JCI Impact separating pulmonary and systemic...

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jci.org/impact JULY 2015 ALSO IN THIS ISSUE: Epigenetic regulation of pancreatic β cells 7 Stem cell–mediated tendon regeneration 8 Microglia clear subarachnoid hemorrhages 10 Short GPCR mediates opioid analgesia 11 A summary of this month’s Journal of Clinical Investigation Scan with your mobile device for the digital version of JCI Impact. Separating pulmonary and systemic circulation p. 6

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Page 1: JCI Impact separating pulmonary and systemic circulationdm5migu4zj3pb.cloudfront.net/impact/pdf/31/jci_impact_2015_07.pdf · Sarah C. Jackson science editor Jillian Hurst Assistant

jci.org/impactJuly 2015

Also in this issue:

Epigenetic regulation of pancreatic β cells 7

Stem cell–mediated tendon regeneration 8

Microglia clear subarachnoid hemorrhages 10

Short GPCR mediates opioid analgesia 11

A summary of this month’s Journal of Clinical investigation

Scan with your mobile device for the digital version of JCI Impact.

separating pulmonary and systemic circulation

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 J u l y 2 0 1 5 1

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, Cam Patterson, 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 editorJillian Hurst

Assistant science editorCorinne 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 2015

Contact the JCiThe Journal of Clinical Investigation2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: [email protected]

For the full JCI online, go to jci.me/125/7 or scan the code at left with your mobile device.

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

Nigel Mackman, PhD, FAHA, Associate Editor, is John C. Parker Professor of Hematology in the Department of Medicine, Professor of Pharmacology, Professor of Pathology and Laboratory Medicine, Director of the McAllister Heart Institute, and Co-Director of the Thrombosis and Hemostasis Program at the UNC School of Medicine, and a member of the Immunology Program in the UNC Lineberger Comprehensive Can-cer Center. Dr. Mackman’s research focuses on hemo-

stasis, thrombosis, and crosstalk between coagulation and inflammation in dis-ease. In particular, he studies tissue factor (TF), which is the primary initiator of the coagulation protease cascade. Additionally, the lab is exploring the role of TF in hemostasis, arterial and venous thrombosis, myocardial ischemia/reperfusion injury, LPS induction in monocytes, and the innate immune response to viral in-fection. Recently, the Mackman lab developed a new assay to measure levels of microvesicle TF in human plasma. Dr. Mackman’s research has been recognized by the American Heart Association, and he has received a Distinguished Career Award from the International Society of Thrombosis and Hemostasis.

Publication highlights

Parry GCN, Erlich JH, Luther T, Mackman N. Low levels of tissue factor are compatible with development and hemostasis in mice. J Clin Invest. 1998;101(3):560– 569.

Owens AP 3rd, Passam FH, Antoniak S, Marshall SM, McDaniel AL, Rudel L, Williams JC, Hubbard BK, Dutton JA, Wang J, Tobias PS, Curtiss LK, Daugherty A, Kirchhofer D, Luyendyk JP, Moriarty PM, Nagarajan S, Furie BC, Furie B, Johns DG, Temel RE, Mackman N. Monocyte tissue factor–dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvas-tatin. J Clin Invest. 2012;122(2):558–568.

Antoniak S, Owens AP 3rd, Baunacke M, Williams JC, Lee RD, Weithäuser A, Sheridan PA, Malz R, Luyendyk JP, Esserman DA, Trejo J, Kirchhofer D, Blaxal BC, Pawlinski R, Beck MA, Rauch U, Mackman N. PAR-1 contributes to the in-nate immune response during viral infection. J Clin Invest. 2013;123(3):1310–1322.

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Research articles in the current issue of the JCI

AIDS/HIVMaternal HIV-1 envelope–specific antibody responses and reduced risk of perinatal transmissionSallie R. Permar, Youyi Fong, Nathan Vandergrift, Genevieve G. Fouda, Peter Gilbert, Robert Parks, Frederick H. Jaeger, Justin Pollara, Amanda Martelli, Brooke E. Liebl, Krissey Lloyd, Nicole L. Yates, R. Glenn Overman, Xiaoying Shen, Kaylan Whitaker, Haiyan Chen, Jamie Pritchett, Erika Solomon, Emma Friberg, Dawn J. Marshall, John F. Whitesides, Thaddeus C. Gurley, Tarra Von Holle, David R. Martinez, Fangping Cai, Amit Kumar, Shi-Mao Xia, Xiaozhi Lu, Raul Louzao, Samantha Wilkes, Saheli Datta, Marcella Sarzotti-Kelsoe, Hua-Xin Liao, Guido Ferrari, S. Munir Alam, David C. Montefiori, Thomas N. Denny, M. Anthony Moody, Georgia D. Tomaras, Feng Gao, and Barton F. Haynes http://jci.me/81593

More, p. 7

CardiologyPHD2/3-dependent hydroxylation tunes cardiac response to β-adrenergic stress via phospholambanLiang Xie, Xinchun Pi, W.H. Davin Townley-Tilson, Na Li, Xander H.T. Wehrens, Mark L. Entman, George E. Taffet, Ashutosh Mishra, Junmin Peng, Jonathan C. Schisler, Gerhard Meissner, and Cam Patterson http://jci.me/80369

Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1Aaron M. Fond, Chang Sup Lee, Ira G. Schulman, Robert S. Kiss, and Kodi S. Ravichandran http://jci.me/80300

More, p. 12

Clinical trialsFresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patientsLisa M. Rice, Cristina M. Padilla, Sarah R. McLaughlin, Allison Mathes, Jessica Ziemek, Salma Goummih, Sashidhar Nakerakanti, Michael York, Giuseppina Farina, Michael L. Whitfield, Robert F. Spiera, Romy B. Christmann, Jessica K. Gordon, Janice Weinberg, Robert W. Simms, and Robert Lafyatis http://jci.me/77958

EndocrinologyS6K1 controls pancreatic β cell size independently of intrauterine growth restrictionSung Hee Um, Melanie Sticker-Jantscheff, Gia Cac Chau, Kristina Vintersten, Matthias Mueller, Yann-Gael Gangloff, Ralf H. Adams, Jean-Francois Spetz, Lynda Elghazi, Paul T. Pfluger, Mario Pende, Ernesto Bernal-Mizrachi, Albert Tauler, Matthias H. Tschöp, George Thomas, and Sara C. Kozma http://jci.me/77030

More, p. 7

PHD2/3-deficient heart

S6K1-deficient embryo

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Research articles in the current issue of the JCI

DNA methylation directs functional maturation of pancreatic β cellsSangeeta Dhawan, Shuen-Ing Tschen, Chun Zeng, Tingxia Guo, Matthias Hebrok, Aleksey Matveyenko, and Anil Bhushan http://jci.me/79956

With related Commentary by Frans Schuit More, p. 7

GastroenterologyEngineering the gut microbiota to treat hyperammonemiaTing-Chin David Shen, Lindsey Albenberg, Kyle Bittinger, Christel Chehoud, Ying-Yu Chen, Colleen A. Judge, Lillian Chau, Josephine Ni, Michael Sheng, Andrew Lin, Benjamin J. Wilkins, Elizabeth L. Buza, James D. Lewis, Yevgeny Daikhin, Ilana Nissim, Marc Yudkoff, Frederic D. Bushman, and Gary D. Wu http://jci.me/79214

ImmunologyInterferon-induced mechanosensing defects impede apoptotic cell clearance in lupusHao Li, Yang-Xin Fu, Qi Wu, Yong Zhou, David K. Crossman, PingAr Yang, Jun Li, Bao Luo, Laurence M. Morel, Janusz H. Kabarowski, Hideo Yagita, Carl F. Ware, Hui-Chen Hsu, and John D. Mountz http://jci.me/81059

With related Commentary by Claudia Mauri and Madhvi Menon More, p. 11

Mature T cell responses are controlled by microRNA-142Yaping Sun, Katherine Oravecz-Wilson, Nathan Mathewson, Ying Wang, Richard McEachin, Chen Liu, Tomomi Toubai, Julia Wu, Corinne Rossi, Thomas Braun,

Thomas Saunders, and Pavan Reddy http://jci.me/78753

Focused antibody response to influenza linked to antigenic driftKuan-Ying A. Huang, Pramila Rijal, Lisa Schimanski, Timothy J. Powell, Tzou-Yien Lin, John W. McCauley, Rodney S. Daniels, and Alain R. Townsend http://jci.me/81104

NeuroscienceshRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease modelAlevtina D. Zharikov, Jason R. Cannon, Victor Tapias, Qing Bai, Max P. Horowitz, Vipul Shah, Amina El Ayadi, Teresa G. Hastings, J. Timothy Greenamyre, and Edward A. Burton http://jci.me/64502

Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1

Nils Schallner, Rambhau Pandit, Robert LeBlanc III, Ajith J. Thomas, Christopher S. Ogilvy, Brian S. Zuckerbraun, David Gallo, Leo E. Otterbein, and Khalid A. Hanafy http://jci.me/78443

More, p. 10

In vivo kinetic approach reveals slow SOD1 turnover in the CNSMatthew J. Crisp, Kwasi G. Mawuenyega, Bruce W. Patterson, Naveen C. Reddy, Robert Chott, Wade K. Self, Conrad C. Weihl, Jennifer Jockel-Balsarotti, Arun S. Varadhachary, Robert C. Bucelli, Kevin E. Yarasheski, Randall J. Bateman, and Timothy M. Miller http://jci.me/80705

Mapping antibody alterations

Tyrosine hydroxylase in striatum

Pancreatic β cell maturation

Marginal zone macrophages

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NeuroscienceEstrogen receptor–α in medial amygdala neurons regulates body weightPingwen Xu, Xuehong Cao, Yanlin He, Liangru Zhu, Yongjie Yang, Kenji Saito, Chunmei Wang, Xiaofeng Yan, Antentor Othrell Hinton Jr., Fang Zou, Hongfang Ding, Yan Xia, Chunling Yan, Gang Shu, San-Pin Wu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Richard DeMarchi, Sohaib A. Khan, Sophia Y. Tsai, Francesco J. DeMayo, Qi Wu, Qingchun Tong, and Yong Xu http://jci.me/80941

With related Commentary by Chia Li and Michael J. Krashes More, p. 10

Mediation of opioid analgesia by a truncated 6-transmembrane GPCRZhigang Lu, Jin Xu, Grace C. Rossi, Susruta Majumdar, Gavril W. Pasternak, and Ying-Xian Pan http://jci.me/81070

With related Commentary by Michael J. Iadarola, Matthew R. Sapio, and Andrew J. Mannes More, p. 11

OncologyDeath-associated protein kinase 1 promotes growth of p53-mutant cancersJing Zhao, Dekuang Zhao, Graham M. Poage, Abhijit Mazumdar, Yun Zhang, Jamal L. Hill, Zachary C. Hartman, Michelle I. Savage, Gordon B. Mills, and Powel H. Brown http://jci.me/70805

Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damageCaitlyn W. Barrett, Vishruth K. Reddy, Sarah P. Short, Amy K. Motley, Mary K. Lintel, Amber M. Bradley, Tanner Freeman, Jefferson Vallance, Wei Ning, Bobak Parang, Shenika V. Poindexter, Barbara Fingleton, Xi Chen, Mary K. Washington, Keith T. Wilson, Noah F. Shroyer, Kristina E. Hill, Raymond F. Burk, and Christopher S. Williams http://jci.me/76099

More, p. 9

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasmsLukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie-Hélène Wasmer, Regula Stuber, Alexandre P. Theocharides, Xiaohong Li, Yu Xia, Hirohisa Saito, Susumu Nakae, Gabriela M. Baerlocher, Markus G. Manz, Kathy D. McCoy, Andrew J. Macpherson, Adrian F. Ochsenbein, Bruce Beutler, and Philippe Krebs http://jci.me/77347

More, p. 9

ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasisSouvik Dey, Carly M. Sayers, Ioannis I. Verginadis, Stacey L. Lehman, Yi Cheng, George J. Cerniglia, Stephen W. Tuttle, Michael D. Feldman, Paul J.L. Zhang, Serge Y. Fuchs, J. Alan Diehl, and Constantinos Koumenis http://jci.me/78031

OphthalmologyMolecular pharmacodynamics of emixustat in protection against retinal degenerationJianye Zhang, Philip D. Kiser, Mohsen Badiee, Grazyna Palczewska, Zhiqian Dong, Marcin Golczak, Gregory P. Tochtrop, and Krzysztof Palczewski http://jci.me/80950

Research articles in the current issue of the JCI

Single-minded 1 neurons

μ-Opioid receptor expression

SEPP1-deficient colon

Bone marrow IL-33

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Research articles in the current issue of the JCI

Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transferJingxing Ou, Camasamudram Vijayasarathy, Lucia Ziccardi, Shan Chen, Yong Zeng, Dario Marangoni, Jodie G. Pope, Ronald A. Bush, Zhijian Wu, Wei Li, and Paul A. Sieving http://jci.me/81380

With related Commentary by Timm Schubert and Bernd Wissinger More, p. 12

Reproductive biologySteroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturitionLu Gao, Elizabeth H. Rabbitt, Jennifer C. Condon, Nora E. Renthal, John M. Johnston, Matthew A. Mitsche, Pierre Chambon, Jianming Xu, Bert W. O’Malley, and Carole R. Mendelson http://jci.me/78544

With related Commentary by Erin L. Reinl and Sarah K. England More, p. 8

Stem cellsHarnessing endogenous stem/progenitor cells for tendon regenerationChang H. Lee, Francis Y. Lee, Solaiman Tarafder, Kristy Kao, Yena Jun, Guodong Yang, and Jeremy J. Mao http://jci.me/81589

More, p. 8

TransplantationOutcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell graftsMarie Bleakley, Shelly Heimfeld, Keith R. Loeb, Lori A. Jones, Colette Chaney, Stuart Seropian, Ted A. Gooley, Franziska Sommermeyer, Stanley R. Riddell, and Warren D. Shlomchik http://jci.me/81229

More, p. 9

Vascular biologyNeural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septationAlice Plein, Amélie Calmont, Alessandro Fantin, Laura Denti, Naomi A. Anderson, Peter J. Scambler, and Christiana Ruhrberg http://jci.me/79668

More, p. 6

AAV-mediated RS1 expression

Heart outflow tract actin

CD146+ cells in tendons

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Nearly a third of all congenital heart de-fects are associated with perturbations in the development of the cardiac outflow tract. Remodeling of the outflow tract into the base of the pulmonary artery and aorta by septa-tion allows delivery of deoxygenated blood to the lungs and oxygenated blood to the systemic circulation. In this issue, Christiana Ruhrberg and colleagues report on their in-vestigation of the signals driving septation and the contribution of the cell types that form the septal bridge. In a series of mouse studies, the authors examined the role of neuropilin 1 (NRP1), a transmembrane re-ceptor that can bind multiple ligands, such as SEMA3C and VEGF family members, in cardiac neural crest cells and endothelial cells. Their work demonstrates that NRP1 is specifically required in endothelial cells to promote proper outflow tract remodeling. Unexpectedly, they found that neural crest cells act as a source of SEMA3C rather than its target. Further, SEMA3C was identified as the primary driver of endothelial NRP1 activ-ity, because loss of SEMA3C in cardiac neu-ral crest cells prevented both outflow tract

Neural crest–derived factor orchestrates cardiac outflow tract septation during development

Editor’s picksResearch

septation and the correct alignment of the base of pulmonary artery and aorta with the ventricles. Their findings support a new paradigm in cardiac development and indicate that neural crest cells initiate septation by secreting SEMA3C, which triggers endothelial cells to undergo developmental changes, leading to septal bridge formation. The accompanying image shows an embryonic day 13.5 mouse heart immunostained for endothelial surfaces (endo-mucin, red) and nonendothelial cells (false-colored in cyan).

Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation

Alice Plein, Amélie Calmont, Alessandro Fantin, Laura Denti, Naomi A. Anderson, Peter J. Scambler, and Christiana Ruhrberg http://jci.me/79668

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Antibody responses predict the risk of vertical HIV-1 transmission

Research | Editor’s picks

aids/hiv

Directing the maturation of pancreatic β cells epigenetically

Pancreatic β cell–intrinsic effects of S6K1 deletion

Pancreatic β cells respond to postprandial glucose increases by secreting insulin, and they respond to fasting conditions by inhibiting insulin secretion. These cells only acquire the ability to respond to glucose postnatally, indicating that epigenetic mechanisms direct β cell maturation after birth. Sangeeta Dhawan and colleagues demonstrate that the DNA methyltransferase DNMT3A mediates the coupling of insulin secretion to glucose levels. Mice with β cell–specific deletion of Dnmt3a did not develop the ability to secrete insulin in response to increased glucose. Mechanistically, DNMT3A-mediated de novo methylation represses the expression of hexokinase 1, lactate dehydrogenase A, and aldolase B. Importantly, this mechanism is conserved in humans. In the accompanying

Commentary, Frans Schuit discusses how these studies identify an epigenetic mechanism that directs postnatal β cell maturation.

DNA methylation directs functional maturation of pancreatic β cellsSangeeta Dhawan, Shuen-ing Tschen, Chun Zeng, Tingxia Guo, Matthias Hebrok, Aleksey Matveyenko, and Anil Bhushan http://jci.me/79956

Related CommentaryEpigenetic programming of glucose-regulated insulin releaseFrans Schuit http://jci.me/82575

Deletion of ribosomal protein s6 kinase 1 (s6K1) increases systemic insulin sensitivity, and inhibitors are currently under investigation for the treatment of type 2 diabetes mellitus (T2DM). However, previous studies have shown that S6K1-deficient mice are hypoinsulinemic, have smaller pancreatic β cells, and display a reduced body size. Sung Hee Um and colleagues demonstrate that S6K1 deficiency leads to impaired placental development and

intrauterine growth restriction (IUGR), a risk factor for T2DM later in life. Restoration of placental function rescued IUGR but did not rescue β cell defects, while restoration of S6K1 expression in embryonic β cells resulted in normal β cell growth, insulin levels, and glucose tolerance but failed to rescue IUGR. These results indicate that S6K1 effects on β cell size and function are independent of its role in IUGR.

S6K1 controls pancreatic β cell size independently of intrauterine growth restrictionSung Hee Um, Melanie Sticker-Jantscheff, Gia Cac Chau, Kristina Vintersten, Matthias Mueller, Yann-Gael Gangloff, Ralf H. Adams, Jean-Francois Spetz, Lynda Elghazi, Paul T. Pfluger, Mario Pende, Ernesto Bernal-Mizrachi, Albert Tauler, Matthias H. Tschöp, George Thomas, and Sara C. Kozma http://jci.me/77030

endocrinology

Antiretroviral therapy significantly reduces the risk of mother-to-child transmission (MTCT) of HIV-1; however, more than 250,000 infants are vertically infected with HIV-1 each year, emphasizing the need for additional interventions. Sallie Permar and colleagues studied 83 untreated, HIV-1–transmitting mothers and 165 matched nontransmitting mothers in order to define humoral immune correlates for vertical infection risk. Using multivariable logistic regression models, they determined that the magnitude of maternal IgG responses specific for the V3 loop of the HIV-1 envelope was predictive of a reduced risk of MTCT. Additionally, neutralizing

antibody responses against tier 1 HIV-1 strains were also predictive of reduced MTCT risk. Moreover, maternal V3–specific antibodies were able to mediate neutralization of the mother’s own virus, and further studies will address whether this is a mechanistic immune correlate of MTCT.

Maternal HIV-1 envelope–specific antibody responses and reduced risk of perinatal transmissionSallie R. Permar, Youyi Fong, Nathan Vandergrift, Genevieve G. Fouda, Peter Gilbert, Robert Parks, Frederick H. Jaeger, Justin Pollara, Amanda Martelli,

Brooke E. Liebl, Krissey Lloyd, Nicole L. Yates, R. Glenn Overman, Xiaoying Shen, Kaylan Whitaker, Haiyan Chen, Jamie Pritchett, Erika Solomon, Emma Friberg, Dawn J. Marshall, John F. Whitesides, Thaddeus C. Gurley, Tarra Von Holle, David R. Martinez, Fangping Cai, Amit Kumar, Shi-Mao Xia, Xiaozhi Lu, Raul Louzao, Samantha Wilkes, Saheli Datta, Marcella Sarzotti-Kelsoe, Hua-Xin Liao, Guido Ferrari, S. Munir Alam, David C. Montefiori, Thomas N. Denny, M. Anthony Moody, Georgia D. Tomaras, Feng Gao, and Barton F. Haynes http://jci.me/81593

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Research | Editor’s picks

Tendon stem/progenitor cells enhance regeneration after injuryin this issue, Chang lee and colleagues report on the use of tendon-resident stem/progenitor cells (TSCs) for the regeneration of injured tendons in rats. They identified a population of CD146+ multipotent, clonogenic cells that were enriched by treatment with connective tissue growth factor (CTGF), which activated ERK1/2 and focal adhesion kinase. Using a patellar tendon transection model, Lee and colleagues showed that treatment with CTGF and fibrin gel enhanced tendon healing compared with fibrin gel alone (see the accompanying image). CTGF-promoted healing was characterized by increased numbers of CD146+ cells and greater collagen deposition at the site of injury, as well as increased proliferation and differentiation of CD146+ cells.

Harnessing endogenous stem/progenitor cells for tendon regenerationChang H. Lee, Francis Y. Lee, Solaiman Tarafder, Kristy Kao, Yena Jun, Guodong Yang, and Jeremy J. Mao http://jci.me/81589

stem cells

reproductive biology

Fetal lung expression of steroid receptor coactivators 1 and 2 triggers laborPreterm birth is a leading cause of neonatal morbidity and mortality, but the signals that initiate labor, both at term and preterm, are not well defined. In this issue, Lu Gao and colleagues show that fetal lung expression of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2) upregulates genes that trigger parturition in mice. Their finding that WT females bred to males that were doubly deficient in SRC-1 and SRC-2 exhibited severely delayed parturition clearly implicates a role for the fetus in the timing of birth. This parturition delay was accompanied by decreased expression of uterine inflammatory and contractile genes and elevated circulating progesterone. The lungs and amniotic fluid of SRC-1/2–deficient fetuses had markedly reduced levels of surfactant protein-A and the inflam-matory phospholipid platelet-activating factor; intraamniotic injection of either of these factors

rescued the delayed labor phenotype. In the accompanying Commentary, Erin Reinl and Sarah England discuss how these studies identify fetal-derived factors that control the initiation of labor.

Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturitionLu Gao, Elizabeth H. Rabbitt, Jennifer C. Condon, Nora E. Renthal, John M. Johnston, Matthew A. Mitsche, Pierre Chambon, Jianming Xu, Bert W. O’Malley, and Carole R. Mendelson http://jci.me/78544

Related CommentaryFetal-to-maternal signaling to initiate parturitionErin L. Reinl and Sarah K. England http://jci.me/82576

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Research | Editor’s picks

IL-33 supports dysregulated myelopoiesis in myeloproliferative neoplasmsMyeloproliferative neoplasms (MPns) are a heterogeneous group of malignant clonal hematopoietic diseases that are characterized by cytokine dysregulation. Using murine models of MPN-like disease, Lukas Mager and colleagues demonstrated that the inflammatory cytokine IL-33 supports dysregulated myelpoiesis to drive MPN pathogenesis. Genetic ablation of IL-33 signaling pathway components restored normal hematopoiesis and prevented the development of MPNs. Moreover, the authors detected increased numbers of IL-33–producing cells in the BM of MPN patients, while exogenous IL-33 increased cytokine production and colony formation by primary MPN stem and progenitor cells from patients. These data identify a crucial role for IL-33 signaling in MPN pathogenesis.

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasmsLukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie-Hélène Wasmer, Regula Stuber, Alexandre P. Theocharides, Xiaohong Li, Yu Xia, Hirohisa Saito, Susumu Nakae, Gabriela M. Baerlocher, Markus G. Manz, Kathy D. McCoy, Andrew J. Macpherson, Adrian F. Ochsenbein, Bruce Beutler, and Philippe Krebs http://jci.me/77347

Reducing graft-versus-host disease after stem cell transplantationAllogeneic hematopoietic stem cell transplantation (hsCt) is often curative in patients with hematological malignancies; however, it carries a risk of graft-versus-host disease (GVHD). Based on preclinical observations that stem cell grafts containing naive T cells cause more severe GVHD than grafts containing only memory T cells, Marie Bleakley and colleagues conducted a single-arm clinical trial in which 35 patients with high-risk leukemia were transplanted with naive T cell–depleted stem cell grafts. All 35 patients engrafted successfully. A major reduction in the incidence of chronic GVHD was observed compared with that of historical controls who received unmanipulated grafts. While there was no decrease in the acute GVHD incidence, all GVHD cases responded to corticosteroid treatment. Moreover, the frequency of infection or relapse was not increased in naive T cell–depleted HSCT recipients. These results indicate that naive T cell depletion may be a useful strategy to reduce the duration and/or severity of GVHD after HSCT..

Outcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell graftsMarie Bleakley, Shelly Heimfeld, Keith R. Loeb, Lori A. Jones, Colette Chaney, Stuart Seropian, Ted A. Gooley, Franziska Sommermeyer, Stanley R. Riddell, and Warren D. Shlomchik http://jci.me/81229

A selenium transporter modulates the tumor microenvironment in colon cancerinflammatory bowel disease increases the risk for colon cancer by exacerbating oxidative stress. Selenoproteins are antioxidant enzymes that require the trace element selenium for function, and epidemiological studies have demonstrated that selenium deficiency contributes to cancer risk. In this issue, Caitlyn Barrett, Vishruth Reddy, and colleagues show that haploinsufficiency for the gene encoding the selenium transporter selenoprotein P (SEPP1) or mutation of either the transporter or enzymatic domains of the protein increased genomic instability and supported a protumorigenic microenvironment in mice, while complete loss of Sepp1 increased apoptosis to reduce tumorigenesis (see the accompany-ing image). Using organoid cultures, Barrett, Reddy, and colleagues demonstrated that SEPP1 deficiency influences tumorigenesis by increasing stem cell–like properties and proliferation and allowing for increased DNA damage, ROS production, and decreased cell survival in response to oxidative stress.

Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damageCaitlyn W. Barrett, Vishruth K. Reddy, Sarah P. Short, Amy K. Motley, Mary K. Lintel, Amber M. Bradley, Tanner Freeman, Jefferson Vallance, Wei Ning, Bobak Parang, Shenika V. Poindexter, Barbara Fingleton, Xi Chen, Mary K. Washington, Keith T. Wilson, Noah F. Shroyer, Kristina E. Hill, Raymond F. Burk, and Christopher S. Williams http://jci.me/76099

oncology

transplantation

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Research | Editor’s picks

Microglial heme oxygenase-1 mediates blood clearance after subarachnoid hemorrhage

Localizing estrogen’s effects on energy homeostasis

neuroscience

subarachnoid hemorrhage (sAh) causes neuronal injury and cognitive impairment, which result from cerebral inflammation induced by heme released from damaged rbc. Using a murine model of SAH, Nils Schallner and colleagues demonstrate that microglial cells express heme oxygenase-1 (HO-1) to clear blood from the subarachnoid space and attenuate neuronal injury. Loss of microglial HO-1 in mice further increased neuronal injury after SAH. Additionally, patients with SAH had elevated levels of HO-1 in cerebrospinal fluid compared with patients with unruptured cerebral aneurysms, and HO-1 activity was correlated with hematoma volume. HO-1 metabolizes free heme, generating biliverdin, iron, and carbon monoxide (CO), the last of which is a potent immune modulator. Inhalation of CO attenuated neuronal injury in both HO-1–deficient and WT mice (see the accompanying image). These data demonstrate that HO-1–generated CO mediates the elimination of blood after SAH and suggest that CO administra-tion is a potential therapeutic modality to reduce injury after SAH.

Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1Nils Schallner, Rambhau Pandit, Robert LeBlanc III, Ajith J. Thomas, Christopher S. Ogilvy, Brian S. Zuckerbraun, David Gallo, Leo E. Otterbein, and Khalid A. Hanafy http://jci.me/78443

Estrogen receptor–α in medial amygdala neurons regulates body weightPingwen Xu, Xuehong Cao, Yanlin He, Liangru Zhu, Yongjie Yang, Kenji Saito, Chunmei Wang, Xiaofeng Yan, Antentor Othrell Hinton Jr., Fang Zou, Hongfang Ding, Yan Xia, Chunling Yan, Gang Shu, San-Pin Wu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Richard DeMarchi, Sohaib A. Khan, Sophia Y. Tsai, Francesco J. DeMayo, Qi Wu, Qingchun Tong, and Yong Xu http://jci.me/80941

Related CommentaryHypoactivity following perturbed estrogen signaling in the medial amygdalaChia Li and Michael J. Krashes http://jci.me/82578

estrogen is a critical regulator of energy homeostasis. Brain-specific deletion of estrogen receptor–α (ERα) leads to increased body weight and adiposity in both male and female mice. In this issue, Pingwen Xu and colleagues show that neurons expressing single-minded–1 (SIM1) in the medial amygdala mediate estrogen’s effects on body weight. Loss of ERα in SIM1 neurons resulted in hypoactivity and obesity in male and female mice, along with increased susceptibility to diet-induced obesity in males, but not in females. Conversely, overexpression of ERα in medial amygdala neurons partially prevented diet-induced obesity in male mice. Using specially engineered receptor constructs known as designer receptors exclusively activated by designer drugs (DREADDs), Xu and colleagues selectively activated SIM1 neurons in the medial amygdala (see the accompanying image), which increased physical activity. In the accompanying Commentary, Chia Li and Michael Krashes discuss how these results indicate that ERα stimulates SIM1 neurons in the medial amygdala to increase physical activity and prevent diet-induced obesity.

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Research | Editor’s picks

immunology

A mechanosensing pathway clears autoantigens in lupus

Pain relief through a truncated µ-opioid receptorOprm1, which encodes the µ-opioid receptor MoR, undergoes multiple alternative pre-mRNA splicing events that result in different MOR isoforms. The majority of these isoforms have seven full-length transmembrane domains (7TM); however, others have only six transmembrane domains (6TM). Zhigang Lu and colleagues demonstrate that a new opiate analgesic, 3-iodobenzoyl-6β-naltrexamide (IBNtxA), exerts its effects exclusively through a 6TM MOR. While IBNtxA was a highly effective analgesic in WT mice, its analgesic effects were lost in mice lacking a set of 6TM MOR splice variants. Reexpression of the 6TM variant mMOR-1G restored IBNtxA analgesia. Importantly, IBNtxA did not cause common opiate analgesic side effects, such as respiratory depression or physical dependence. In the accompanying Commentary, Michael Iadarola discusses how these findings indicate that 6TM variants may be attractive therapeutic targets for opiate-like analgesics.

Mediation of opioid analgesia by a truncated 6-transmembrane GPCRZhigang Lu, Jin Xu, Grace C. Rossi, Susruta Majumdar, Gavril W. Pasternak, and Ying-Xian Pan http://jci.me/81070

Related CommentaryA new splice of life for the μ-opioid receptorMichael J. Iadarola, Matthew R. Sapio, and Andrew J. Mannes http://jci.me/82060

neuroscience

systemic lupus erythematous (sle) is characterized by increased type I IFN and circulating autoantigens (Ags) derived from apoptotic cells (ACs). Hao Li and colleagues describe a mechanism by which AC clearance is impaired in SLE. Using a murine model of lupus, they showed that follicular translocation of marginal zone (MZ) B cells in the spleen disrupted MZ macrophages (MZMs), which clear ACs and prevent follicular entry of AC-Ags. MZ B cells express membrane lymphotoxin-α1β2 (mLT), thereby activating a megakaryoblastic leukemia 1 (MKL1) transcriptional coactivator–mediated mechanosensing pathway in MZMs. Loss of either mLT or MKL1 blocked activation of this pathway and impaired the F-actin polymerization in MZMs that is required for AC clearance (see the accompanying image). Additionally, type I IFN induced follicular shuttling of MZ B cells, disrupting the interaction between MZ B cells and MZMs and downregulating MKL1. This

pathway was recapitulated in spleens from human SLE patients. In the accompanying Commentary, Claudia Mauri and Madhvi Menon discuss how these findings indicate that strategies that maintain this mechanosensing pathway may block follicular entry of AC-Ags.

Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupusHao Li, Yang-Xin Fu, Qi Wu, Yong Zhou, David K. Crossman, PingAr Yang, Jun Li, Bao Luo, Laurence M. Morel, Janusz H. Kabarowski, Hideo Yagita, Carl F. Ware, Hui-Chen Hsu, and John D. Mountz http://jci.me/81059

Related CommentaryThe many faces of type I interferon in systemic lupus erythematosusClaudia Mauri and Madhvi Menon http://jci.me/82574

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Research | Editor’s picks

Macrophages mediate reverse cholesterol transport, a process whereby peripheral cholesterol is returned to the liver for excretion. The cholesterol transporter ABCA1 exports cholesterol from macrophages, which take up large quantities of cholesterol during clearance of apoptotic cells. Aaron Fond and colleagues delineated a plasma membrane–initiated signaling pathway that drives upregulation of ABCA1 in macrophages. Macrophages recognize phosphatidylserine on

the surface of apoptotic cells via the phagocyt-ic receptor BAI1, which then activates a downstream signaling pathway that requires RAC1 and ELMO1 to upregulate ABCA1. Notably, this pathway does not involve liver X nuclear sterol receptors. BAI1-deficient mice fed a high-fat diet had greater numbers of uncleared apoptotic cells in their aortic roots and altered lipid profiles compared with WT mice, while macrophages from mice overexpressing BAI1 exhibited greater ABCA1 induction in the

presence of apoptotic cells. These data identify an ABCA1-induction pathway that regulates cholesterol homeostasis in vivo.

Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1Aaron M. Fond, Chang Sup Lee, Ira G. Schulman, Robert S. Kiss, and Kodi S. Ravichandran http://jci.me/80300

Restoring synaptic function in X-linked retinoschisis

A path toward increased cholesterol transport in macrophages

X-linked retinoschisis (XlRs) is an inherited retinal synaptic disorder caused by mutation of the extracellular matrix (ECM) gene retinoschisin (RS1), which is required to preserve the structure and function of the retina. Jingxing Ou, Camasamudram Vijayasarathy, and colleagues demonstrated that photoreceptor–depolarizing bipolar cell (DBC) synaptic function can be rescued with retina-specific delivery of adeno-associated virus type 8–RS1 (AAV8-RS1) in a murine model of XLRS (see the accompanying image). RS1 restoration induced proper localization of the metabotropic glutamate receptor 6/transient receptor potential melastatin subfamily M member 1–signaling (mGluR6/TRPM1-signaling) components, allowing for normal synaptic function. In the accompanying Commentary, Timm Schubert and Bernd Wissinger discuss how therapeutic strategies to restore synaptic organization and function could potentially be used to treat a number of neurological disorders that involve synaptic pathology.

Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transferJingxing Ou, Camasamudram Vijayasarathy, Lucia Ziccardi, Shan Chen, Yong Zeng, Dario Marangoni, Jodie G. Pope, Ronald A. Bush, Zhijian Wu, Wei Li, and Paul A. Sieving http://jci.me/81380

Related CommentaryRestoration of synaptic function in sight for degenerative retinal diseaseTimm Schubert and Bernd Wissinger http://jci.me/82577

ophthalmology

cardiology

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Features

Robert SchrierDr. Robert schrier is a nephrologist and Professor of Medicine at the University of Colorado School of Medicine, where he served as Chair of the Department of Medicine and Chief of the Kidney Division for more than 20 years. He is an expert in patient-oriented research on acute kidney injury, autosomal dominant polycystic kidney disease, hypertension, and diabetic nephropathy. Dr. Schrier has authored over 1,000 papers and several books and has been continuously funded by the NIH for 45 years. In an interview with JCI Editor-at-Large Ushma Neill, Schrier discusses his love of sports, his studies in Germany as a Fulbright scholar, his decision to go to medical school, and his entry into research at the Walter Reed Army Medical Center, where he became interested in kidney failure. http://jci.me/82627

reviews

Taking pluripotent stem cells from bench to bedsidePluripotent stem cells (PsCs), either derived from embryos or induced from adult cells, have the ability to differentiate into any cell type, making these cells a potential boon to regenerative medicine. PSCs could be used in preclinical applications (“disease-in-a-dish” models for drug screening) and in clinical applications, in which they could be used to replaced damaged or defective tissues. In this issue, Joseph Wu and colleagues discuss the steps required to generate a therapeutic cell product and discuss the preclinical challenges in developing PSC-based therapeutics. Additionally, they discuss the advantages and disadvantages of allogeneic and autologous stem cell products, as well as clinical requirements, quality standards, time lines, and the costs of developing successful PSC-based therapies.

Hurdles to clinical translation of human induced pluripotent stem cellsEvgenios Neofytou, Connor Galen O’Brien, Larry A. Couture, and Joseph C. Wu http://jci.me/80575

conversations with giants in medicine

A D V E R T I S E M E N T

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The JCI welcomes submissions in the following categories:

Regular: Substantial new mechanistic insights into biology and disease.

Technical advance: New and important research tools and techniques with the potential for broad impact.

Brief report: Discrete, highly significant findings in a short format.

Sample article: Epigenomic plasticity enables human pancreatic α 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

Published March 2013 http://jci.me/66514 Times cited: 64

Sample article: 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

Published March 2013 http://jci.me/67677 Times cited: 44

Sample article: Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaquesNichole R. Klatt, Lauren A. Canary, Xiaoyong Sun, Carol L. Vinton, Nicholas T. Funderburg, David R. Morcock, Mariam Quiñones, Clayton B. Deming, Molly Perkins, Daria J. Hazuda, Michael D. Miller, Michael M. Lederman, Julie A. Segre, Jeffrey D. Lifson, Elias K. Haddad, Jacob D. Estes, and Jason M. Brenchley

Published February 2013 http://jci.me/66227 Times cited: 31

Clinical medicine:Research that reports early-stage, effective new therapies that impact disease outcomes in patients.

Sample article: Il-12p70–producing patient DC vaccine elicits Tc1-polarized immunityBeatriz M. Carreno, Michelle Becker-Hapak, Alexander Huang, Megan Chan, Amer Alyasiry, Wen-Rong Lie, Rebecca L. Aft, Lynn A. Cornelius, Kathryn M. Trinkaus, and Gerald P. Linette

Published August 2013 http://jci.me/68395 Times cited: 20

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