in other brain regions as well as in peripheral tissues — such as fat, liver, and pancreas — that are involved in metabolism and energy balance. Kristen Tolson and colleagues examined the metabolic phenotype of Kiss1r-deficient adult mice and found that female mice had dramatically elevated body weights, leptin levels, and adiposity as well as impaired glucose tolerance, a phenotype that was only partially recapitulated in adult male mice. Although they weighed substantially more than WT females, Kiss1r-deficient females surprisingly had lower food intake, but also exhibited markedly decreased locomotion and lower energy expenditure. Interestingly, thyroid and gonadal hormone levels did not contribute to the Kiss1r KO metabolic phenotype. These results establish a novel role for kisspeptin signaling in the regulation of body weight, adiposity, and glucose homeostasis. In the accompanying Commentary, Stephanie Seminara discusses the reciprocal relationship between reproduction and energy balance.
Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesityKristen P. Tolson, Christian Garcia, Stephanie Yen, Stephanie Simonds, Aneta Stefanidis, Alison Lawrence, Jeremy T. Smith, and Alexander S. Kauffman http://jci.me/71075
Related CommentaryFatness and fertility: which direction?Stephanie B. Seminara http://jci.me/76623
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Features
hindsight
review
Intestinal epithelial cells play defense
Uncovering the drivers of vancomycin resistance in S. aureusVancomycin is a glycopeptide antibiotic that has become the drug of last resort for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Unfortunately, MRSA strains with varying degrees of vancomycin resistance have begun to emerge. In this issue, Susana Gardete and Alexander Tomasz describe the molecular characteristics that distinguish strains that are resistant to intermediate and high levels of vancomycin (vancomycin intermediate-resistant S. aureus [VISA] and vancomycin-resistant S. aureus [VRSA], respectively). Resistance in VRSA strains is conferred by acquisition of a transposon, Tn1546, from Enterrococcus faecalis that alters the cell wall structure and metabolism of the bacteria. The molecular alterations in VISA are still obscure; however, the use of matched clinical specimens and bacterial whole genome sequencing has helped to identify treatment-driven genetic shifts in bacterial populations.
Mechanisms of vancomycin resistance in Staphylococcus aureusSusana Gardete and Alexander Tomasz http://jci.me/68834
Tony Fauci
the intestinal epithelium serves as a physical barrier between the intestinal lumen and the underlying intestinal mucosa, as well as a filter that regulates the absorption of nutrients and fluid and secretions from the underlying mucosa. In this issue, Martin Kagnoff reflects on the studies he and his colleagues published in the early 1990s that revealed that intestinal epithelial cells also play a critical role in mucosal defense and homeostasis by initiating an inflammatory response upon exposure to enteric pathogens. Subsequent studies have demonstrated that loss of this defensive response results in greater systemic spread of infection and potentially greater morbidity and death. These findings helped spark current investigations into the complex relationship among enteric pathogens, the commensal microbiome, and the host’s internal milieu. The accompanying image details the interaction of intestinal epithelial cells with pathogens and their subsequent inflammatory response.
The intestinal epithelium is an integral component of a communications networkMartin F. Kagnoff http://jci.me/75225
conversations with giants in medicine
in this issue, JCI Editor at Large Ushma Neill interviews Tony Fauci, the Director of the National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health. Fauci joined the NIAID as a clinical associate in 1968, where he studied vasculitis and developed treatments for polyarteritis nodosa and Wegener granulomatosis. In 1981, he began seeing some of the first patients with HIV and described the aberrant immune activation that is now known to drive the infection. Fauci’s work helped define HIV/AIDS pathogenesis and develop treatment strategies that have boosted expected survival times from 6–8 months to up to 50 years. In addition to his clinical work and continuing research, Fauci also plays a significant role in scientific advocacy and was a key architect of the President’s Emergency Plan for AIDS Relief, which provides anti-HIV drugs to the world’s poor.
http://jci.me/77277
