jci.org/impactMarch 2015

Also in this issue:

Collagen cross-links in tumors 7

WNT signaling in cholangiocarcinoma 7

A longitudinal study of living kidney donors 9

Review series: enteric nervous system edited by Rodger A. Liddle 10

A summary of this month’s Journal of Clinical investigation

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

parasite infectionp. 6

http://www.uhhospitals.org/services/harrington-discovery-institute?utm_source=JornalClinicalInvestigation&utm_medium=print&utm_campaign=HDIprint

t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t m a r c h 2 0 1 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.

ImpactMarch 2015

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Research articlesIrradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in miceLiufu Deng, Hua Liang, Byron Burnette, Michael Beckett, Thomas Darga, Ralph R. Weichselbaum, and Yang-Xin FuPublished February 2014 http://jci.me/67313 Times cited: 25

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patientsEle Ferrannini, Elza Muscelli, Silvia Frascerra, Simona Baldi, Andrea Mari, Tim Heise, Uli C. Broedl, and Hans-Juergen WoerlePublished February 2014 http://jci.me/72227 Times cited: 23

Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose productionAurora Merovci, Carolina Solis-Herrera, Giuseppe Daniele, Roy Eldor, Teresa Vanessa Fiorentino, Devjit Tripathy, Juan Xiong, Zandra Perez, Luke Norton, Muhammad A. Abdul-Ghani, and Ralph A. DeFronzoPublished February 2014 http://jci.me/70704 Times cited: 21

Macrophages are required for neonatal heart regenerationArin B. Aurora, Enzo R. Porrello, Wei Tan, Ahmed I. Mahmoud, Joseph A. Hill, Rhonda Bassel-Duby, Hesham A. Sadek, and Eric N. Olson

Published March 2014 http://jci.me/72181 Times cited: 19

ReviewsNew and emerging HDAC inhibitors for cancer treatmentAlison C. West and Ricky W. JohnstonePublished January 2014 http://jci.me/69738 Times cited: 26

Aging and epigenetic drift: a vicious cycleJean-Pierre IssaPublished January 2014 http://jci.me/69735 Times cited: 13

Development of the mammalian lymphatic vasculatureYing Yang and Guillermo OliverPublished March 2014 http://jci.me/71609 Times cited: 10

Citation information is from Scopus as of January 2015.

Top cited, 2014Of Note

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Research articles in the current issue of the JCI

Clinical trialsβ cell death and dysfunction during type 1 diabetes development in at-risk individualsKevan C. Herold, Sahar Usmani-Brown, Tara Ghazi, Jasmin Lebastchi, Craig A. Beam, Melena D. Bellin, Michel Ledizet, Jay M. Sosenko, Jeffrey P. Krischer, Jerry P. Palmer, and the Type 1 Diabetes TrialNet Study Group http://jci.me/78142

Longitudinal study of living kidney donor glomerular dynamics after nephrectomyColin R. Lenihan, Stephan Busque, Geraldine Derby, Kristina Blouch, Bryan D. Myers, and Jane C. Tan http://jci.me/78885

With related commentary by roland c. Blantz and robert W. Steiner More, p. 9

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patientsGesine Paul, Olof Zachrisson, Andrea Varrone, Per Almqvist, Markus Jerling, Göran Lind, Stig Rehncrona, Bengt Linderoth, Hjalmar Bjartmarz, Lisa L. Shafer, Robert Coffey, Mikael Svensson, Katarina Jansson Mercer, Anton Forsberg, Christer Halldin, Per Svenningsson, Håkan Widner, Jonas Frisén, Sven Pålhagen, and Anders Haegerstrand http://jci.me/79635

With related commentary by Thomas Foltynie More, p. 9

DevelopmentTaspase1-dependent TFIIa cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcriptionShugaku Takeda, Satoru Sasagawa, Toshinao Oyama, Adam C. Searleman, Todd D. Westergard, Emily H. Cheng, and James J. Hsieh http://jci.me/77075

GastroenterologyDefective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal diseaseJinghua Liu, Nancy M. Walker, Akifumi Ootani, Ashlee M. Strubberg, and Lane L. Clarke http://jci.me/73193

cytosolic hMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammationXiaorong Zhu, Jeannette S. Messer, Yunwei Wang, Fanfei Lin, Candace M. Cham, Jonathan Chang, Timothy R. Billiar, Michael T. Lotze, David L. Boone, and Eugene B. Chang http://jci.me/76344

annexin a1–containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repairGiovanna Leoni, Philipp-Alexander Neumann, Nazila Kamaly, Miguel Quiros, Hikaru Nishio, Hefin R. Jones, Ronen Sumagin, Roland S. Hilgarth, Ashfaqul Alam, Gabrielle Fredman, Ioannis Argyris, Emile Rijcken, Dennis Kusters, Chris Reutelingsperger, Mauro Perretti, Charles A. Parkos, Omid C. Farokhzad, Andrew S. Neish, and Asma Nusrat http://jci.me/76693Migrating intestinal epithelial cells

Intracerebroventricular injection

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Research articles in the current issue of the JCI

GeneticsFunctional variants of POC5 identified in patients with idiopathic scoliosisShunmoogum A. Patten, Patricia Magaritte-Jeannin, Jean-Claude Bernard, Eudeline Alix, Audrey Labalme, Alicia Besson, Simon L. Girard, Khaled Fendri, Nicolas Fraisse, Bernard Biot, Coline Poizat, Amandine Campan-Fournier, Kariman Abelin-Genevois, Vincent Cunin, Charlotte Zaouter, Meijiang Liao, Raphaelle Lamy, Gaetan Lesca, Rita Menassa, Charles Marcaillou, Melanie Letexier, Damien Sanlaville, Jerome Berard, Guy A. Rouleau, Françoise Clerget-Darpoux, Pierre Drapeau, Florina Moldovan, and Patrick Edery http://jci.me/77262

HematologyEvaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromesYogen Saunthararajah, Mikkael Sekeres, Anjali Advani, Reda Mahfouz, Lisa Durkin, Tomas Radivoyevitch, Ricki Englehaupt, Joy Juersivich, Kathleen Cooper, Holleh Husseinzadeh, Bartlomiej Przychodzen, Matthew Rump, Sean Hobson, Marc Earl, Ronald Sobecks, Robert Dean, Frederic Reu, Ramon Tiu, Betty Hamilton, Edward Copelan, Alan Lichtin, Eric Hsi, Matt Kalaycio, and Jaroslaw Maciejewski http://jci.me/78789

HepatologyOxidative 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/73957

ImmunologyPreexisting human antibodies neutralize recently emerged h7N9 influenza strainsCarole J. Henry Dunand, Paul E. Leon, Kaval Kaur, Gene S. Tan, Nai-Ying Zheng, Sarah Andrews, Min Huang, Xinyan Qu, Yunping Huang, Marlene Salgado-Ferrer, Irvin Y. Ho, William Taylor, Rong Hai, Jens Wrammert, Rafi Ahmed, Adolfo García-Sastre, Peter Palese, Florian Krammer, and Patrick C. Wilson http://jci.me/74374

MicrorNa-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitisGopal Murugaiyan, Andre Pires da Cunha, Amrendra K. Ajay, Nicole Joller, Lucien P. Garo, Sowmiya Kumaradevan, Nir Yosef, Vishal S. Vaidya, and Howard L. Weiner http://jci.me/74347

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Liqing Wang, Yujie Liu, Rongxiang Han, Ulf H. Beier, Tricia R. Bhatti, Tatiana Akimova, Mark I. Greene, Scott W. Hiebert, and Wayne W. Hancock http://jci.me/77088

More, p. 7

crK proteins selectively regulate T cell migration into inflamed tissuesYanping Huang, Fiona Clarke, Mobin Karimi, Nathan H. Roy, Edward K. Williamson, Mariko Okumura, Kazuhiro Mochizuki, Emily J.H. Chen, Tae-Ju Park, Gudrun F. Debes, Yi Zhang, Tom Curran, Taku Kambayashi, and Janis K. Burkhardt http://jci.me/77278

an NLrP3 inflammasome–triggered Th2-biased adaptive immune response promotes leishmaniasisPrajwal Gurung, Rajendra Karki, Peter Vogel, Makiko Watanabe, Mark Bix, Mohamed Lamkanfi, and Thirumala-Devi Kanneganti http://jci.me/79526

More, p. 6

Hepatocyte β-catenin

EAE spinal cord

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Research articles in the current issue of the JCI

NephrologyLymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammationMohamed A. Saleh, William G. McMaster, Jing Wu, Allison E. Norlander, Samuel A. Funt, Salim R. Thabet, Annet Kirabo, Liang Xiao, Wei Chen, Hana A. Itani, Danielle Michell, Tianxiao Huan, Yahua Zhang, Satoshi Takaki, Jens Titze, Daniel Levy, David G. Harrison, and Meena S. Madhur http://jci.me/76327

Krüppel-like factor 6 regulates mitochondrial function in the kidneySandeep K. Mallipattu, Sylvia J. Horne, Vivette D’Agati, Goutham Narla, Ruijie Liu, Michael A. Frohman, Kathleen Dickman, Edward Y. Chen, Avi Ma’ayan, Agnieszka B. Bialkowska, Amr M. Ghaleb, Mandayam O. Nandan, Mukesh K. Jain, Ilse Daehn, Peter Y. Chuang, Vincent W. Yang, and John C. He http://jci.me/77084

With related commentary by Jeffrey B. Kopp More, p. 9

Neurosciencehuman-derived neural progenitors functionally replace astrocytes in adult miceHong Chen, Kun Qian, Wei Chen, Baoyang Hu, Lisle W. Blackbourn IV, Zhongwei Du, Lixiang Ma, Huisheng Liu, Karla M. Knobel, Melvin Ayala, and Su-Chun Zhang http://jci.me/69097

More, p. 8

Vessel maturation schedule determines vulnerability to neuronal injuries of prematurity

Tamar Licht, Talia Dor-Wollman, Ayal Ben-Zvi, Gadiel Rothe, and Eli Keshet http://jci.me/79401

With related attending Physician by Jason Boehme and Emin Maltepe More, p. 8

OncologyLysyl hydroxylase 2 induces a collagen cross-link switch in tumor stromaYulong Chen, Masahiko Terajima, Yanan Yang, Li Sun, Young-Ho Ahn, Daniela Pankova, Daniel S. Puperi, Takeshi Watanabe, Min P. Kim, Shanda H. Blackmon, Jaime Rodriguez, Hui Liu, Carmen Behrens, Ignacio I. Wistuba, Rosalba Minelli, Kenneth L. Scott, Johannah Sanchez-Adams, Farshid Guilak, Debananda Pati, Nishan Thilaganathan, Alan R. Burns, Chad J. Creighton, Elisabeth D. Martinez, Tomasz Zal, K. Jane Grande-Allen, Mitsuo Yamauchi, and Jonathan M. Kurie http://jci.me/74725

More, p. 7

Inhibition of IraK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapiesZhaoyang Li, Kenisha Younger, Ronald Gartenhaus, Ann Mary Joseph, Fang Hu, Maria R. Baer, Patrick Brown, and Eduardo Davila http://jci.me/75821

coactivator Src-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasisSubhamoy Dasgupta, Nagireddy Putluri, Weiwen Long, Bin Zhang, Jianghua Wang, Akash K. Kaushik, James M. Arnold, Salil K. Bhowmik, Erin Stashi, Christine A. Brennan, Kimal Rajapakshe, Cristian Coarfa, Nicholas Mitsiades, Michael M. Ittmann, Arul M. Chinnaiyan, Arun Sreekumar, and Bert W. O’Malley http://jci.me/76029

Prostate tumor lipogenesis

Podocyte apoptosis

Astrocyte integration

Human lung cancer

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Research articles in the current issue of the JCI

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibitedLuke Boulter, Rachel V. Guest, Timothy J. Kendall, David H. Wilson, Davina Wojtacha, Andrew J. Robson, Rachel A. Ridgway, Kay Samuel, Nico Van Rooijen, Simon T. Barry, Stephen J. Wigmore, Owen J. Sansom, and Stuart J. Forbes http://jci.me/76452

With related commentary by David M. Virshup More, p. 7

recombinant human cD19L-sTraIL effectively targets B cell precursor acute lymphoblastic leukemiaFaith M. Uckun, Dorothea E. Myers, Sanjive Qazi, Zahide Ozer, Rebecca Rose, Osmond J. D’Cruz, and Hong Ma http://jci.me/76610

Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory programSun-Mi Park, Mithat Gönen, Ly Vu, Gerard Minuesa, Patrick Tivnan, Trevor S. Barlowe, James Taggart, Yuheng Lu,

Raquel P. Deering, Nir Hacohen, Maria E. Figueroa, Elisabeth Paietta, Hugo F. Fernandez, Martin S. Tallman, Ari Melnick, Ross Levine, Christina Leslie, Christopher J. Lengner, and Michael G. Kharas http://jci.me/78440

PulmonologyEP3 receptor deficiency attenuates pulmonary hypertension through suppression of rho/TGF-β1 signalingAnkang Lu, Caojian Zuo, Yuhu He, Guilin Chen, Lingjuan Piao, Jian Zhang, Bing Xiao, Yujun Shen, Juan Tang, Deping Kong, Sara Alberti, Di Chen, Shenkai Zuo, Qianqian Zhang, Shuai Yan, Xiaochun Fei, Fei Yuan, Bin Zhou, Shengzhong Duan, Yu Yu, Michael Lazarus, Yunchao Su, Richard M. Breyer, Colin D. Funk, and Ying Yu http://jci.me/77656

Stem cellsVascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cellsJennifer L. Gori, Jason M. Butler, Yan-Yi Chan, Devikha Chandrasekaran, Michael G. Poulos, Michael Ginsberg, Daniel J. Nolan, Olivier Elemento, Brent L. Wood, Jennifer E. Adair, Shahin Rafii, and Hans-Peter Kiem http://jci.me/79328

Pluripotent stem cells reveal erythroid-specific activities of the GaTa1 N-terminus

Marta Byrska-Bishop, Daniel VanDorn, Amy E. Campbell, Marisol Betensky, Philip R. Arca, Yu Yao, Paul Gadue, Fernando F. Costa, Richard L. Nemiroff, Gerd A. Blobel, Deborah L. French, Ross C. Hardison, Mitchell J. Weiss, and Stella T. Chou http://jci.me/75714

Vaccinesantigen expression determines adenoviral vaccine potency independent of IFN and STING signalingKylie M. Quinn, Daniel E. Zak, Andreia Costa, Ayako Yamamoto, Kathrin Kastenmuller, Brenna J. Hill, Geoffrey M. Lynn, Patricia A. Darrah, Ross W.B. Lindsay, Lingshu Wang, Cheng Cheng, Alfredo Nicosia, Antonella Folgori, Stefano Colloca, Riccardo Cortese, Emma Gostick, David A. Price, Jason G.D. Gall, Mario Roederer, Alan Aderem, and Robert A. Seder http://jci.me/78280

Vascular biologyDisturbed flow-activated p90rSK kinase accelerates atherosclerosis by inhibiting SENP2 functionKyung-Sun Heo, Nhat-Tu Le, Hannah J. Cushman, Carolyn J. Giancursio, Eugene Chang, Chang-Hoon Woo, Mark A. Sullivan, Jack Taunton, Edward T.H. Yeh, Keigi Fujiwara, and Jun-ichi Abe http://jci.me/76453

ALL bone marrow

Hypoxic pulmonary artery

Endothelial cell engraftment

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Leishmaniasis is a disease caused by parasitic pro-tozoa that spread through bites by phlebotomine sandflies. More than twenty different protozoa in the Leishmania genus cause a spectrum of infec-tions, and the most severe forms account for the high morbidity and mortality associated with the disease. In this month’s issue of the JCI, a research team led by Thirumala-Devi Kanneganti explored the contribution of the inflammasome to T cell responses and leishmaniasis pathogenesis. The inflammasome is a multisubunit complex that is a critical regulator of the innate immune response to bacteria and viruses, but its role in parasitic in-fections has not been well studied. The research-ers found that mice with genetic loss of NLRP3, ASC, or caspase-1, components of the inflamma-some pathway, were deficient in IL-1β and IL-18 production and protected from Leishmania major infection. IL-18 production in vitro and in vivo was associated with IL-4 production and skewing of Th cells toward a Th2 polarization, consistent with previous observations that Th2 prevalence correlates with increased disease susceptibility. They further showed that neutralizing IL-18 with an IL-18–binding protein conferred protective ef-fects against L. major infection in WT mice. Col-lectively, their work offers new insights into the pivotal role of the inflammasome in leishmaniasis pathogenesis and suggests that strategies target-ing the inflammasome may confer therapeutic benefits. The accompanying 3D image shows BM-derived macrophages infected with L. major. The staining indicates macrophage nuclei (Hoechst, blue), mitochondria (Tom20, gray), and tubulin (purple). L. major are depicted in rainbow colors. Image credit: Clifford Guy.

The inflammasome promotes Leishmania infection by skewing Th cell polarization

Editor’s picksresearch

An NLRP3 inflammasome–triggered Th2-biased adaptive immune response promotes leishmaniasisPrajwal Gurung, Rajendra Karki, Peter Vogel, Makiko Watanabe, Mark Bix, Mohamed Lamkanfi, and Thirumala-Devi Kanneganti http://jci.me/79526

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Research | Editor’s picks

Histone/protein deacetylase 3 controls Treg function and developmentRegulatory t cells (tregs) maintain immune homeostasis, and Treg dysfunction is increasingly associated with inflammatory disease. Tregs are characterized by the expression of the transcription factor FOXP3 and an inability to produce the cytokine IL-2, which is required for T cell maintenance and survival. Liqing Wang and colleagues demonstrate that FOXP3+ Tregs require histone/protein deacetylase 3 (HDAC3) for their development and function. In murine models, conditional deletion of Hdac3 allowed Tregs to produce IL-2 and abrogated Treg immune-suppressive functions. The accompanying image shows colons in mice that received WT Tregs (top) and HDAC3-deficient Tregs (bottom) after induction of colitis. Hdac3-deficient mice died of autoimmunity at 4–6 weeks of age, but survival was prolonged if the mice were injected with WT FOXP3+ Tregs. Additionally, HDAC3 was required for the development of peripherally induced Tregs. Taken together, these data identify HDAC3 as a critical regulator of Treg function.

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3Liqing Wang, Yujie Liu, Rongxiang Han, Ulf H. Beier, Tricia R. Bhatti, Tatiana Akimova, Mark I. Greene, Scott W. Hiebert, and Wayne W. Hancock http://jci.me/77088

immunology

oncology

Elucidating the types of collagen cross-links in metastatic epithelial cancer

Pharmacological inhibition of WNT signaling ameliorates cholangiocarcinoma

epithelial tumor metastasis is preceded by stromal alterations, including increased stiffness induced by collagen cross-linking. To elucidate the biochemical nature of the collagen cross-links in cancer, Yulong Chen and colleagues examined human lung cancer specimens and a murine model of metastatic lung cancer and found that, compared with normal tissue, tumor stroma had higher amounts of hydroxylysine aldehyde–derived collagen cross-links (HLCCs) and lower amounts of lysine aldehyde–derived collagen cross-links (LCCs). Expression of lysyl hydroxylase 2 (LH2) in tumor cells increased the HLCC-to-LCC ratio in tumor stroma, enhanced stromal stiffness, and stimulated tumor cell invasion and metastasis. These findings suggest that the types of collagen cross-links in cancer may play

a crucial role in regulating stromal stiffness and determining tumor cell metastatic fate.

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stromaYulong Chen, Masahiko Terajima, Yanan Yang, Li Sun, Young-Ho Ahn, Daniela Pankova, Daniel S. Puperi, Takeshi Watanabe, Min P. Kim, Shanda H. Blackmon, Jaime Rodriguez, Hui Liu, Carmen Behrens, Ignacio I. Wistuba, Rosalba Minelli, Kenneth L. Scott, Johannah Sanchez-Adams, Farshid Guilak, Debananda Pati, Nishan Thilaganathan, Alan R. Burns, Chad J. Creighton, Elisabeth D. Martinez, Tomasz Zal, K. Jane Grande-Allen, Mitsuo Yamauchi, and Jonathan M. Kurie http://jci.me/74725

the incidence of cholangiogarcinoma is rising, and there are few effective treatments for the disease. A recent study demonstrated that a subset of liver fluke-associated cholangiocarcinomas have mutations that could enhance WNT signaling, leading Luke Boulter and colleagues to hypothesize that enhanced WNT signaling may also drive sporadic cholangiocarcinoma. Using multiple human and rodent models of cholangiocarcinoma, Boulter and colleagues demonstrate that the WNT pathway is upregulated in cholangiocarcinoma and that activation increases with disease progression. Pharmacological inhibition of the WNT pathway substantially reduced the size and number of tumors by reducing proliferation and inducing tumor cell apoptosis. In the accompanying Commentary, David Virshup discusses how these results support the investigation of WNT inhibitors in the treatment of cholangiocarcinoma.

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibitedLuke Boulter, Rachel V. Guest, Timothy J. Kendall, David H. Wilson, Davina Wojtacha, Andrew J. Robson, Rachel A. Ridgway, Kay Samuel, Nico Van Rooijen, Simon T. Barry, Stephen J. Wigmore, Owen J. Sansom, and Stuart J. Forbes http://jci.me/76452

Related CommentaryMoving upstream in the war on WNTsDavid M. Virshup http://jci.me/80819

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Research | Editor’s picks

neuroscience

Neuronal injuries of prematurity are determined by cerebral vessel maturation

Premature, very low-birth-weight newborns are at risk of developing a number of neuronal injuries, including periventricular leukomalacia (PVL), which is characterized by neuronal death in the brain regions around the ventricles. Tamar Licht, Talia Dor-Wollman, and colleagues hypothesized that vulnerability to PVL is determined by the immaturity of cerebral blood vessels within the periventricular regions during a specific gestational window. Vessel maturity is characterized by the acquisition of a functional blood-brain barrier and the end of a VEGF-dependent phase. Using a murine model of conditional VEGF loss of function, Licht, Dor-Wollman, and colleagues showed that periventricular vessels are the last cerebral vessels to mature. VEGF blockade immediately prior to, but not after, the critical gestational window selectively ablated the periventricular vessels and resulted in a PVL-like phenotype (see the accompanying image). This study establishes an animal model that replicates the temporal and spatial characteristics of PVL and suggests that damage to immature periventricular vessels underlies the disease. In the accompanying Attending Physician, Jason Boehme and Emin Maltepe discuss this study in terms of oxygen therapy in premature infants at risk for vascular injuries.

Vessel maturation schedule determines vulnerability to neuronal injuries of prematurityTamar Licht, Talia Dor-Wollman, Ayal Ben-Zvi, Gadiel Rothe, and Eli Keshet http://jci.me/79401

Related Attending PhysicianSpare hypoxia, spoil the child?Jason Boehme and Emin Maltepe http://jci.me/80820

Astrocytes, which are the most abundant cells in the human brain, participate in the formation and maintenance of the blood-brain barrier, provide metabolic support for neurons, modulate synaptic transmission, and participate in numerous pathological conditions and repair processes. It has been difficult to study human astrocyte function in intact, adult animal models, as rodents have fewer and less complex astrocytes than humans. In this issue, Hong Chen and colleagues injected human neural progenitors derived from embry-onic stem cells and induced pluripotent stem cells (iPSCs) into adult mouse spinal cord. The injected cells differentiated into astrocytes and gradually replaced the endogenous mouse astrocytes over a 9-month period, creating a “chimeric” spinal cord (see accompany-ing image). Moreover, iPSCs from patients with amyotrophic lateral sclerosis were able to integrate into the mouse spinal cord and cause functional deficits. These results indicate that this model could be used to study the function of human astrocytes in an intact CNS.

human-derived neural progenitors functionally replace astrocytes in adult miceHong Chen, Kun Qian, Wei Chen, Baoyang Hu, Lisle W. Blackbourn IV, Zhongwei Du, Lixiang Ma, Huisheng Liu, Karla M. Knobel, Melvin Ayala, and Su-Chun Zhang http://jci.me/69097

Star power: human astrocytes integrate into mouse spinal cord

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Krüppel-like factor 6 preserves mitochondrial function in podocytesPodocyte injury and apoptosis cause kidney diseases such as focal segmental glomerular sclerosis (FSGS), which is associated with mutations in genes involved in mitochondrial function. Sandeep Mallipattu and colleagues demonstrate that the transcription factor Krüppel-like factor 6 (KLF6) preserves mitochondrial function in podocytes. Compared with WT mice, Klf6-deficient mice exhibited substantially worse podocyte injury and developed FSGS after adriamycin treatment. Promoter analysis and chromatin immunoprecipitation studies identified putative KLF6-binding sites in the promoter regions of SCO2, which encodes a mitochondrial cytochrome c assembly protein that prevents activation of an apoptotic pathway. Moreover, KLF6 expression was reduced in kidney biopsies from patients with HIV-associated nephropathy and FSGS. In the accompanying Commentary, Jeffrey Kopp discusses how these results reveal a mechanism by which KLF6 maintains mitochondrial function to prevent podocyte apoptosis.

Krüppel-like factor 6 regulates mitochondrial function in the kidneySandeep K. Mallipattu, Sylvia J. Horne, Vivette D’Agati, Goutham Narla, Ruijie Liu, Michael A. Frohman, Kathleen Dickman, Edward Y. Chen, Avi Ma’ayan, Agnieszka B. Bialkowska, Amr M. Ghaleb, Mandayam O. Nandan, Mukesh K. Jain, Ilse Daehn, Peter Y. Chuang, Vincent W. Yang, and John C. He http://jci.me/77084

related commentaryLoss of Krüppel-like factor 6 cripples podocyte mitochondrial functionJeffrey B. Kopp http://jci.me/80280

Research | Editor’s picks

Longitudinal study tracks the long-term consequences of living kidney donationnearly one-third of transplant patients receive a kidney from a live donor. To assess the long-term effects of kidney donation on the function of the remaining kidney, Colin Lenihan and colleagues followed 21 adult living kidney donors using physiological and radiological assessments prior to donation, shortly after donation, and approximately 6 years after donation. They found that after donation, patients exhibited parallel increases in renal plasma flow, renocortical volume, and glomerular filtration rate that were sustained years later. Moreover, the researchers’ modeling of glomerular dynamics suggests that post-donation hyperfiltration was maintained primarily through renal hyperperfusion and glomerular hypertrophy rather than through glomerular hypertension. In the accompanying Commentary, Roland Blantz and Robert Steiner discuss how compensatory hypertrophy prevents the development of functional deficiencies in the long term.

Longitudinal study of living kidney donor glomerular dynamics after nephrectomyColin R. Lenihan, Stephan Busque, Geraldine Derby, Kristina Blouch, Bryan D. Myers, and Jane C. Tan http://jci.me/78885

related commentaryBenign hyperfiltration after living kidney donationRoland C. Blantz and Robert W. Steiner http://jci.me/80818

Parkinson’s disease (PD) is characterized by the progressive loss of midbrain dopaminergic neurons. The PDGFR agonist PDGF-BB has been shown previously to restore dopaminergic neurotransmission in animal models of PD. Based on these preclinical data, Gesine Paul and colleagues conducted a double-blind, randomized, placebo-controlled phase I/IIa clinical trial of recombinant human PDGF-BB in 12 patients with PD. All patients were implanted with an i.c.v. pump infusion system for delivery of PDGF-BB and were assigned to three different dosage groups. The investigators found that PDGF-BB treatment was well tolerated but that there were no dose-dependent changes in clinical rating scales. Patients receiving the highest dose of PDGF-BB exhibited improved dopamine transporter binding in the right putamen. In the accompanying

Commentary, Thomas Foltynie discusses the therapeutic use of growth factors in PD.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patientsGesine Paul, Olof Zachrisson, Andrea Varrone, Per Almqvist, Markus Jerling, Göran Lind, Stig Rehncrona, Bengt Linderoth, Hjalmar Bjartmarz, Lisa L. Shafer, Robert Coffey, Mikael Svensson, Katarina Jansson Mercer, Anton Forsberg, Christer Halldin, Per Svenningsson, Håkan Widner, Jonas Frisén, Sven Pålhagen, and Anders Haegerstrand http://jci.me/79635

related commentarycan Parkinson’s disease be cured by stimulating neurogenesis?Thomas Foltynie http://jci.me/80822

clinical trials

nephrology

Clinical trial of i.c.v. PDGFR agonist in patients with Parkinson’s disease

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review Series

Enteric nervous system

The enteric nervous system (ENS) encompasses extrinsic and intrinsic neurons, glia, and sensory epithelial cells that are embedded throughout the gastrointestinal tract. The circuits formed by these cells are respon-sible for interpreting sensory information in the gut lumen in order to regulate gut motility, secretion, food intake, and immune function. The ENS communicates with the CNS in a bidirectional manner (see the ac-companying image), allowing stimuli in the gut to influence mood, food intake, and behaviors. Reviews in this series examine the mechanisms by which the ENS develops from neural crest cells, the chemosensory mech-anisms that allow for the detection of and response to fats and other nu-trients within the gut lumen, the role of the enteric glia, the regulation of ENS function by the immune system and inflammation, and the impact of surgery and gut microbiota on ENS communication with the brain. Diego Bohórquez and series editor Rodger Liddle discuss the evolution of the field of neurogastroenterology, highlighting the expansion of the cell types and connections that contribute to ENS function, and propose that this neuronal ensemble be referred to as the “gut connectome.”

The gut connectome: making sense of what you eatDiego V. Bohórquez and Rodger A. Liddle http://jci.me/81121

Rodger liddle, M.D., is a Professor of Medicine at Duke University Medical Center. He is a member of Alpha Omega Alpha, the American Society for Clinical Investigation, and the Association of American Physicians. His research focuses on gastrointestinal hormone secretion, pancreatic physiology, and experimental models of pancreatitis. The Liddle laboratory developed the first reliable assay to measure cholecystokinin in blood. Most recently, they discovered that enteroendocrine cells have axon-like basal processes, termed neuropods, that communicate with neurons. These neuroepithelial circuits serve as sensory conduits that allow the luminal contents of the gut to interact with the nervous system, as well as a portal for viruses to access the enteric and central nervous systems.

The gut has a mind of its ownSeries Editor: Rodger A. liddle

Intestinal lipid–derived signals that sense dietary fatNicholas V. DiPatrizio and Daniele Piomelli

Building a second brain in the bowelMarina Avetisyan, Ellen Merrick Schill, and Robert O. Heuckeroth

Gut chemosensing mechanismsArianna Psichas, Frank Reimann, and Fiona M. Gribble

Emerging roles for enteric glia in gastrointestinal disordersKeith A. Sharkey

Gut/brain axis and the microbiotaEmeran A. Mayer, Kirsten Tillisch, and Arpana Gupta

roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanismsSean Manning, Andrea Pucci, and Rachel L. Batterham

colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colonGary M. Mawe

Emerging roles of gut microbiota and the immune system in the development of the enteric nervous systemPanagiotis S. Kabouridis and Vassilis Pachnis

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Review Series | Enteric nervous system

The microbiota as a mediator of gut-brain interactionsthe gut/brain axis refers to the bidirectional neurohumoral communication system that connects the gastrointestinal tract and the nervous system. Alterations in this system have been linked to functional gastrointestinal disorders such as irritable bowel syndrome (IBS), as well as neurological disorders such as autism spectrum disorders, Parkinson’s disease, mood disorders, and chronic pain. The intestinal microbiota and its metabolites also participate in gut-brain communication, and preclinical studies suggest that the microbiota modulates behavior and brain processes as well as gastrointestinal function. However, there is a dearth of clinical evidence, and the translatability of preclinical studies is unclear. Emeran Mayer and colleagues review both the preclinical and clinical evidence for the effects of gut microbial alterations on brain development, brain function, and behavior and discuss how future translational research can address the role of the gut microbiota in human health and disease.

Gut/brain axis and the microbiotaEmeran A. Mayer, Kirsten Tillisch, and Arpana Gupta http://jci.me/76304

Sensing dietary fat in the gutFat is a critical nutrient that plays a complex role in the control of energy homeostasis. Humans have evolved multiple chemosensory and neural mechanisms that monitor fat intake and optimize the seeking, sensing, and storage of fat. Unfortunately, this hard-wired attraction to fat has lost much of its value in contemporary societies, as fatty foods are easily attainable. In this issue, Nicholas DiPatrizio and Daniele Piomelli review the mechanisms by which fat is sensed throughout the alimentary canal. Dietary fat is sensed first in the mouth, in which it induces signals that stimulate food intake, including gut endocannabinoids. As dietary fats enter the gut, they promote satiety by stimulating the production of anorexic lipid mediators. Coordination of these “stop” and “go” signals ultimately controls feeding behavior (see the accompanying image).

Intestinal lipid–derived signals that sense dietary fatNicholas V. DiPatrizio and Daniele Piomelli http://jci.me/76302

Immune and microbial influences shape the enteric nervous systemDuring embryogenesis, the development of neurons and glial cells in the enteric nervous system is guided by neural crest cell–intrinsic factors and the gut mesenchyme. Postnatally, the enteric nervous system continues to develop, with continued neurogenesis and gliogenesis; however, this development occurs in the presence of the microbiota and immune system. Panagiotis Kabouridis and Vassilis Pachnis review the effects of the gut microbiota and immune system on embryonic and early postnatal enteric nervous system development. Importantly, there is increasing evidence that the microbiota and the innate immune system of the gut mucosa regulate synaptogenesis and synaptic transmission in both development and disease. These findings indicate that intestinal infections and antibiotics could have potentially profound effects on the function of the enteric nervous system.

Emerging roles of gut microbiota and the immune system in the development of the enteric nervous systemPanagiotis S. Kabouridis and Vassilis Pachnis http://jci.me/76308

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Colonic motility is the result of a coordinated series of excitatory and inhibitory neuromuscular signals controlled by the enteric nervous system. Recent studies have indicated that inflammation leads to alterations in the physiological properties of the neuronal circuitry in this region, disrupting motor activity in the colon. In this issue, Gary Mawe details the components of the enteric nervous

system that mediate propulsive motility and the alterations that are induced by inflammation, including hyperexcitability of afferent neurons, synaptic facilitation, and attenuated inhibitory neurotransmission. Additionally, Mawe discusses the links between inflammation-induced neuroplasticity and disrupted colonic motility that characterize inflammatory bowel disease and other

functional gastrointestinal disorders (see the accompanying image).

colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colonGary M. Mawe http://jci.me/76306

Review Series | Enteric nervous system

Inflammation, neuroplasticity, and gastric motility

the enteric nervous system (ens) is a complex network of neurons and glia within the myenteric and submucosal plexuses of the bowel. The myenteric plexus, located between the longitudinal and circular muscles, primarily controls contraction and relaxation, while the submucosal plexus, located between the circular muscle and bowel mucosa, regulates fluid secretion and absorption and responds to stimuli in the gut epithelium and lumen. Defects in the ENS are likely to underlie disorders such as irritable

bowel syndrome, gastroparesis, Hirschsprung disease, and chronic intestinal pseudoobstruction syndrome. Robert Heuckeroth and colleagues review the mechanisms governing ENS development and discuss how insights into these processes can aid our understanding and treatment of related disorders.

Building a second brain in the bowelMarina Avetisyan, Ellen Merrick Schill, and Robert O. Heuckeroth http://jci.me/76307

Mechanisms of enteric nervous system development

Enteric glia in gastrointestinal disordersinitially regarded as passive support cells, enteric glia have emerged recently as important components of the enteric nervous system. Enteric glia are located in the myenteric and submucosal plexuses, in which they form cellular and molecular connections among enteric nerves, enteroendocrine cells, immune cells, and epithelial cells. In this issue, Keith Sharkey reviews the physiological roles of the enteric glia and examines how their dysfunction can contribute to pathophysiology. The enteric glia modulate gastrointestinal motility and secretion and regulate barrier and immune functions within the mucosa. Notably, these cells participate in CNS disorders and are known to be involved in prion diseases and Parkinson’s disease.

Emerging roles for enteric glia in gastrointestinal disordersKeith A. Sharkey http://jci.me/76303

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Review Series | Enteric nervous system

the enteroendocrine system is the largest endocrine organ in the body and is responsible for sensing and responding to stimuli within the gut lumen. Enteroendocrine cells are scattered throughout the stomach, small intestine, and colon, with cells in each region producing a particular set of hormones that regulate gut motility, glucose homeostasis, and appetite.

GPCRs serve as the primary sensors in enteroendocrine cells, and they respond to carbohydrates, proteins, lipids, and nonnutrient stimuli such as inflammatory cytokines and bile acids. Fiona Gribble and colleagues review the mechanisms underpinning nutrient and nonnutrient chemosensing, focusing on the release of incretins, which act on pancreatic β

cells to modulate glucose-stimulated insulin secretion.

Gut chemosensing mechanismsArianna Psichas, Frank Reimann, and Fiona M. Gribble http://jci.me/76309

A new outlook on revitalizing physician-scientist trainingWith extensive training in both medicine and research, physician-scientists provide an important perspective on solving the most vexing problems in biomedical research. However, the percentage of physician-scientist has dwindled in recent years, and young trainees face enormous challenges on their path to becoming independent investigators. In this month’s JCI, a group of early-career and in-training physician-scientists discuss obstacles that hinder trainees and highlight potential changes within institutions and funding agencies that may provide better support. Dania Daye et al. explore a variety of training avenues and key transition points that contribute to attrition of trainees. Notably, the authors offer their recommendations for restructuring training programs, reducing total training time, and establishing more institutional support for the transition to independence. Such efforts to revitalize the pipeline might ultimately contribute to better retention and more successful independent physician-scientists.

challenges and opportunities for reinvigorating the physician-scientist pipelineDania Daye, Chirag B. Patel, Jaimo Ahn, and Freddy T. Nguyen http://jci.me/80933

Bariatric surgery is the most effective treatment for severe obesity. The most common form of the procedure, Roux-en-Y gastric bypass (RYGBP), is a gastric restrictive procedure that causes intestinal malabsorption. Research over the past decade has demonstrated that, in addition to restricting food intake and nutrient absorption, RYGBP mediates weight loss by altering feeding behavior. Rachel Batterham and colleagues review studies detailing RYGBP-associated physiological alterations that govern feeding behavior. The anatomical modifications of the surgery decrease the length of time that nutrients spend in the stomach and upper bowel, resulting in increased secretion of the gut hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) and augmentation of enteroendocrine melanocortin 4 receptor (MC4R) (see the accompanying image). Other potential mechanisms include changes in vagal nerve signaling, gut microbiota composition, and bile secretion.

roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms

Sean Manning, Andrea Pucci, and Rachel L. Batterham http://jci.me/76305

Chemosensing mechanisms of the gut enteroendocrine system

perspective

Mechanisms underlying changes in food intake after gastric bypass

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