Hélène Gilgenkrantz

Université René Descartes - Paris 5, Lutetia Parisorum, Île-de-France, France

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Publications (75)413.47 Total impact

  • Hélène Gilgenkrantz
    Medecine sciences: M/S 04/2015; 31(4):357-9. DOI:10.1051/medsci/20153104004 · 0.67 Impact Factor
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    Hélène Gilgenkrantz
    Medecine sciences: M/S 12/2014; 30(12):1066-9. DOI:10.1051/medsci/20143012004 · 0.67 Impact Factor
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    ABSTRACT: Growth hormone (GH) pathway has been shown to play a major role in liver regeneration through the control of EGFR activation. This pathway is downregulated in non-alcoholic fatty liver disease (NAFLD). Since regeneration is known to be impaired in fatty livers, we wondered whether a deregulation of the growth hormone/EGFR pathway could explain this deficiency. Hepatic EGFR expression and triglyceride levels were quantified in liver biopsies of thirty-two obese patients with different degrees of steatosis. We showed a significant inverse correlation between liver EGFR expression and the level of hepatic steatosis. GH/EGFR downregulation was also demonstrated in two steatosis mouse models, a genetic (ob/ob) and a methionine and choline deficient (MCD) diet mouse model, in correlation with liver regeneration defect. Ob/ob mice exhibited a more severe liver regeneration defect after partial hepatectomy (PH) than MCD diet fed mice, a difference that could be explained by a decrease in STAT3 phosphorylation 32h after PH. Having checked that GH deficiency accounted for the GH signaling pathway downregulation in the liver of ob/ob mice, we showed that GH administration in these mice led to a partial rescue in hepatocyte proliferation after partial hepatectomy associated with a concomitant restoration of liver EGFR expression and STAT3 activation. In conclusion, we propose that the GH/EGFR pathway downregulation is a general mechanism responsible for liver regeneration deficiency associated with steatosis, which could be partially rescued by GH administration.
    Endocrinology 04/2014; 155(7):en20141010. DOI:10.1210/en.2014-1010 · 4.50 Impact Factor
  • Hélène Gilgenkrantz
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    ABSTRACT: Since many years, Wnt canonical pathway was known to be involved in proliferation and cell fate. More recently, Hippo pathway has been recognized as a major actor in the control of organ size homeostasis. Both pathways are induced in the activation of stem cells, modulated during carcinogenesis and both use a second messenger, a cascade of phosphorylations and the same ubiquitin ligase degradation complex. Enough for their roads to cross! This review highlights the recent advances in the understanding of the complex crosstalks between Wnt/β-catenin and Hippo/YAP pathways, focusing on two tissues, liver and intestine. In the future, we hope that the identification of the molecular mechanisms underlining these entangled relationships will open towards novel therapeutic strategies for digestive carcinogenesis.
    Medecine sciences: M/S 10/2013; 29(10):868-74. DOI:10.1051/medsci/20132910014 · 0.67 Impact Factor
  • Annales de Pathologie 11/2012; 32(5):S143. DOI:10.1016/j.annpat.2012.09.180 · 0.29 Impact Factor
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    ABSTRACT: Unraveling the molecular clues of liver proliferation has become conceivable thanks to the model of two-third hepatectomy. The synchronicity and the well-scheduled aspect of this process allow scientists to slowly decipher this mystery. During this phenomenon, quiescent hepatocytes of the remnant lobes are able to reenter into the cell cycle initiating the G1-S progression synchronously before completing the cell cycle. The major role played by this step of the cell cycle has been emphasized by loss-of-function studies showing a delay or a lack of coordination in the hepatocytes G1-S progression. Two growth factor receptors, c-Met and EGFR, tightly drive this transition. Due to the level of complexity surrounding EGFR signaling, involving numerous ligands, highly controlled regulations and multiple downstream pathways, we chose to focus on the EGFR pathway for this paper. We will first describe the EGFR pathway in its integrity and then address its essential role in the G1/S phase transition for hepatocyte proliferation. Recently, other levels of control have been discovered to monitor this pathway, which will lead us to discuss regulations of the EGFR pathway and highlight the potential effect of misregulations in pathologies.
    09/2012; 2012:476910. DOI:10.1155/2012/476910
  • A Mignon · JE Guidotti · C Mitchell · M Fabre · H Gilgenkrantz
    08/2012; 14(10):1147. DOI:10.4267/10608/930
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    ABSTRACT: Intrahepatic malignant tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and combined hepatocholangiocarcinomas (cHCC-CC), a group of rare and poorly characterized tumours that exhibit both biliary and hepatocytic differentiation. The aim of the study was to characterize the molecular pathways specifically associated with cHCC-CC pathogenesis. We performed a genome-wide transcriptional analysis of 20 histologically defined cHCC-CC and compared them with a series of typical HCC and of CC. Data were analysed by gene set enrichment and integrative genomics and results were further validated in situ by tissue microarray using an independent series of 152 tumours. We report that cHCC-CC exhibit stem/progenitor features, a down-regulation of the hepatocyte differentiation program and a commitment to the biliary lineage. TGFβ and Wnt/β-catenin were identified as the two major signalling pathways activated in cHCC-CC. A β-catenin signature distinct from that observed in well-differentiated HCC with mutant β-catenin was found in cHCC-CC. This signature was associated with microenvironment remodelling and TGFβ activation. Furthermore, integrative genomics revealed that cHCC-CC share characteristics of poorly differentiated HCC with stem cell traits and poor prognosis. The common traits displayed by CC, cHCC-CC and some HCC suggest that these tumours could originate from stem/progenitor cell(s) and raised the hypothesis of a potential continuum between intrahepatic CC, cHCC-CC and poorly differentiated HCC.
    Carcinogenesis 06/2012; 33(9):1791-6. DOI:10.1093/carcin/bgs208 · 5.33 Impact Factor
  • Hélène Gilgenkrantz · Christine Perret
    Medecine sciences: M/S 03/2012; 28(3):269-71. DOI:10.1051/medsci/2012283014 · 0.67 Impact Factor
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    ABSTRACT: GH is a pleiotropic hormone that plays a major role in proliferation, differentiation, and metabolism via its specific receptor. It has been previously suggested that GH signaling pathways are required for normal liver regeneration but the molecular mechanisms involved have yet to be determined. The aim of this study was to identify the mechanisms by which GH controls liver regeneration. We performed two thirds partial hepatectomies in GH receptor (GHR)-deficient mice and wild-type littermates and showed a blunted progression in the G(1)/S transition phase of the mutant hepatocytes. This impaired liver regeneration was not corrected by reestablishing IGF-1 expression. Although the initial response to partial hepatectomy at the priming phase appeared to be similar between mutant and wild-type mice, cell cycle progression was significantly blunted in mutant mice. The main defect in GHR-deficient mice was the deficiency of the epidermal growth factor receptor activation during the process of liver regeneration. Finally, among the pathways activated downstream of GHR during G(1) phase progression, namely Erk1/2, Akt, and signal transducer and activator of transcription 3, we only found a reduced Erk1/2 phosphorylation in mutant mice. In conclusion, our results demonstrate that GH signaling plays a major role in liver regeneration and strongly suggest that it acts through the activation of both epidermal growth factor receptor and Erk1/2 pathways.
    Endocrinology 07/2011; 152(7):2731-41. DOI:10.1210/en.2010-1193 · 4.50 Impact Factor
  • Hélène Gilgenkrantz
    Medecine sciences: M/S 06/2011; 27(6-7):587-9. DOI:10.1051/medsci/2011276009 · 0.67 Impact Factor
  • H Gilgenkrantz · A Collin de l'Hortet
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    ABSTRACT: Even if the Greeks probably anticipated rather than discovered the extraordinary regenerative capacity of the liver with the Prometheus myth, this phenomenon still fascinates scientists nowadays with the same enthusiasm. There are good reasons to decipher this process other than to find an answer to our fantasy of immortality: it could indeed help patients needing large liver resections or living-donor liver transplantation, it could increase our understanding of liver pathology and finally it could enable novel cell-therapy approaches. For decades, most of our knowledge about the mechanisms involved in liver regeneration came from the classic two-thirds partial hepatectomy (PH) model. In this scenario, hepatocytes play the leading role, which raises the question of the simple existence of a stem cell population. Recently however, hepatic progenitor cells come again under the limelight, seeming to play a role in liver physiology and in various liver diseases such as steatosis or cirrhosis. Excellent reviews have recently addressed liver regeneration. Our goal is therefore to focus on recent improvements in the field, highlighting data mostly published in the last two years in order to draw a putative picture of what the future research axes on liver regeneration might look like.
    Gastroentérologie Clinique et Biologique 05/2011; 35(10):623-9. DOI:10.1016/j.clinre.2011.04.002 · 1.64 Impact Factor
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    ABSTRACT: It has been suggested that increasing age is correlated with an acceleration of the progression of liver fibrosis induced by various agents, such as hepatitis C virus or chronic alcohol consumption. However, the cellular and molecular changes underlying this predisposition are not entirely understood. In the context of an aging population, it becomes challenging to decipher the mechanisms responsible for this higher susceptibility of older individuals to this acquired liver disorder. To address this issue, we induced liver fibrosis by carbon tetrachloride (CCl(4)) chronic administration to 8-week- and 15-month-old mice. We confirmed that susceptibility to fibrosis development increased with age and showed that aging did not affect fibrosis resolution capacity. We then focused on the impairment of hepatocyte proliferation, oxidative stress, and inflammation as potential mechanisms accelerating the development of fibrosis in the elderly. We detected no inhibition of hepatocyte proliferation after CCl(4) injury in 15-month-old mice, whereas it was inhibited after a partial hepatectomy. Finally, we observed that, in a context in which liver oxidative stress was not differentially increased in both experimental groups, there was a higher recruitment of inflammatory cells, including mostly macrophages and lymphocytes, oriented toward a T helper 2 (T(H)2) response in older mice. Our data show that in conditions of equivalent levels of oxidative stress and maintained hepatocyte proliferative capacity, an increased inflammatory reaction mainly composed of CD4(+) lymphocytes and macrophages expressing T(H)2 cytokines is the main factor involved in the higher susceptibility to fibrosis with increasing age.
    Rejuvenation Research 05/2011; 14(4):353-63. DOI:10.1089/rej.2010.1146 · 3.31 Impact Factor
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    ABSTRACT: The role of hepatocyte apoptosis in the physiopathology of obstructive cholestasis is still controversial. Although some data have strongly suggested that hepatocellular cholestatic injury is due to Fas-mediated hepatocyte apoptosis, some others concluded that necrosis, rather than apoptosis, represents the main type of hepatocyte death in chronic cholestasis. Moreover, it has also been suggested that the reduced liver injury observed in the absence of Fas receptor after bile duct ligation was not due to lower hepatocyte apoptosis but to the indirect role of this receptor in non-hepatocytic cells such as cholangiocytes and inflammatory cells. The aim of this work was therefore to determine whether a protection against cell death limited to hepatocytes could be sufficient to reduce liver injury and delay cholestatic fibrosis. With this purpose, we performed bile duct ligation in transgenic mice overexpressing Bcl-2 in hepatocytes and in wild-type littermates. We found that, compared with necrosis, apoptosis was negligible in this model. Our results also showed that hepatocyte Bcl-2 expression protected hepatocytes against liver injury only in the early steps of the disease. This protection was correlated with reduced mitochondrial dysfunction and lipid peroxidation. However, in contrast to Fas receptor-deficient lpr mice, fibrosis progression was not hampered and liver inflammatory response was not reduced by Bcl-2 overexpression. These results therefore comfort the hypothesis that Fas-mediated apoptotic hepatocyte pathway is not a significant contributing factor to the clinical features observed in cholestasis. Moreover, in the absence of a blunted inflammatory response in transgenic mice, Bcl-2 protection against hepatocyte mitochondrial dysfunction and lipid peroxidation was not sufficient to block fibrosis progression.
    Laboratory Investigation 02/2011; 91(2):273-82. DOI:10.1038/labinvest.2010.163 · 3.68 Impact Factor
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    ABSTRACT: To develop and validate a transient micro-elastography device to measure liver stiffness (LS) in mice. A novel transient micro-elastography (TME) device, dedicated to LS measurements in mice with a range of measurement from 1-170 kPa, was developed using an optimized vibration frequency of 300 Hz and a 2 mm piston. The novel probe was validated in a classical fibrosis model (CCl(4)) and in a transgenic murine model of systemic amyloidosis. TME could be successfully performed in control mice below the xiphoid cartilage, with a mean LS of 4.4 ± 1.3 kPa, a mean success rate of 88%, and an excellent intra-observer agreement (0.98). Treatment with CCl(4) over seven weeks drastically increased LS as compared to controls (18.2 ± 3.7 kPa vs 3.6 ± 1.2 kPa). Moreover, fibrosis stage was highly correlated with LS (Spearman coefficient = 0.88, P < 0.01). In the amyloidosis model, much higher LS values were obtained, reaching maximum values of > 150 kPa. LS significantly correlated with the amyloidosis index (0.93, P < 0.0001) and the plasma concentration of mutant hapoA-II (0.62, P < 0.005). Here, we have established the first non-invasive approach to measure LS in mice, and have successfully validated it in two murine models of high LS.
    World Journal of Gastroenterology 02/2011; 17(8):968-75. DOI:10.3748/wjg.v17.i8.968 · 2.37 Impact Factor
  • Journal of Hepatology 04/2010; 52. DOI:10.1016/S0168-8278(10)60938-5 · 11.34 Impact Factor
  • Dominique Labie · Hélène Gilgenkrantz
    Medecine sciences: M/S 03/2010; 26(3):225-6. DOI:10.1051/medsci/2010263225 · 0.67 Impact Factor
  • Hélène Gilgenkrantz
    Medecine sciences: M/S 01/2010; 1(26):107-8. · 0.67 Impact Factor
  • Helène Gilgenkrantz
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    ABSTRACT: The liver has an extraordinary faculty to regenerate. Hepatocytes are highly differentiated cells that, despite a resting G0 state in the normal quiescent liver, can re-enter the cell cycle to reconstitute the organ after an injury. However, the first cell therapy approaches trying to harness this specific characteristic of the hepatocytes came up against the competition with resident hepatocytes in the ability to proliferate. This review will describe the different rodent models that have been developed in the last 15 years to demonstrate the concept of liver repopulation with transplanted cells harbouring a selective advantage over resident hepatocytes. Examples will then be given to show how these models demonstrated the therapeutic efficiency of cell transplantation in specific disorders. The transplantation of human hepatocytes into some of these mouse models led to the creation of humanized livers. These humanized mice provide a powerful tool to study the physiopathology of human hepatotropic pathogens and to develop drugs against them. Finally, emphasis will be placed on the role of these rodent models in the demonstration of the hepatocytic potential of stem cells.
    Methods in molecular biology (Clifton, N.J.) 01/2010; 640:475-90. DOI:10.1007/978-1-60761-688-7_26 · 1.29 Impact Factor
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    ABSTRACT: Accumulating evidence indicates that oxidative stress is involved in the physiopathology of liver fibrogenesis. However, amid the global context of hepatic oxidative stress, the specific role of hepatocyte mitochondrial dysfunction in the fibrogenic process is still unknown. The aim of this study was to determine whether a targeted protection of hepatocytes against mitochondrial dysfunction could modulate fibrosis progression. We induced liver fibrogenesis by chronic carbon tetrachloride treatment (3 or 6 weeks of biweekly injections) in transgenic mice expressing Bcl-2 in their hepatocytes or in normal control mice. Analyses of mitochondrial DNA, respiratory chain complexes, and lipid peroxidation showed that Bcl-2 transgenic animals were protected against mitochondrial dysfunction and oxidative stress resulting from carbon tetrachloride injury. Picrosirius red staining, alpha-smooth muscle actin immunohistochemistry, and real-time PCR for transforming growth factor-beta and collagen alpha-I revealed that Bcl-2 transgenic mice presented reduced fibrosis at early stages of fibrogenesis. However, at later stages increased nonmitochondrial/nonhepatocytic oxidative stress eventually overcame the capacity of Bcl-2 overexpression to prevent the fibrotic process. In conclusion, we demonstrate for the first time that specific protection against hepatocyte mitochondrial dysfunction plays a preventive role in early stages of fibrogenesis, delaying its onset. However, with the persistence of the aggression, this protection is no longer sufficient to impede fibrosis progression.
    American Journal Of Pathology 10/2009; 175(5):1929-37. DOI:10.2353/ajpath.2009.090332 · 4.59 Impact Factor

Publication Stats

2k Citations
413.47 Total Impact Points


  • 2002–2015
    • Université René Descartes - Paris 5
      • • Faculty of medicine
      • • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 2005–2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2003–2012
    • Institut Cochin
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • University Hospital RWTH Aachen
      Aachen, North Rhine-Westphalia, Germany
  • 1991–2010
    • French Institute of Health and Medical Research
      • Center of Biomedical Research Bichat-Beaujon
      Lutetia Parisorum, Île-de-France, France
  • 1989–2008
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2002–2003
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      Strasburg, Alsace, France
  • 1992–2002
    • Institut de Génétique Moléculaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 1993–2001
    • Institut Charles Gerhardt
      Montpelhièr, Languedoc-Roussillon, France
  • 1998
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 1994
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France