Update on the Mechanisms of Liver Regeneration

AbstractLiver possesses many critical functions such as synthesis, detoxification, and metabolism. It continually receives nutrient-rich blood from gut, which incidentally is also toxin-rich. That may be why liver is uniquely bestowed with a capacity to regenerate. A commonly studied procedure to understand the cellular and molecular basis of liver regeneration is that of surgical resection. Removal of two-thirds of the liver in rodents or patients instigates alterations in hepatic homeostasis, which are sensed by the deficient organ to drive the restoration process. Although the exact mechanisms that initiate regeneration are unknown, alterations in hemodynamics and metabolism have been suspected as important effectors. Key signaling pathways are activated that drive cell proliferation in various hepatic cell types through autocrine and paracrine mechanisms. Once the prehepatectomy mass is regained, the process of regeneration is adequately terminated. This review highlights recent discoveries in the cellular and molecular basis of liver regeneration.

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Comparative analysis of expression profiles of chemokines, chemokine receptors, and components of signaling pathways mediated by chemokines in eight cell types during rat liver regeneration

Genome ◽

10.1139/g10-040 ◽

2010 ◽

Vol 53 (8) ◽

pp. 608-618 ◽

Cited By ~ 16

Author(s):

Xiaoguang Chen ◽

Cunshuan Xu ◽

Fuchun Zhang ◽

Ji Ma

Keyword(s):

Liver Regeneration ◽

Signaling Pathways ◽

Expression Profiles ◽

Gradient Centrifugation ◽

Cell Types ◽

Cellular Level ◽

Pcr Analysis ◽

Immunomagnetic Bead ◽

Percoll Density Gradient Centrifugation ◽

Chemokine Signaling

It has been documented that chemokines can positively regulate liver regeneration at the tissue level after partial hepatectomy. However, the precise mechanism of the effects of chemokines on regeneration at the cellular level remains poorly defined. In this study, 8 cell types from rat regenerating liver at 8 recovery time points after 2/3 hepatectomy were isolated and purified using Percoll density gradient centrifugation and immunomagnetic bead methods. The expression profiles of each cell type were monitored using a microarray. RT-PCR analysis was performed to validate the reliability of the microarray results. The results showed that, on the whole, the expression profiles of chemokine and receptor genes varied among different cell types; most genes involved in chemokine signaling pathways showed an increase in expression across the 8 liver cell types during liver regeneration. The implication of these genes in regeneration was analyzed by bioinformatics and systems biology methods. According to the microarray results and gene synergy, activation of chemokine signaling pathways at 24 h in biliary epithelial cells and at 2–12 h in dendritic cells may be triggered by CCL2–CCR2 and CCL7–CCR3, respectively; activation of Plc/Pkc and Pi3k/Akt pathways at 2–12 h in sinusoidal endothelial cells might be caused by CCL7–CCR1; and activation of the Src/Ptk, Src/Vav, and Plc/Pkc pathways at the priming stage may be related to the inductive effect of CCL7. These data suggest the potential relevance of the pro-inflammatory chemokines for liver regeneration at the cellular level.

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Interleukin 18 accelerates the hepatic cell proliferation in rat liver regeneration after partial hepatectomy

Gene ◽

10.1016/j.gene.2013.12.062 ◽

2014 ◽

Vol 537 (2) ◽

pp. 230-237 ◽

Cited By ~ 11

Author(s):

Jihong Zhang ◽

Chengkai Ma ◽

Yunqing Liu ◽

Gang Yang ◽

Yun Jiang ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Rat Liver ◽

Hepatic Cell ◽

Interleukin 18 ◽

Rat Liver Regeneration

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111-OR: Pancreatic Elastase Regulates Human Beta-Cell Proliferation via the Focal Adhesion and PAR2 Signaling Pathways

Diabetes ◽

10.2337/db19-111-or ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 111-OR

Author(s):

GIORGIO BASILE ◽

AMEDEO VETERE ◽

KA-CHEUK LIU ◽

JIANG HU ◽

OLOV ANDERSSON ◽

...

Keyword(s):

Cell Proliferation ◽

Beta Cell ◽

Signaling Pathways ◽

Focal Adhesion ◽

Beta Cell Proliferation ◽

Pancreatic Elastase ◽

Human Beta Cell

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Signaling Pathways Involved in Antidepressant-Induced Cell Proliferation and Synaptic Plasticity

Current Pharmaceutical Design ◽

10.2174/13816128113196660736 ◽

2014 ◽

Vol 20 (23) ◽

pp. 3776-3794 ◽

Cited By ~ 18

Author(s):

Fuencisla Pilar-Cuellar ◽

Rebeca Vidal ◽

Alvaro Díaz ◽

Elena Castro ◽

Severiano Anjos ◽

...

Keyword(s):

Cell Proliferation ◽

Synaptic Plasticity ◽

Signaling Pathways

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Extracellular-Vesicle-Based Coatings Enhance Bioactivity of Titanium Implants—SurfEV

Nanomaterials ◽

10.3390/nano11061445 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1445

Author(s):

Taisa Nogueira Pansani ◽

Thanh Huyen Phan ◽

Qingyu Lei ◽

Alexey Kondyurin ◽

Bill Kalionis ◽

...

Keyword(s):

Cell Proliferation ◽

Titanium Surface ◽

Wound Closure ◽

Cell Types ◽

Extracellular Vesicle ◽

Tissue Growth ◽

Titanium Implants ◽

The Body ◽

High Concentrations ◽

And Migration

Extracellular vesicles (EVs) are nanoparticles released by cells that contain a multitude of biomolecules, which act synergistically to signal multiple cell types. EVs are ideal candidates for promoting tissue growth and regeneration. The tissue regenerative potential of EVs raises the tantalizing possibility that immobilizing EVs on implant surfaces could potentially generate highly bioactive and cell-instructive surfaces that would enhance implant integration into the body. Such surfaces could address a critical limitation of current implants, which do not promote bone tissue formation or bond bone. Here, we developed bioactive titanium surface coatings (SurfEV) using two types of EVs: secreted by decidual mesenchymal stem cells (DEVs) and isolated from fermented papaya fluid (PEVs). For each EV type, we determined the size, morphology, and molecular composition. High concentrations of DEVs enhanced cell proliferation, wound closure, and migration distance of osteoblasts. In contrast, the cell proliferation and wound closure decreased with increasing concentration of PEVs. DEVs enhanced Ca/P deposition on the titanium surface, which suggests improvement in bone bonding ability of the implant (i.e., osteointegration). EVs also increased production of Ca and P by osteoblasts and promoted the deposition of mineral phase, which suggests EVs play key roles in cell mineralization. We also found that DEVs stimulated the secretion of secondary EVs observed by the presence of protruding structures on the cell membrane. We concluded that, by functionalizing implant surfaces with specialized EVs, we will be able to enhance implant osteointegration by improving hydroxyapatite formation directly at the surface and potentially circumvent aseptic loosening of implants.

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Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications

Bioengineering ◽

10.3390/bioengineering7020036 ◽

2020 ◽

Vol 7 (2) ◽

pp. 36 ◽

Cited By ~ 5

Author(s):

João P. Cotovio ◽

Tiago G. Fernandes

Keyword(s):

Cell Types ◽

In Vitro Models ◽

Hepatic Cell ◽

Current Status ◽

Organ Shortage ◽

Cell Lineages ◽

Potential Applications ◽

Liver Organoids

Liver disease is one of the leading causes of death worldwide, leading to the death of approximately 2 million people per year. Current therapies include orthotopic liver transplantation, however, donor organ shortage remains a great challenge. In addition, the development of novel therapeutics has been limited due to the lack of in vitro models that mimic in vivo liver physiology. Accordingly, hepatic cell lineages derived from human pluripotent stem cells (hPSCs) represent a promising cell source for liver cell therapy, disease modelling, and drug discovery. Moreover, the development of new culture systems bringing together the multiple liver-specific hepatic cell types triggered the development of hPSC-derived liver organoids. Therefore, these human liver-based platforms hold great potential for clinical applications. In this review, the production of the different hepatic cell lineages from hPSCs, including hepatocytes, as well as the emerging strategies to generate hPSC-derived liver organoids will be assessed, while current biomedical applications will be highlighted.

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Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation

Journal of Experimental Medicine ◽

10.1084/jem.20150388 ◽

2015 ◽

Vol 212 (13) ◽

pp. 2289-2304 ◽

Cited By ~ 34

Author(s):

Binh L. Phong ◽

Lyndsay Avery ◽

Tina L. Sumpter ◽

Jacob V. Gorman ◽

Simon C. Watkins ◽

...

Keyword(s):

T Cells ◽

Mast Cell ◽

Signaling Pathways ◽

Cell Activation ◽

Molecular Mechanisms ◽

Late Phase ◽

Cell Types ◽

Mast Cell Activation ◽

Positive Role ◽

Ample Evidence

T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation.

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The Role of EGFR/PI3K/Akt/cyclinD1 Signaling Pathway in Acquired Middle Ear Cholesteatoma

Mediators of Inflammation ◽

10.1155/2013/651207 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 16

Author(s):

Wei Liu ◽

Hongmiao Ren ◽

Jihao Ren ◽

Tuanfang Yin ◽

Bing Hu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Signaling Pathways ◽

Signaling Pathway ◽

External Auditory Canal ◽

Cell Cycle Progression ◽

Critical Role ◽

Immunohistochemical Method ◽

Cycle Progression ◽

Middle Ear Cholesteatoma

Cholesteatoma is a benign keratinizing and hyper proliferative squamous epithelial lesion of the temporal bone. Epidermal growth factor (EGF) is one of the most important cytokines which has been shown to play a critical role in cholesteatoma. In this investigation, we studied the effects of EGF on the proliferation of keratinocytes and EGF-mediated signaling pathways underlying the pathogenesis of cholesteatoma. We examined the expressions of phosphorylated EGF receptor (p-EGFR), phosphorylated Akt (p-Akt), cyclinD1, and proliferating cell nuclear antigen (PCNA) in 40 cholesteatoma samples and 20 samples of normal external auditory canal (EAC) epithelium by immunohistochemical method. Furthermore,in vitrostudies were performed to investigate EGF-induced downstream signaling pathways in primary external auditory canal keratinocytes (EACKs). The expressions of p-EGFR, p-Akt, cyclinD1, and PCNA in cholesteatoma epithelium were significantly increased when compared with those of control subjects. We also demonstrated that EGF led to the activation of the EGFR/PI3K/Akt/cyclinD1 signaling pathway, which played a critical role in EGF-induced cell proliferation and cell cycle progression of EACKs. Both EGFR inhibitor AG1478 and PI3K inhibitor wortmannin inhibited the EGF-induced EGFR/PI3K/Akt/cyclinD1 signaling pathway concomitantly with inhibition of cell proliferation and cell cycle progression of EACKs. Taken together, our data suggest that the EGFR/PI3K/Akt/cyclinD1 signaling pathway is active in cholesteatoma and may play a crucial role in cholesteatoma epithelial hyper-proliferation. This study will facilitate the development of potential therapeutic targets for intratympanic drug therapy for cholesteatoma.

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