Hepatic stellate cells and astrocytes

Schachtrup, Christian; Moan, Natacha Le; Passino, Melissa; Akassoglou, Katerina

doi:10.4161/cc.10.11.15828

Cited by 43 publications

(26 citation statements)

References 110 publications

(111 reference statements)

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“…Previous studies have shown that p75NTR is widely expressed throughout the body, and that its expression can be upregulated by injury or disease, including liver cirrhosis [2], [3], [54]. Due to this ubiquitous expression, we additionally analyzed the distribution of intravenously administered modified Ads by GFP-mRNA expression in lung and brain.…”

Section: Discussionmentioning

confidence: 99%

Development of Adenoviral Delivery Systems to Target Hepatic Stellate Cells In Vivo

et al. 2013

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Hepatic stellate cells (HSCs) are known as initiator cells that induce liver fibrosis upon intoxication or other noxes. Deactivation of this ongoing remodeling process of liver parenchyma into fibrotic tissue induced by HSCs is an interesting goal to be achieved by targeted genetic modification of HSCs. The most widely applied approach in gene therapy is the utilization of specifically targeted vectors based on Adenovirus (Ad) serotype 5. To narrow down the otherwise ubiquitous tropism of parental Ad, two modifications are required: a) ablating the native tropism and b) redirecting the vector particles towards a specific entity solely present on the cells of interest. Therefore, we designed a peptide of the nerve growth factor (NGFp) with specific affinity for the p75 neurotrophin receptor (p75NTR) present on HSCs. Coupling of this NGFp to vector particles was done either via chemical conjugation using bifunctional polyethylene glycol (PEG) or, alternatively, by molecular bridging with a fusion protein specific for viral fiber knob and p75NTR. Both Ad vectors transmit the gene for the green fluorescent protein (GFP). GFP expression was monitored in vitro on primary murine HSCs as well as after systemic administration in mice with healthy and fibrotic livers using intravital fluorescence microscopy. Coupling of NGFp to Ad via S11 and/or PEGylation resulted in markedly reduced liver tropism and an enhanced adenoviral-mediated gene transfer to HSCs. Transduction efficiency of both specific Ads was uniformly higher in fibrotic livers, whereas Ad.GFP-S11-NGFp transduce activated HSCs better than Ad.GFP-PEG-NGFp. These experiments contribute to the development of a targeted gene transfer system to specifically deliver antifibrotic compounds into activated HSCs by systemically applied adenoviral vector modified with NGFp.

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Section: Discussionmentioning

confidence: 99%

Development of Adenoviral Delivery Systems to Target Hepatic Stellate Cells In Vivo

et al. 2013

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“…Cochlear SCs, similar to glial cells in the central nervous system (Schachtrup et al, 2011; Peng and Carbonetto, 2012), contribute to scar formation after injury. In the case of SCs this occurs by modifications in their contacts at the reticular lamina to keep it sealed (Forge, 1985; Raphael and Altschuler, 1991b, a; Raphael, 1993; Leonova and Raphael, 1997).…”

Section: Discussionmentioning

confidence: 99%

Selective Ablation of Pillar and Deiters' Cells Severely Affects Cochlear Postnatal Development and Hearing in Mice

et al. 2013

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Mammalian auditory hair cells (HCs) are inserted into a well-structured environment of supporting cells (SCs) and acellular matrices. It has been proposed that when HCs are irreversibly damaged by noise or ototoxic drugs surrounding SCs seal the epithelial surface and likely extend the survival of auditory neurons. Because SCs are more resistant to damage than HCs the effects of primary SC loss on HC survival and hearing have received little attention. We used the Cre/loxP system in mice to specifically ablate pillar and Deiters’ cells (PCs and DCs). In Prox1CreERT2+/−;Rosa26DTA/+ (Prox1DTA) mice, CreER expression driven by the endogenous Prox1 promoter in presence of tamoxifen removes a stop-codon in the Rosa26DTA/+ allele and induces diphtheria toxin fragment A (DTA) expression. DTA produces cell-autonomous apoptosis. Prox1DTA mice injected with tamoxifen at postnatal days (P)0 and P1, show significant DC and outer PC loss at P2-P4, that reaches ~70% by one month. Outer HC loss follows at P14 and it is almost complete at one month, while inner HCs remain intact. Neural innervation to the outer HCs is disrupted in Prox1DTA mice and auditory brainstem response thresholds in adults are 40-50 dB higher than in controls. The hearing deficit correlates with loss of cochlear amplification. Remarkably, in Prox1DTA mice the auditory epithelium preserves the ability to seal the reticular lamina and spiral ganglion neuron counts are normal, a key requirement for cochlear implant success. Our results highlight that cochlear SC pools should be appropriately replenished during HC regeneration strategies.

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“…The hepatic stellate cells are also called Ito cells, which store fat, produce excessive amounts of abnormal matrix including collagen, other glycoproteins and glycans, and matricellular proteins [4]. Thus, stellate cell activation results in abnormal extracellular matrix, both in quantity and composition [4]. Nonetheless, the regulation of hepatic stellate cell activities in hepatic fibrosis remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

“…A recent study suggests that the activation of the hepatic stellate cell causes accumulation of extracellular matrix and formation of scar, leading to deterioration in the hepatic functions [3]. The hepatic stellate cells are also called Ito cells, which store fat, produce excessive amounts of abnormal matrix including collagen, other glycoproteins and glycans, and matricellular proteins [4]. Thus, stellate cell activation results in abnormal extracellular matrix, both in quantity and composition [4].…”

Section: Introductionmentioning

confidence: 99%

Astragaloside Alleviates Hepatic Fibrosis Function via PAR2 Signaling Pathway in Diabetic Rats

Wang

Xiang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Astragaloside (AGS) extracted from radix astragalin (Huangqi) has been considered to be beneficial to liver diseases. In this study, we examined the role played by AGS in alleviating hepatic fibrosis function via protease-activated receptor-2 (PAR2) mechanisms. We hypothesized that AGS affects PAR2 signaling pathway thereby improving hepatic function in rats with hepatic fibrosis induced by carbon tetrachloride (CCl₄). We further hypothesized that AGS attenuates impaired hepatic function evoked by CCl₄ to a greater degree in diabetic animals. Methods: ELISA and Western Blot analysis were used to examine PAR2 signaling pathway in diabetic CCl₄-rats and non-diabetic CCl₄-rats. Results: AGS inhibited the protein expression of PAR2 and its downstream pathway PKA and PKCɛ in CCl₄-rats. Notably, the effects of AGS were greater in CCl₄-rats with diabetes. AGS also significantly attenuated the CCl₄-induced upregulations of pro-inflammatory cytokines, namely interleukin-1β, interleukin-6 and tumor necrosis factor-α accompanied with decreases of collagenic parameters such as hexadecenoic acid, laminin and hydroxyproline. Additionally, AGS improved the CCl₄-induced exaggerations of liver index and functions including alanine aminotransferase, aspartate aminotransferase. Moreover, TGF-β1, a marker of hepatic fibrosis, was increased in CCl₄-rats and AGS inhibited increases in TGF-β1 induced by CCl₄. Conclusions: AGS alleviates hepatic fibrosis by inhibiting PAR2 signaling expression and its effects are largely enhanced in diabetic animals. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of hepatic fibrosis; and results of our study are likely to shed light on strategies for application of AGS because it has potentially greater therapeutic effectiveness for hepatic fibrosis in diabetes.

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Hepatic stellate cells and astrocytes

Cited by 43 publications

References 110 publications

Development of Adenoviral Delivery Systems to Target Hepatic Stellate Cells In Vivo

Development of Adenoviral Delivery Systems to Target Hepatic Stellate Cells In Vivo

Selective Ablation of Pillar and Deiters' Cells Severely Affects Cochlear Postnatal Development and Hearing in Mice

Astragaloside Alleviates Hepatic Fibrosis Function via PAR2 Signaling Pathway in Diabetic Rats

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