Liver sinusoidal endothelial cells are implicated in multiple fibrotic mechanisms

Ma, Hongtao; Xu, Lei; Zhang, Mingyuan; Niu, Junqi

doi:10.1007/s11033-021-06269-1

Cited by 13 publications

(11 citation statements)

References 96 publications

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“…Liver sinusoidal epithelial cells were recently shown to be key players in liver injury and that they are associated with the development of fibrosis [74]. Following liver injury, the levels of SDF-1α increase significantly inside the injured regions; this is important to attract stem cells [75] and macrophages [76] to initiate tissue repair processes in the injured liver.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways

Nashar

Alghamdi

Alasmari

et al. 2021

Cells

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Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-β1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-β1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.

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Section: Discussionmentioning

confidence: 99%

Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways

Nashar

Alghamdi

Alasmari

et al. 2021

Cells

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“… 32,34,35,43 Additionally, Notch signaling has been implicated in LSEC capillarization in vivo , and activated Notch signaling has been observed in patients with cirrhosis. 44,45 Considering the observed impact of stiffness on LSEC phenotype as well as the robust cell–cell junction formation observed from VE-cadherin and CD-31 data, we hypothesized that mechanostransduction and Notch signaling pathways were involved in regulating LSEC phenotype. To interrogate the influence of these pathways, we treated cells with gamma secretase inhibitor (GSI), which prevents the proteolytic cleavage of the Notch receptor, and thus the release of the Notch intracellular domain, and Rho-associated kinase (ROCK) inhibitor (Y-27632), which blocks myosin II activity, to better understand the role of Notch and mechanostransduction pathways in determining LSEC phenotype.…”

Section: Resultsmentioning

confidence: 98%

Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses

et al. 2022

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Fibrosis is one of the hallmarks of chronic liver disease and is associated with aberrant wound healing. Changes in the composition of the liver microenvironment during fibrosis result in a complex crosstalk of extracellular cues that promote altered behaviors in the cell types that comprise the liver sinusoid, particularly liver sinusoidal endothelial cells (LSECs). Recently, it has been observed that LSECs may sustain injury before other fibrogenesis-associated cells of the sinusoid, implicating LSECs as key actors in the fibrotic cascade. A high-throughput cellular microarray platform was used to deconstruct the collective influences of defined combinations of extracellular matrix (ECM) proteins, substrate stiffness, and soluble factors on primary human LSEC phenotype in vitro. We observed remarkable heterogeneity in LSEC phenotype as a function of stiffness, ECM, and soluble factor context. LYVE-1 and CD-31 expressions were highest on 1 kPa substrates, and the VE-cadherin junction localization was highest on 25 kPa substrates. Also, LSECs formed distinct spatial patterns of LYVE-1 expression, with LYVE-1+ cells observed in the center of multicellular domains, and pattern size regulated by microenvironmental context. ECM composition also influenced a substantial dynamic range of expression levels for all markers, and the collagen type IV was observed to promote elevated expressions of LYVE-1, VE-cadherin, and CD-31. These studies highlight key microenvironmental regulators of LSEC phenotype and reveal unique spatial patterning of the sinusoidal marker LYVE-1. Furthermore, these data provide insight into understanding more precisely how LSECs respond to fibrotic microenvironments, which will aid drug development and identification of targets to treat liver fibrosis.

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“…In chronic liver injury, the fenestration diameter of LSECs decreased, and a complete basement membrane gradually formed. This results in changes to LSEC dedifferentiation [ 12 ]. During the early stage of non-alcoholic liver injury, chronic hepatitis, and other models, LSECs exhibit changes in dedifferentiation [ 13 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…After infection, LSECs developed a dedifferentiated phenotype and changed into mesenchymal cells. CD32b is an essential indicator of differentiated LSEC, and high levels of TGF-β were detected in dedifferentiated LSEC [ 12 , 33 ]. Following infection for 20, 28, and 42 days, the proportion of total LSECs (CD45 − CD146 + ) and differentiation phenotype CD32b + LSECs in infected mice decreased continuously, whereas the dedifferentiation phenotype (TGF-β + LSECs) increased significantly.…”

Section: Discussionmentioning

confidence: 99%

“…Dedifferentiated LSECs lose their fenestral structure and form a complete basement membrane beneath the cells. This can activate HSC transformation into myofibroblasts and promote the development of liver fibrosis [ 11 , 12 ]. Some studies have shown that LSECs can induce the dedifferentiation type [ 13 ] or endothelial-to-mesenchymal transition (EMT) during the early stage of hepatic fibrosis [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Pathological Changes in Hepatic Sinusoidal Endothelial Cells in Schistosoma japonicum-Infected Mice

Jiang

Zhou

et al. 2023

TropicalMed

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Schistosomiasis japonica is a zoonotic parasitic disease causing liver fibrosis. Liver sinusoidal endothelial cells (LSECs) exhibit fenestrations, which promote hepatocyte regeneration and reverses the process of liver fibrosis. To investigate the pathological changes of LSECs in schistosomiasis, we established a Schistosomiasis model. The population, phenotype, and secretory function of LSECs were detected by flow cytometry at 20, 28, and 42 days post infection. The changes in LSEC fenestration and basement membrane were observed through scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Quantitative real-time PCR and Western blotting were used to detect the expression of molecules associated with epithelial–mesenchymal transition (EMT) and fibrosis of LSECs and the liver. The flow cytometry results showed that the total LSEC proportions, differentiated LSEC proportions, and nitric oxide (NO) secretion of LSECs were decreased, and the proportion of dedifferentiated LSECs increased significantly post infection. The electron microscopy results showed that the number of fenestrate was decreased and there was complete basement membrane formation in LSECs following infection. The qPCR and Western blot results showed that EMT, and fibrosis-related indicators of LSECs and the liver changed significantly during the early stages of infection and were aggravated in the middle and late stages. The pathological changes in LSECs may promote EMT and liver fibrosis induced by Schistosoma japonicum infection.

show abstract

Liver sinusoidal endothelial cells are implicated in multiple fibrotic mechanisms

Cited by 13 publications

References 96 publications

Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways

Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways

Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses

Pathological Changes in Hepatic Sinusoidal Endothelial Cells in Schistosoma japonicum-Infected Mice

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