scholarly journals Progranulin A Promotes Compensatory Hepatocyte Proliferation via HGF/c-Met Signaling after Partial Hepatectomy in Zebrafish

2021 ◽  
Vol 22 (20) ◽  
pp. 11217
Author(s):  
Keng-Yu Chiang ◽  
Ya-Wen Li ◽  
Yen-Hsing Li ◽  
Shin-Jie Huang ◽  
Chih-Lu Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Cell Cycle Progression ◽  
Hepatocyte Proliferation ◽  
Transgenic Zebrafish ◽  
Cycle Progression ◽  
Fluorescent Reporter ◽  
Hepatocyte Growth ◽  
Normal Physiological Function

Compensatory hepatocyte proliferation and other liver regenerative processes are activated to sustain normal physiological function after liver injury. A major mitogen for liver regeneration is hepatocyte growth factor (HGF), and a previous study indicated that progranulin could modulate c-met, the receptor for HGF, to initiate hepatic outgrowth from hepatoblasts during embryonic development. However, a role for progranulin in compensatory hepatocyte proliferation has not been shown previously. Therefore, this study was undertaken to clarify whether progranulin plays a regulatory role during liver regeneration. To this end, we established a partial hepatectomy regeneration model in adult zebrafish that express a liver-specific fluorescent reporter. Using this model, we found that loss of progranulin A (GrnA) function by intraperitoneal-injection of a Vivo-Morpholino impaired and delayed liver regeneration after partial hepatectomy. Furthermore, transcriptome analysis and confirmatory quantitative real-time PCR suggested that cell cycle progression and cell proliferation was not as active in the morphants as controls, which may have been the result of comparative downregulation of the HGF/c-met axis by 36 h after partial hepatectomy. Finally, liver-specific overexpression of GrnA in transgenic zebrafish caused more abundant cell proliferation after partial hepatectomy compared to wild types. Thus, we conclude that GrnA positively regulates HGF/c-met signaling to promote hepatocyte proliferation during liver regeneration.

scholarly journals Platelet Interactions with Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells Lead to Hepatocyte Proliferation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1243 ◽  
Author(s):  
Jeremy Meyer ◽  
Alexandre Balaphas ◽  
Pierre Fontana ◽  
Philippe Morel ◽  
Simon C. Robson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Hepatocyte Proliferation ◽  
Liver Sinusoidal Endothelial Cells ◽  
Hepatocyte Growth

(1) Background: Platelets were postulated to constitute the trigger of liver regeneration. The aim of this study was to dissect the cellular interactions between the various liver cells involved in liver regeneration and to clarify the role of platelets. (2) Methods: Primary mouse liver sinusoidal endothelial cells (LSECs) were co-incubated with increasing numbers of resting platelets, activated platelets, or platelet releasates. Alterations in the secretion of growth factors were measured. The active fractions of platelet releasates were characterized and their effects on hepatocyte proliferation assessed. Finally, conditioned media of LSECs exposed to platelets were added to primary hepatic stellate cells (HSCs). Secretion of hepatocyte growth factor (HGF) and hepatocyte proliferation were measured. After partial hepatectomy in mice, platelet and liver sinusoidal endothelial cell (LSEC) interactions were analyzed in vivo by confocal microscopy, and interleukin-6 (IL-6) and HGF levels were determined. (3) Results: Co-incubation of increasing numbers of platelets with LSECs resulted in enhanced IL-6 secretion by LSECs. The effect was mediated by the platelet releasate, notably a thermolabile soluble factor with a molecular weight over 100 kDa. The conditioned medium of LSECs exposed to platelets did not increase proliferation of primary hepatocytes when compared to LSECs alone but stimulated hepatocyte growth factor (HGF) secretion by HSCs, which led to hepatocyte proliferation. Following partial hepatectomy, in vivo adhesion of platelets to LSECs was significantly increased when compared to sham-operated mice. Clopidogrel inhibited HGF secretion after partial hepatectomy. (4) Conclusion: Our findings indicate that platelets interact with LSECs after partial hepatectomy and activate them to release a large molecule of protein nature, which constitutes the initial trigger for liver regeneration.

scholarly journals A novel form of Deleted in breast cancer 1 (DBC1) lacking the N-terminal domain does not bind SIRT1 and is dynamically regulated in vivo

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Leonardo Santos ◽  
Laura Colman ◽  
Paola Contreras ◽  
Claudia C. Chini ◽  
Adriana Carlomagno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Normal Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Quiescent Cells ◽  
Normal Cell Cycle

Abstract The protein Deleted in Breast Cancer-1 is a regulator of several transcription factors and epigenetic regulators, including HDAC3, Rev-erb-alpha, PARP1 and SIRT1. It is well known that DBC1 regulates its targets, including SIRT1, by protein-protein interaction. However, little is known about how DBC1 biological activity is regulated. In this work, we show that in quiescent cells DBC1 is proteolytically cleaved, producing a protein (DN-DBC1) that misses the S1-like domain and no longer binds to SIRT1. DN-DBC1 is also found in vivo in mouse and human tissues. Interestingly, DN-DBC1 is cleared once quiescent cells re-enter to the cell cycle. Using a model of liver regeneration after partial hepatectomy, we found that DN-DBC1 is down-regulated in vivo during regeneration. In fact, WT mice show a decrease in SIRT1 activity during liver regeneration, coincidentally with DN-DBC1 downregulation and the appearance of full length DBC1. This effect on SIRT1 activity was not observed in DBC1 KO mice. Finally, we found that DBC1 KO mice have altered cell cycle progression and liver regeneration after partial hepatectomy, suggesting that DBC1/DN-DBC1 transitions play a role in normal cell cycle progression in vivo after cells leave quiescence. We propose that quiescent cells express DN-DBC1, which either replaces or coexist with the full-length protein, and that restoring of DBC1 is required for normal cell cycle progression in vitro and in vivo. Our results describe for the first time in vivo a naturally occurring form of DBC1, which does not bind SIRT1 and is dynamically regulated, thus contributing to redefine the knowledge about its function.

scholarly journals Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yi Xiong ◽  
Adriana Souza Torsoni ◽  
Feihua Wu ◽  
Hong Shen ◽  
Yan Liu ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Regeneration ◽  
Chronic Liver Disease ◽  
Disease Progression ◽  
Partial Hepatectomy ◽  
Cell Cycle Progression ◽  
Underlying Mechanism ◽  
Chronic Liver ◽  
Hepatocyte Proliferation ◽  
Liver Disease Progression

Reparative hepatocyte replication is impaired in chronic liver disease, contributing to disease progression; however, the underlying mechanism remains elusive. Here, we identify Map3k14 (also known as NIK) and its substrate Chuk (also called IKKα) as unrecognized suppressors of hepatocyte replication. Chronic liver disease is associated with aberrant activation of hepatic NIK pathways. We found that hepatocyte-specific deletion of Map3k14 or Chuk substantially accelerated mouse hepatocyte proliferation and liver regeneration following partial-hepatectomy. Hepatotoxin treatment or high fat diet feeding inhibited the ability of partial-hepatectomy to stimulate hepatocyte replication; remarkably, inactivation of hepatic NIK markedly increased reparative hepatocyte proliferation under these liver disease conditions. Mechanistically, NIK and IKKα suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting cell cycle progression. Our data suggest that hepatic NIK and IKKα act as rheostats for liver regeneration by restraining overgrowth. Pathological activation of hepatic NIK or IKKα likely blocks hepatocyte replication, contributing to liver disease progression.

scholarly journals P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

2014 ◽  
Vol 307 (11) ◽  
pp. G1073-G1087 ◽  
Author(s):  
Bryan C. Tackett ◽  
Hongdan Sun ◽  
Yu Mei ◽  
Janielle P. Maynard ◽  
Sayuri Cheruvu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Partial Hepatectomy ◽  
Cell Cycle Progression ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Receptor Activation ◽  
Hepatocyte Proliferation ◽  
Receptor Subtypes ◽  
Cycle Progression ◽  
The Impact

Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2−/−) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24–72 h) in response to 70% PH were impaired in P2Y2−/− mice. Interestingly, early induction of cytokines (TNF-α, IL-6) and cytokine-mediated signaling (NF-κB, STAT-3) were intact in P2Y2−/− remnant livers, uncovering the importance of cytokine-independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2−/− mice were treated with ATP or ATPγS for 5–120 min and 12–24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH.

scholarly journals Inhibition of miR-21 rescues liver regeneration after partial hepatectomy in ethanol-fed rats

2016 ◽  
Vol 311 (5) ◽  
pp. G794-G806 ◽  
Author(s):  
Egle Juskeviciute ◽  
Rachael P. Dippold ◽  
Anil N. Antony ◽  
Aditi Swarup ◽  
Rajanikanth Vadigepalli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Stellate Cell ◽  
Locked Nucleic Acid ◽  
Hepatocyte Proliferation

Liver regeneration is a clinically significant tissue repair process that is suppressed by chronic alcohol intake through poorly understood mechanisms. Recently, microRNA-21 (miR-21) has been suggested to serve as a crucial microRNA (miRNA) regulator driving hepatocyte proliferation after partial hepatectomy (PHx) in mice. However, we reported recently that miR-21 is significantly upregulated in ethanol-fed rats 24 h after PHx, despite inhibition of cell proliferation, suggesting a more complex role for this miRNA. Here, we investigate how inhibition of miR-21 in vivo affects the early phase of liver regeneration in ethanol-fed rats. Chronically ethanol-fed rats and pair-fed control animals were treated with AM21, a mixed locked nucleic acid-DNA analog antisense to miR-21 that inhibited miR-21 in vivo to undetectable levels. Liver regeneration after PHx was followed by cell proliferation marker and gene expression analysis, miRNA profiling, and cell signaling pathway analysis. Although liver regeneration was not significantly impaired by AM21 in chow-fed rats, AM21 treatment in ethanol-fed animals completely restored regeneration and enhanced PHx-induced hepatocyte proliferation to levels comparable to those of untreated or chow-fed animals. In addition, a marked deposition of α-smooth muscle actin, a marker of stellate cell activation, which was evident in ethanol-treated animals after PHx, was effectively suppressed by AM21 treatment. Gene expression analysis further indicated that suppression of stellate cell-specific profibrogenic profiles and the Notch signaling contributed to AM21-mediated rescue from deficient hepatocyte proliferation in ethanol-fed animals. Our results indicate that the impact of miR-21 balances proproliferative effects with antiproliferative profibrogenic actions in regulating distinctive regenerative responses in normal vs. disease conditions.

GDF11 impairs liver regeneration in mice after partial hepatectomy

2019 ◽  
Vol 133 (20) ◽  
pp. 2069-2084
Author(s):  
Wenjie Wang ◽  
Xiao Yang ◽  
Jiankun Yang ◽  
Shenpei Liu ◽  
Yongman Lv ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Liver Regeneration ◽  
Signaling Pathway ◽  
Partial Hepatectomy ◽  
Neutralizing Antibodies ◽  
Cell Cycle Progression ◽  
Transforming Growth Factor

Abstract Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-β superfamily. The rejuvenative effect of GDF11 has been called into question recently, and its role in liver regeneration is unclear. Here, we investigated the pathophysiologic role of GDF11, as well as its plausible signaling mechanisms in a mouse model of partial hepatectomy (PH). We demonstrated that both serum and hepatic GDF11 protein expression increased following PH. Treatment with adeno-associated viruses-GDF11 and recombinant GDF11 protein severely impaired liver regeneration, whereas inhibition of GDF11 activity with neutralizing antibodies significantly improved liver regeneration after PH. In vitro, GDF11 treatment significantly delayed cell proliferation and induced cell-cycle arrest in α mouse liver 12 (AML12) cells. Moreover, GDF11 activated TGF-β-SMAD2/3 signaling pathway. Inhibition of GDF11-induced SMAD2/3 activity significantly blocked GDF11-mediated reduction in cell proliferation both in vivo and in vitro. In the clinical setting, GDF11 levels were significantly elevated in patients after hepatectomy. Collectively, these results indicate that rather than a ‘rejuvenating’ agent, GDF11 impairs liver regeneration after PH. Suppression of cell-cycle progression via TGF-β-SMAD2/3 signaling pathway may be a key mechanism by which GDF11 inhibits liver regeneration.

scholarly journals Protein tyrosine phosphatase of liver regeneration-1 is required for normal timing of cell cycle progression during liver regeneration

2015 ◽  
Vol 308 (2) ◽  
pp. G85-G91 ◽  
Author(s):  
Yang Jiao ◽  
Diana Z. Ye ◽  
Zhaoyu Li ◽  
Monica Teta-Bissett ◽  
Yong Peng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Protein Tyrosine Phosphatase ◽  
Cell Cycle Progression ◽  
Tyrosine Phosphatase ◽  
Mutant Mice ◽  
Cell Cycle Regulators ◽  
Cycle Progression ◽  
Protein Tyrosine

Protein tyrosine phosphatase of liver regeneration-1 ( Prl-1) is an immediate-early gene that is significantly induced during liver regeneration. Several in vitro studies have suggested that Prl-1 is important for the regulation of cell cycle progression. To evaluate its function in liver regeneration, we ablated the Prl-1 gene specifically in mouse hepatocytes using the Cre-loxP system. Prl-1 mutant mice ( Prl-1loxP/loxP;AlfpCre) appeared normal and fertile. Liver size and metabolic function in Prl-1 mutants were comparable to controls, indicating that Prl-1 is dispensable for liver development, postnatal growth, and hepatocyte differentiation. Mutant mice demonstrated a delay in DNA synthesis after 70% partial hepatectomy, although ultimate liver mass restoration was not affected. At 40 h posthepatectomy, reduced protein levels of the cell cycle regulators cyclin E, cyclin A2, cyclin B1, and cyclin-dependent kinase 1 were observed in Prl-1 mutant liver. Investigation of the major signaling pathways involved in liver regeneration demonstrated that phosphorylation of protein kinase B (AKT) and signal transducer and activator of transcription (STAT) 3 were significantly reduced at 40 h posthepatectomy in Prl-1 mutants. Taken together, this study provides evidence that Prl-1 is required for proper timing of liver regeneration after partial hepatectomy. Prl-1 promotes G1/S progression via modulating expression of several cell cycle regulators through activation of the AKT and STAT3 signaling pathway.

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