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. .. In-situ-immunostaining,

. .. Primary-culture-of-hepatocytes,

. .. Conclusion,

. .. Acknowledgments,

. .. Supplemendary-data,

. .. References,

, Abstract Polyploidy, the state of having greater than a diploid DNA content (tetraploid, octoploid, etc.) is a characteristic feature of mammalian hepatocytes and accompanies late fetal development and postnatal maturation of the liver. During the weaning period, diploid hepatocytes can engage either into normal cell division cycle giving rise to two diploid hepatocytes or follow a scheduled division program characterized by incomplete cytokinesis. In that case, diploid hepatocytes undergo mitosis, but do not form a contractile ring. Indeed, cleavage-plane specification is never established, because of the deficiencies of actin cytoskeleton reorganization. Furthermore, microtubules fail both to contact the cortex and to deliver their molecular signal, preventing localization and activation of RhoA. Therefore, cytokinesis aborts and a binucleate tetraploid liver cell is generated, which subsequently plays a pivotal role in liver progressive polyploidization, Methods in Cell Biology, vol.137, 2017.

. Margall-ducos, Furthermore, we showed that the disruption of cytokinesis program in hepatocytes is due to an absence of cytoskeleton reorganization: actin cytoskeleton is not reorganized into the division plane in anaphaseetelophase transition, then impairing cell elongation. In concert, microtubules fail to contact the cortex and therefore, molecular signals, essential for furrow induction (eg, Aurora B and polo-like kinase 1), are not correctly delivered, 2007.

, Here, we present different methods to assess hepatocyte proliferation and cytokinesis process both in vivo by in situ immunostaining and ex vivo by using primary culture of hepatocytes

?. Materials and . Rodents, C57BL/6NRj micedRjHan:Wistar rats from Janvier Labs

, ? 1X phosphate buffered saline (PBS) ? Formalin (Carlo Erba reagents, 415691) ? 70% Ethanol ? Tissue-Tek VIP

, Animals are weaned at 19 days after birth. Animals are killed by cervical dislocation (mice) or by lethal injection of anesthetic (rats), Their livers are harvested and incubated in 4% phosphate-buffered Ultra Plus Adhesion Slides

, Transfer the slides in epitope retrieval solution and place them in a pressure cooker for 15 min at 95 C. At the end of the run, wait 20 min and then transfer slides in a bath of distilled water

, Delimitate an interest zone using hydrophobic pen on the slides

, Add blocking solution on the delimited zone during the recommended time

, Aspirate the blocking solution and add b-catenin primary antibody solution

, Rinse with 1X PBS-T thrice

, Add secondary antibody solution

, Rinse with 1X PBS-T thrice

, Incubate in Hoechst solution (diluted at 1/500 in 1X PBS-T) during 20 min to counterstain nuclei

, One wash with 1X PBS-T

, ? Data analysis Z-axis stacks were collected using a piezoelectric device mounted at the base of a 20Â magnification, on a Olympus BX63F microscope and an ORCA-Flash4.0 LT C11440-42U Hamamatsu camera controlled by Metamorph software (Molecular Device). A total of 40 planes (0.2-mm slice) are captured and compiled as single two-dimensional projections using ImageJ software. All images are imported into Adobe Photoshop CS for contrast manipulation and figure assembly. For diploid and tetraploid hepatocyte counting experiments, at least 15 randomly chosen fields of liver tissue should be imaged (more than 2500 cells analyzed). Fig. 2 shows an example of in situ b-catenin/Hoechst staining

, cooker ? Epitope retrieval solution: Tris 0.1 M/0.1% Tween-20, vol.9

?. Hydrophobic-pen-?-antibody-diluent and R. Dako,

, ? Mouse antieb-tubulin Tub 2.1 antibody (Sigma, T4026) ? Goat antierabbit IgG (H þ L) secondary antibody

, Aspirate the medium and add 1X PBS

, Rinse a second time with 1X PBS

, Add 2 mL of cold fixer according to the envisaged labeling

, Place dishes at À20 C during indicated time

, Discard the fixator and rinse thrice with 1X PBS, and finally display 2 mL of 1X PBS. Fixated dishes could be used immediately or be stored at 4 C for 1 week

, pen ? 1X PBS ? 1X PBS-T ? 5-Bromo-2 0 -deoxy-uridine labeling and detection kit I (Roche, 11296736001) containing: e Bromodeoxyuridine (BrdU) labeling medium (1000X) e Anti-BrdU antibody e Antiemouse-Ig-fluorescein antibody e Buffer, vol.3

. Antibody, Dako REAL ? Rabbit anti-phospho histone H3 (anti-PHH3) antibody (Millipore, pp.6-570

, Goat antierabbit IgG (H þ L) secondary antibody, Alexa Fluor 488 conjugate (Molecular Probes, A11034)

, Bromodeoxyuridine (BrdU) is incorporated in culture medium during time course kinetic (at T12 h, T24 h, T36 h, T48 h) for a duration of 12 h. T0: Liver perfusion and hepatocytes plating

, Quantitative representation of BrdU-positive hepatocytes during the time course of the primary culture (T24 h, T36 h, T48 h, T60 h). The proliferative profile of hepatocytes describes a Gaussian curve. (D) Immunostaining of primary hepatocytes with anti-PHH3 (green) and Hoechst (red) 48 h after plating. Hepatocytes in G2 phase present dot labeling (arrows) and hepatocytes in mitosis have a dense staining (windows), Immunostaining of primary hepatocytes with anti-BrdU (green) and Hoechst (red)36h after plating. Scale bar: 15 mm. (C)

. D'avino, is rarely observed in this cortical region. Then, detailed analysis of the microtubule network represents a very dynamical way to investigate the cytokinesis process in hepatocytes. ? Material ? Hydrophobic pen ? Antibody diluent, astral microtubules become stabilized upon contacting the cortex, 2005.

, ? Mouse antieb-catenin antibody (BD Transduction Laboratories, 610154) ? Mouse antieb-tubulin antibody (Sigma, T4026) ? Mouse antieEB1 antibody, p.610535

G. Morizur-celton, S. Couton, D. Bregerie, O. Desdouets, and C. , MgcRacGAP is concentrated at the midbody. RhoA (green, lower panel) accumulates at the equatorial cortex in early telophase in hepatocytes that complete cytokinesis; then it concentrates at the cleavage furrow and finally at the midbody. Scale: 10 mm. (B) During incomplete cytokinesis process (right panel), MgcRacGAP (red, upper panel) is observed on the remaining interdigitating microtubules in anaphase B and telophase but is never localized on unattached astral equatorial microtubules. Furthermore, RhoA (green, lower panel) does not correctly localize at the equatorial cortex, in which astral microtubules concentration is decreased. Scale: 10 mm. Adapted from Margall-Ducos, MgcRacGAP (red, upper panel) is localized during anaphase both on the central spindle and on astral equatorial microtubules. During telophase, vol.120, 2003.

, ? Material ? 3.5-cm dishes (Falcon)

G. Morizur-celton, S. Couton, D. Bregerie, O. Desdouets, and C. , A) and after weaning (25-day-old rat) (B) and cultured for 48 h in mitogenic (EGF/pyruvate) conditions. (A) During complete cytokinesis process, hepatocytes progress normally through anaphase: cells elongated preceding furrow formation and ingression. (B) During incomplete cytokinesis process, neither dynamic shape changes (cell elongation) nor furrow ingression is observed. Images are shown at selected time points (minutes). The outlines show cell shape. Adapted from Margall-Ducos, Journal of Cell Science, vol.120, issue.20, 2007.

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