Great excitement greeted the discovery a few years ago that certain cells from mice and humans could be reprogrammed to become inducible pluripotent stem cells (iPS cells), as they hold promise for cell replacement therapy and modeling human disease. Two independent research groups — one led by Ludovic Vallier, at the University of Cambridge, United Kingdom, and the other led by Holger Willenbring, at the University of California San Francisco — have now shown that both possibilities are true for iPS cell–derived liver cells known as hepatocytes.
In the first study, Vallier and colleagues generated iPS cells from patients with various inherited diseases of the liver. These cells were then cultured in a defined way to generate hepatocytes, which were found to recapitulate key features of the diseases affecting the patients from which they were derived. While this study indicates that iPS cells can be used to model diseases of the liver, Willenbring and colleagues showed that iPS cell–derived hepatocytes have both the functional and proliferative capabilities needed for liver regeneration in mice. In an accompanying commentary, Linda Greenbaum, at Thomas Jefferson University School of Medicine, Philadelphia, describes how these studies have extended our understanding of the potential for iPS cells to be used for cell replacement therapy and modeling human disease.
TITLE: Induced pluripotent stem cell–derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice
AUTHOR CONTACT:
Holger Willenbring
University of California San Francisco, San Francisco, California, USA.
Phone: 415.476.2417; Fax: 415.514.2346; E-mail: willenbringh@stemcell.ucsf.edu.
View this article at: http://www.jci.org/articles/view/43267?key=3a682a87848af072f6bc
ACCOMPANYING ARTICLE
TITLE: Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells
AUTHOR CONTACT:
Ludovic Vallier
University of Cambridge, Cambridge, United Kingdom.
Phone: 44.1223.747489; Fax: 44.1223.763350; E-mail: lv225@cam.ac.uk.
S. Tamir Rashid
University of Cambridge, Cambridge, United Kingdom.
Phone: 44.1223.747489; Fax: 44.1223.763350; E-mail: str29@cam.ac.uk.
View this article at: http://www.jci.org/articles/view/43122?key=834cc7f6d8b865c5ba88
ACCOMPANYING COMMENTARY
TITLE: From skin cells to hepatocytes: advances in application of iPS cell technology
AUTHOR CONTACT:
Linda E. Greenbaum
Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.503.6345; Fax: 215.503.6282; E-mail: Linda.greenbaum@jefferson.edu.
View this article at: http://www.jci.org/articles/view/44422?key=514b3b37b543850064a2
BACTERIOLOGY: Antifreeze molecule enhances survival of bacteria-carrying ticks
Ticks can carry and transmit to humans disease-causing bacteria. For example, the black-legged tick, Ixodes scapularis, can transmit several bacteria that cause disease in humans, including Anaplasma phagocytophilum, which causes human granulocytic anaplasmosis, a disease characterized by fever, severe headache, muscle aches, chills, and shaking. If bacteria can in any way enhance the survival of the ticks that transmit them, this increases their likelihood of infecting a human, thereby impacting human health. A team of researchers, led by Erol Fikrig, at Yale University School of Medicine, New Haven, has now determined that Anaplasma phagocytophilum induces Ixodes scapularis ticks to express an antifreeze molecule that enhances tick survival in the cold. As Ixodes scapularis ticks overwinter in the US in the Northeast and Upper Midwest, this likely increases the number of Anaplasma phagocytophilum available to infect humans. As noted by Stephen Dumler, at The Johns Hopkins University School of Medicine, Baltimore, in an accompanying commentary, these data highlight how important understanding ecology and tick biology can be to unraveling the intricacies of human disease.
TITLE: Anaplasma phagocytophilum induces Ixodes scapularis ticks to express an antifreeze glycoprotein gene that enhances their survival in the cold
AUTHOR CONTACT:
Erol Fikrig
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203.785.4140; Fax: 203.785.3864; Email: erol.fikrig@yale.edu.
View this article at: http://www.jci.org/articles/view/42868?key=84783f9002c86e2c3682
ACCOMPANYING COMMENTARY TITLE: Fitness and freezing: vector biology and human health
AUTHOR CONTACT:
J. Stephen Dumler
The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: 410.955.8654; Fax: 443.287.3665; E-mail sdumler@jhmi.edu.
View this article at: http://www.jci.org/articles/view/44402?key=755d15fe8a48aab7f4bf
BACTERIOLOGY: Immune interference, an explanation for vaccine failure?
Infection with Staphylococcus aureus bacteria is a major cause of bloodstream, lower respiratory tract, and skin and soft tissue infections. Given the dramatic increase in the number of infections caused by methicillin-resistant Staphylococcus aureus (MRSA), a Staphylococcus aureus vaccine is much needed. However, vaccines developed thus far have failed to induce protection in clinical trials, and even prior infection with the bacterium fails to engender protection against subsequent infection. A team of researchers, led by Gerald Pier, at Brigham and Women's Hospital, Harvard Medical School, Boston, has now generated data in mice to explain why vaccines and prior infection do not provide individuals with protection from Staphylococcus aureus.
In the study, immune molecules known as antibodies that target the Staphylococcus aureus components CP and PNAG were each shown to indirectly mediate bacterial killing in vitro and to provide protection in mouse models of Staphylococcus aureus infection. However, when mixed together, in vitro killing and in vivo protection were markedly reduced because the antibodies interfered with each other. Further analysis indicated that interference occurred because the parts of the antibodies that bound CP and PNAG interacted with each other in a process known as idiotype–anti-idiotype binding. Similar binding was observed for antibodies isolated from humans with Staphylococcus aureus bloodstream infections. As noted by the authors, and Liise-anne Pirofski, at Albert Einstein College of Medicine, New York, in an accompanying commentary, this identification of a mechanism to explain the inability of humans to mount good protective antibody responses to Staphylococcus aureus should help in the design of future candidate vaccines.
TITLE: Animal and human antibodies to distinct Staphylococcus aureus antigens mutually neutralize opsonic killing and protection in mice
AUTHOR CONTACT:
Gerald B. Pier
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.525.2269; Fax: 617.525.2510; E-mail: gpier@channing.harvard.edu.
View this article at: http://www.jci.org/articles/view/42748?key=3a012e00c5523492efec
ACCOMPANYING COMMENTARY
TITLE: Why antibodies disobey the Hippocratic Oath and end up doing harm: a new clue
AUTHOR CONTACT:
Liise-anne Pirofski
Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York, USA.
Phone: 718.430.2940; Fax: 718.430.8969; E-mail: l.pirofski@einstein.yu.edu.
View this article at: http://www.jci.org/articles/view/44312?key=ce1d90308e111364240f
PULMONARY: New cystic fibrosis models teach us about disease
Cystic fibrosis (CF) is caused by genetic mutations that disrupt the function of the protein CFTR. Although many organs are affected in cystic fibrosis, the most life-threatening aspect of the disease is lung disease. To understand this more deeply, animal models of cystic fibrosis that more closely mimic the human disease than do mouse models are needed. To this end, three independent research groups — one led by Kevin Foskett, at the University of Pennsylvania, Philadelphia; one led by John Engelhardt, at the University of Iowa, Iowa City; and one led by Jeffrey Wine, at Stanford University, Stanford — have analyzed pig and ferret models of cystic fibrosis and determined that they represent good models of lung disease in individuals with cystic fibrosis. As concluded by each of the authors and noted by Jonathan Widdicombe, at the University of California Davis, Davis, in an accompanying commentary, these animals will prove valuable models to both further understanding of the mechanisms underlying lung disease in individuals with cystic fibrosis and test potential therapies.
TITLE: cAMP-activated Ca2+ signaling is required for CFTR-mediated serous cell fluid secretion in porcine and human airways
AUTHOR CONTACT:
J. Kevin Foskett
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.898.1354; Fax: 215.573.6808; E-mail: foskett@mail.med.upenn.edu.
View this article at: http://www.jci.org/articles/view/42992?key=af5b5b0df227f939052b
ACCOMPANYING ARTICLE
TITLE: Hyposecretion of fluid from tracheal submucosal glands of CFTR-deficient pigs
AUTHOR CONTACT:
Jeffrey J. Wine
Stanford University, Stanford, California, USA.
Phone: 650.725.2462; Fax: 650.725.5699; E-mail: wine@stanford.edu.
View this article at: http://www.jci.org/articles/view/43466?key=6b72a10f5d9f1504504b
ACCOMPANYING ARTICLE
TITLE: Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis
AUTHOR CONTACT:
John F. Engelhardt
College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Phone: 319.335.7744; Fax: 319.335.6581; E-mail: john-engelhardt@uiowa.edu.
View this article at: http://www.jci.org/articles/view/43052?key=954f356c61df718ed22d
ACCOMPANYING COMMENTARY
TITLE: Transgenic animals may resolve a sticky situation in cystic fibrosis
AUTHOR CONTACT:
Jonathan H. Widdicombe
University of California Davis, Davis, California, USA.
Phone: 530.754.7369; Fax: 530.752.5423; E-mail: jhwiddicombe@ucdavis.edu
View this article at: http://www.jci.org/articles/view/44235?key=89c99c871e85be1bf3e9
REPRODUCTIVE BIOLOGY: Long standing question in sperm biology answered
Nahum Sonenberg, Bernard Robaire, and colleagues, at McGill University, Montreal, have generated data in mice that provides insight into a long unanswered question in sperm biology. Specifically, how protein expression is regulated in the late stages of sperm development. The importance of these data are outlined in an accompanying commentary by Stephen Liebhaber and colleagues, at the University of Pennsylvania, Philadelphia.
A protein in a cell is made from a template known as an mRNA molecule, which in turn is a copy of the information contained in a gene. About half way through sperm development, mRNA formation ceases so the mRNA templates for proteins needed in the late stages of sperm development must be made early in development and stored. Understanding of the mechanisms that underlie mRNA storage and subsequent activation has been long sought after. In the study, Sonenberg, Robaire, and colleagues find that mice lacking the protein Paip2a and mice lacking Paip2a and Paip2b exhibit male infertility associated with impaired activation of stored mRNAs. Further analysis indicated that aberrant increased expression of the protein Pabp caused the impaired activation of stored mRNAs, leading the authors to conclude that mRNA activation in late sperm development requires an optimal concentration of Pabp, as determined by Paip2a.
TITLE: The poly(A)-binding protein partner Paip2a controls translation during late spermiogenesis in mice
AUTHOR CONTACT: Nahum Sonenberg McGill University, Montreal, Quebec, Canada. Phone: 514.398.7274; Fax: 514.398.1287; E-mail: nahum.sonenberg@mcgill.ca.
Bernard Robaire McGill University, Montreal, Quebec, Canada. Phone: 514.398.3630; Fax: 514.398.7120; E-mail: bernard.robaire@mcgill.ca.
View this article at: http://www.jci.org/articles/view/43350?key=84be9f4aaad65b96fac4
ACCOMPANYING COMMENTARY TITLE: Too much PABP, too little translation
AUTHOR CONTACT: Stephen A. Liebhaber University of Pennsylvania, Philadelphia, Pennsylvania, USA. Phone: (215) 898-7834; Fax: (215) 573-5157; E-mail: liebhabe@mail.med.upenn.edu.
View this article at: http://www.jci.org/articles/view/44091?key=c69e6c286dc403b6278f
Journal
Journal of Clinical Investigation