Development of an in vitro model to test antifibrotic drugs on primary human liver myofibroblasts

Aoudjehane, Lynda; Boëlle, Pierre‐Yves; Bisch, Grégoire; Delelo, Rolland; Paye, François; Scatton, Olivier; Housset, Chantal; Becquart, Jérôme; Calmus, Yvon; Conti, Filoména

doi:10.1038/labinvest.2016.36

Cited by 11 publications

(4 citation statements)

References 38 publications

(46 reference statements)

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“…Primary human hepatocytes were isolated using the Human HepCell platform (IHU‐ICAN, Paris, France, http://www.ican-institute.org/category/plateformes) as previously described. [ 37 ] Ethical approval for the isolation of human hepatocytes was granted by the Persons Protection Committee (CPP Ile de France III) and by the French Ministry of Health (N°: COL 2929 and COL 2930).…”

Section: Methodsmentioning

confidence: 99%

Bifunctional Therapeutic Peptides for Targeting Malignant B Cells and Hepatocytes: Proof of Concept in Chronic Lymphocytic Leukemia

Simón‐Gracia

Savier

Parizot

et al. 2020

Advanced Therapeutics

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Protein-protein interactions are well recognized as therapeutic targets and therefore interfering peptides (IP) that block these interactions are receiving increasing attention. Four different tumor-penetrating peptides (TPPs) (iRGD, RPARPAR, Linear TT1 (LinTT1), and cyclic TT1 (TT1)) are associated to an IP that blocks the interaction between the protein phosphatase PP2A and its binding protein SET, generating new bifunctional peptides able to intracellularly target the PP2A/SET interaction in malignant B cells and tumoral hepatocytes. The TPPs are able to penetrate into B cells of patients suffering chronic lymphocytic leukemia (CLL) and into tumoral hepatocytes but not into B cells from healthy donors and healthy hepatocytes. The association of cargo does not affect the penetration of the TPPs in CLL B cells. All the bifunctional peptides induce apoptosis in human CLL B cells and tumoral hepatocytes, and stability tests reveal that iRGD-IP, RPARPAR-IP, and TT1-IP are stable after 24 h incubation in human serum. The iRGD associated with the IP significantly increases the survival of mice bearing xenograft models of CLL without any symptom of toxicity, suggesting that the bifunctional peptides may have a therapeutic application for selective tumoral targeting of PP2A/SET interaction, which is deregulated in several cancers, including CLL.

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Section: Methodsmentioning

confidence: 99%

Bifunctional Therapeutic Peptides for Targeting Malignant B Cells and Hepatocytes: Proof of Concept in Chronic Lymphocytic Leukemia

Simón‐Gracia

Savier

Parizot

et al. 2020

Advanced Therapeutics

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“…Hepatic fibrosis (HF) is a great health problem unless controlled it can progress to cirrhosis and primary liver cancer, which are responsible for most liver transplants and deaths [1]. HF is a healing respond of liver tissue damage.…”

Section: Introductionmentioning

confidence: 99%

Ameliorative Effect of Hesperidin on Carbon Tetrachloride Induced Liver Fibrosis in Rats

Abdel-sttar

Khalaf

Abo-Youssef

et al. 2017

Int J Pharm Pharm Sci

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Objective: Exposure to carbon tetrachloride leads to serious liver injury and fibrosis. This study was aimed to evaluate the hepatoprotective effects of hesperidin against carbon tetrachloride (CCl4)-induced liver fibrosis in rats compared with the reference drug silymarin.Methods: Wistar albino rats were divided into five groups, each of eight rats. Animals were allocated into a control group, corn oil group and fibrosis control group. The remaining two groups received in addition to CCl4, silymarin (100 mg/kg/d) as a reference treatment and hesperidin (200 mg/kg/d). At the end of experimental period, the biomarkers of specific fibrosis [hepatic transforming growth factor β1 (TGF-β1) and hydroxyproline (HYP)], liver function [serum alanine transaminase (ALT), aspartate transaminase (AST), albumin and total bilirubin], oxidative stress [hepatic malondialdehyde (MDA), glutathione (GSH) and catalase (CAT)], inflammatory [hepatic myeloperoxidase (MPO), serum tumor necrosis factor alpha (TNF-α)], relative liver weight, lipid profile [total cholesterol, serum triglycerides, high-density lipoprotein cholesterol (HDLCh) and low density lipoprotein cholesterol (LDL-Ch)] were evaluated, supported by liver histopathological study and immunohistochemistry of alpha-smooth muscle actin (α-SMA) in liver sections.Results: Hesperidin significantly decreased hepatic transforming growth factor β1, hydroxyproline, the serum liver function markers of ALT, AST and total bilirubin, the hepatic content of MDA and MPO activity, the serum pro-inflammatory cytokine TNF-α, relative liver weight, and the serum lipid profile markers cholesterol, triglycerides and LDL. On the other hand, Hesperidin significantly increased albumin, the hepatic content of GSH and CAT, and serum lipid profile of LDL. In addition, liver sections obtained from these groups showed marked histopathological and immunohistochemistry of α-SMA improvement. Conclusion:Hesperidin may be promising protective agent against liver fibrosis through improvement of liver function, modulation of the fibrous scar formation, anti-inflammatory and antioxidant potentials.

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“…Myofibroblast-like cells were generated from Of-hiPSC-and Ff-hiPSC-derived NCLCs. The previously reported differentiation efficiency of iPSCs into NCLCs was only 10-80% [12 ,21], whereas it was more than 90 % using our extracellular space [4,[26][27][28]. Thus, we stimulated hiPSC-derived myofibroblast-like cells with TGF-β and compared their levels of Col1a1 and αSMA expression with those of commercial human primary renal fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of human iPSC-derived myofibroblast-like cells

Suyama¹,

Ishida²,

Yoshimura³

et al. 2018

J Transl Sci

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Neural crest cells give rise to the peripheral nervous system, craniofacial tissues, and adult tissue-specific stem cells, which contribute to tissue homeostasis and regeneration. Misregulation of adult tissue-specific stem cells leads to a variety of diseases. Myofibroblasts, which cause fibrosis, are reported to be derived from tissuespecific stem cells, such as mesenchymal stem cells (MSCs). In this study, we report the generation of myofibroblast-like cells from neural crest-like cells derived from feeder-free human induced pluripotent stem cells (hiPSCs), using a novel protocol that could potentially generate sufficient myofibroblast-like cells for drug screening. The hiPSC-derived myofibroblast-like cells were sensitive to transforming growth factor (TGF)β stimulation, similar to human primary renal fibroblasts. TGF-β stimulation increased expression of collagen type1a1 in hiPSC-derived myofibroblast-like cells, and this effect was inhibited by treatment with a TGF-β inhibitor. These results indicate that hiPSC-derived myofibroblast-like cells could be a useful tool for in vitro antifibrotic drug screening.

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Development of an in vitro model to test antifibrotic drugs on primary human liver myofibroblasts

Cited by 11 publications

References 38 publications

Bifunctional Therapeutic Peptides for Targeting Malignant B Cells and Hepatocytes: Proof of Concept in Chronic Lymphocytic Leukemia

Bifunctional Therapeutic Peptides for Targeting Malignant B Cells and Hepatocytes: Proof of Concept in Chronic Lymphocytic Leukemia

Ameliorative Effect of Hesperidin on Carbon Tetrachloride Induced Liver Fibrosis in Rats

Development and characterization of human iPSC-derived myofibroblast-like cells

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