Isabelle A Leclercq

Catholic University of Louvain, Лувен-ла-Нев, Walloon, Belgium

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Publications (118)778.97 Total impact

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    ABSTRACT: Human hepatocytes are used for liver cell therapy, but the small number of engrafting cells limits the benefit of cell transplantation. We tested whether co-transplantation of hepatocytes with hepatic stellate cells (HSC) could improve hepatocyte engraftment in vivo. Human primary hepatocytes were transplanted into SCID mice either alone or in a mixture with HSC (quiescent or after culture-activation) or LX-2 cells (ratio 20:1). Four weeks after transplantation into mouse livers, human albumin positive (huAlb(+)) hepatocytes were found scattered. When co-transplanted in a mixture with HSC or LX-2 cells, huAlb(+) hepatocytes formed clusters and were more numerous occupying 2 to 5.9-fold more surface on the tissue section than in livers transplanted with hepatocytes alone. Increased huAlb mRNA expression in livers transplanted with the cell mixtures confirmed those results. The presence of HSC increased the number of hepatocytes entrapped in the host liver at an early time point post-transplantation but not their proliferation in situ as assessed by cumulative incorporation of BrdU. Importantly, 4 weeks post-transplantation, we found no accumulation of αSMA(+) activated HSC or collagen deposition. To follow the fate of transplanted HSC, HSC derived from GFP(+) mice were injected into GFP(-) littermate: 17 hours post-transplant, GFP(+) HSC were found in the sinusoids, without proliferating or actively producing ECM; they were undetectable at later time points. Co-culture with HSC improved the number of adherent hepatocytes, with best attachment obtained when hepatocytes were seeded in contact with activated HSC. In vivo, co-transplantation of hepatocytes with HSC into a healthy liver recipient does not generate fibrosis but significantly improves the engraftment of hepatocytes, probably by ameliorating cell homing.
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    ABSTRACT: High aldehyde dehydrogenase (ALDH) activity is a feature of stem cells from normal and cancerous tissues and a reliable universal marker used to isolate them. There are numerous ALDH isoforms with preferred substrate-specificity variably expressed depending on tissue, cell-type, and organelle and cell status. On the other hand, a given substrate may be metabolized by several enzyme isoforms. Currently ALDH activity is evidenced using ALDEFLUOR(TM) a fluorescent substrate likely to be metabolized by numerous ALDH isoforms. Therefore, isolation techniques based on ALDH activity detection select a heterogeneous population of stem- or progenitor cells. Despite active research in the field, the precise role(s) of different ALDH isoforms in stem cells remains enigmatic. Understanding the metabolic role of different ALDH isoform in the control of stem cell phenotype and cell fate during development, tissue homeostasis or repair, as well as carcinogenesis should open perspectives to significant discoveries in tissue biology. In this perspective, novel ALDH substrates are being developed. Here we described how new substrates could be instrumental for better isolation of cell population with stemness potential and for defining hierarchy of cell populations in tissue. Finally, we speculate on other potential applications. Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology.
    AJP Gastrointestinal and Liver Physiology 02/2015; DOI:10.1152/ajpgi.00420.2014 · 3.74 Impact Factor
  • Nicolas Lanthier, Isabelle A. Leclercq
    Hepatology 09/2014; 60(3). DOI:10.1002/hep.27017 · 11.19 Impact Factor
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    Nicolas Lanthier, Isabelle A. Leclercq
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    ABSTRACT: In the context of obesity, white adipocyte hypertrophy and adipose tissue macrophage infiltration result in the production of pro-inflammatory adipocytokines inducing insulin resistance locally but also in distant organs and contributing to low grade inflammatory status associated with the metabolic syndrome. Visceral adipose tissue is believed to play a prominent role. Brown and beige adipose tissues are capable of energy dissipation, but also of cytokine production and their role in dysmetabolic syndrome is emerging. This review focuses on metabolic and inflammatory changes in these adipose depots and contribution to metabolic syndrome. Also we will review surgical and pharmacological procedures to target adiposity as therapeutic interventions to treat obesity-associated disorders.
    Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology 08/2014; 28(4). DOI:10.1016/j.bpg.2014.07.002 · 3.28 Impact Factor
  • 06/2014; 72(Suppl 1):O7. DOI:10.1186/2049-3258-72-S1-O7
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    ABSTRACT: Non-alcoholic fatty liver (steatosis) and steatohepatitis (NASH) are hepatic complications of metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin resistant animals (such as ob/ob mice) with simple steatosis but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and the histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to high-fat diet (HFD) after several time points. We then evaluated the effect of treatment with ER stress inducer tunicamycin, or conversely with ER protectant tauro-ursodeoxycholic acid (TUDCA) on the metabolic and hepatic features. Foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response (phospho-eIF2α, IRE1α activity, spliced Xbp1). Activation of JNK and up-regulation of Atf4 and Chop transcripts were however compatible with a "pathologic" response to ER stress. We tested it by intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese, diabetic mice with steatohepatitis.
    Clinical Science 04/2014; DOI:10.1042/CS20140026 · 5.63 Impact Factor
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    ABSTRACT: Liver-specific overexpression of the insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IGF2BP2-2 induces a fatty liver, which highly expresses IGF2. Since IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased ELOVL fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. p62 overexpression induced the activation of the ELOVL6 transcriptional activator SREBF1. Recombinant IGF2 induced the nuclear translocation of sterol regulatory element binding transcription factor 1 (SREBF1) and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels as found in p62 tg livers can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These findings underline the detrimental role of p62 in liver disease.
    The Journal of Lipid Research 04/2014; 55(6). DOI:10.1194/jlr.M045500 · 4.73 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S149-S150. DOI:10.1016/S0168-8278(14)60415-3 · 10.40 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S176. DOI:10.1016/S0168-8278(14)60492-X · 10.40 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S101. DOI:10.1016/S0168-8278(14)60267-1 · 10.40 Impact Factor
  • Journal of Hepatology 07/2013; DOI:10.1016/j.jhep.2013.07.013 · 10.40 Impact Factor
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    ABSTRACT: Background: Alcohol consumption is a major cause of liver disease. It also associates with increased cardiovascular risk and type 2 diabetes. Alcoholic liver diseases (ALD) and non-alcoholic fatty liver diseases (NAFLD) share pathologic features, pathogenic mechanisms and pattern of disease progression. In NAFLD, steatosis, lipotoxicity and liver inflammation participate to hepatic insulin resistance. Our aim here is to verify the effect of alcohol on hepatic insulin sensitivity and to evaluate the role of alcohol-induced steatosis and inflammation on glucose homeostasis. Results : C57BL/6J mice were fed for 20 days a modified Lieber-DeCarli diet in which alcohol concentration was gradually increased up to 35% of daily caloric intake. Alcohol-fed mice show liver steatosis and inflammatory infiltration. OH-fed mice developed insulin resistance in the liver but not in muscles, as demonstrated by euglycemic-hyperinsulinemic clamp and analysis of the insulin signaling cascade. Treatment with the PPAR-α agonist Wy14,643 protected against OH-induced steatosis and Kupffer cell (KC) activation and almost abolished OH-induced insulin resistance. As KC activation may modulate insulin sensitivity, we repeated the clamp studies in mice depleted in KC to decipher the role of macrophages. Depletion of KC using liposomes-encapsuled clodronate in OH-fed mice failed both to improve hepatic steatosis and to restore insulin sensitivity as assessed by clamp. Conclusions : Our study shows that chronic alcohol consumption induces steatosis, Kuffer cell activation and hepatic insulin resistance in mice. PPAR-α agonist treatment that prevents steatosis and dampens hepatic inflammation also prevents alcohol-induced hepatic insulin resistance. However, Kupffer cell depletion little impacts on OH-induced metabolic disturbances.
    Clinical Science 06/2013; DOI:10.1042/CS20130064 · 5.63 Impact Factor
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    Gastroenterology 05/2013; DOI:10.1053/j.gastro.2013.05.037 · 13.93 Impact Factor
  • Gut 03/2013; 63(1). DOI:10.1136/gutjnl-2012-304338 · 13.32 Impact Factor
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    ABSTRACT: Ras activation is a frequent event in human hepatocarcinoma that may contribute to resistance towards apoptosis. Salirasib is a ras and mTOR inhibitor that induces a pro-apoptotic phenotype in human hepatocarcinoma cell lines. In this work, we evaluate whether salirasib sensitizes those cells to TRAIL-induced apoptosis. Cell viability, cell death and apoptosis were evaluated in vitro in HepG2, Hep3B and Huh7 cells treated with DMSO, salirasib and YM155 (a survivin inhibitor), alone or in combination with recombinant TRAIL. Our results show that pretreatment with salirasib sensitized human hepatocarcinoma cell lines, but not normal human hepatocytes, to TRAIL-induced apoptosis. Indeed, FACS analysis showed that 25 (Huh7) to 50 (HepG2 and Hep3B) percent of the cells treated with both drugs were apoptotic. This occurred through activation of the extrinsic and the intrinsic pathways, as evidenced by a marked increase in caspase 3/7 (five to ninefold), caspase 8 (four to sevenfold) and caspase 9 (eight to 12-fold) activities in cells treated with salirasib and TRAIL compared with control. Survivin inhibition had an important role in this process and was sufficient to sensitize hepatocarcinoma cells to apoptosis. Furthermore, TRAIL-induced apoptosis in HCC cells pretreated with salirasib was dependent on activation of death receptor (DR) 5. In conclusion, salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis by a mechanism involving the DR5 receptor and survivin inhibition. These results in human hepatocarcinoma cell lines and primary hepatocytes provide a rationale for testing the combination of salirasib and TRAIL agonists in human hepatocarcinoma.
    Cell Death & Disease 01/2013; 4(1):e471. DOI:10.1038/cddis.2012.200 · 5.18 Impact Factor
  • Isabelle A Leclercq
    Journal of Gastroenterology and Hepatology 11/2012; 27(11):1651-3. DOI:10.1111/j.1440-1746.2012.07255.x · 3.63 Impact Factor
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    ABSTRACT: Activation of Ras and its downstream signaling pathways, likely contribute to the development of hepatocarcinoma. We have previously shown that intraperitoneal injections of the Ras inhibitor S-trans, trans-farnesylthiosalicyclic acid (FTS) blocks Ras activation and prevents heptocarcinoma development in rats receiving weekly injections of the carcinogene diethylnitrosamine (DEN) for 16 wk. Using this in vivo model, we evaluated the relationship between the tumor preventive effect of Ras inhibition and activation of downstream signaling pathways, cell proliferation, cell cycle events, and angiogenesis. Western blotting, quantitative PCR, immunohistochemistry, and transcription factor activity assays were used. DEN-induced activation of NFkB and Stat3 was abrogated by FTS treatment. FTS treatment showed no effect on DEN-induced elevation of TNFα, interleukin 6 and TLR4, known activators of these transcription factors. FTS significantly reduced phosphorylation of the MAPkinase p38 and of the p70S6 kinase, a surrogate marker for mTor activation, without affecting ERK and AKT phosphorylation. These events were associated with reduced c-myc and cyclin D expression as well as reduced cell proliferation in transformed, GSTp-positive hepatocytes. Moreover, FTS treatment shifted cell proliferation from transformed hepatocytes to apparently normal, GSTp negative hepatocytes. FTS treatment did not down-regulate expression of angiogenesis markers HIFα, VEGF, VEGF receptor1, and placenta growth factor. FTS treatment inhibits important signaling pathways involved in cellular proliferation leading to strongly reduced proliferation of transformed hepatocytes without affecting normal hepatocytes. This re-adjustment of the proliferation balance likely contributes to the tumor preventive of FTS in the context of Ras inhibition in hepatocarcinogenesis. © 2011 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 10/2012; 51(10):816-25. DOI:10.1002/mc.20849 · 4.77 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: Self-renewal of mature hepatocytes promotes homeostasis and regeneration of adult liver. However, recent studies have indicated that liver progenitor cells (LPC) could give rise to hepatic epithelial cells during normal turnover of the liver and after acute injury. We investigated the capacity of LPC to differentiate into hepatocytes in vivo and contribute to liver regeneration. METHODS: We performed lineage tracing experiments, using mice that express tamoxifen-inducible Cre recombinase under control of osteopontin regulatory region crossed with yelow fluorescent protein reporter mice, to follow the fate of LPC and biliary cells. Adult mice received partial (two-thirds) hepatectomy, acute or chronic administration of carbon tetrachloride (CCl(4)), choline-deficient diet supplemented with ethionine, or 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. RESULTS: LPC and/or biliary cells generated 0.78% and 2.45% of hepatocytes during and upon recovery of mice from liver injury, respectively. Repopulation efficiency by LPC and/or biliary cells increased when extracellular matrix and laminin deposition were reduced. The newly formed hepatocytes integrated into hepatic cords, formed biliary canaliculi, expressed hepato-specific enzymes, accumulated glycogen, and proliferated in response to partial hepatectomy, as neighboring native hepatocytes. By contrast, LPC did not contribute to hepatocyte regeneration during normal liver homeostasis, in response to surgical or toxic loss of liver mass, during chronic liver injury (CCl(4)-induced), or during ductular reactions. CONCLUSIONS: LPC or biliary cells terminally differentiate into functional hepatocytes in mice with liver injury.
    Gastroenterology 08/2012; 143(6). DOI:10.1053/j.gastro.2012.08.024 · 13.93 Impact Factor
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    ABSTRACT: To investigate which transmembrane choline transporters and intracellular choline kinases play a prominent role at gene expression level in the rise of the total choline (tCho) peak at proton MR spectra in a rodent rhabdomyosarcoma model. Twenty-two rats bearing grafted bilateral syngenic rhabdomyosarcoma were examined on a clinical 3 T MR system. Total choline concentration was measured from proton MR spectra using cubic centimeter volumes of interest (VOIs) located contiguously along the greater axis of the tumour. After euthanasia, cubic centimetre tissue specimens corresponding to Proton magnetic resonance spectroscopy (H-MRS) VOIs were frozen in liquid nitrogen. Out of 89 H-MRS voxels, only 39 with a corresponding tissue specimen suitable for biochemical processing were included in the analysis. RNA was extracted from all the 39 samples and reverse-transcribed into cDNA. Choline kinase α and β gene expression as well as genes of the transmembrane transporters OCT1, OCT2, OCT3, CTL1, CTL3, CTL4 and CHT1 were studied using reverse transcriptase polymerase chain reaction. The expression level of each gene (ΔCt), was normalized referred to that of the RPL19 gene. The Spearman rank correlation coefficient was used to analyse variables. There was no overexpression of genes coding for kinases; however, significant correlation was observed between kinase α sub-type and the tCho peak (P=.002; r=0.51). OCT1 was the most overexpressed transporter gene. Less overexpressed CTL1 gene was significantly correlated with the tCho peak (P=.02; r=0.38). Choline transporters seem to play a predominant role in the increase in total choline concentration at the gene expression level in our model.
    Magnetic Resonance Imaging 04/2012; 30(7):1010-6. DOI:10.1016/j.mri.2012.03.003 · 2.02 Impact Factor
  • Journal of Hepatology 04/2012; 56:S486-S487. DOI:10.1016/S0168-8278(12)61239-2 · 10.40 Impact Factor

Publication Stats

4k Citations
778.97 Total Impact Points

Institutions

  • 1996–2015
    • Catholic University of Louvain
      • • Institute of Experimental and Clinical Research (IREC)
      • • Laboratory of Hepatogastroenterology
      Лувен-ла-Нев, Walloon, Belgium
  • 2006–2007
    • Cliniques Universitaires Saint-Luc
      • Division of Gastroenterology
      Bruxelles, Brussels Capital Region, Belgium
  • 2003–2007
    • Westmead Millennium Institute
      Sydney, New South Wales, Australia
    • University of Cape Town
      Kaapstad, Western Cape, South Africa
  • 1999–2007
    • Westmead Hospital
      • Department of Medicine
      Sydney, New South Wales, Australia