Dataset Information

Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis.

ABSTRACT: Chronic hepatic inflammation from multiple etiologies leads to a fibrogenic response that can progress to cirrhosis and liver failure. Transplantation of human amniotic epithelial cells (hAEC) from term delivered placenta has been shown to decrease mild to moderate hepatic fibrosis in a murine model. To model advanced human liver disease and assess the efficacy of hAEC therapy, we transplanted hAEC in mice with advanced hepatic fibrosis. Immunocompetent C57BL/6 mice were administered carbon tetrachloride (CCl(4)) twice weekly resulting in bridging fibrosis by 12 weeks. hAEC (2 × 10(6)) were infused via the tail vein at week 8 or weeks 8 and 10 (single and double dose, respectively). Human cells were detected in mouse liver four weeks after transplantation showing hAEC engraftment. CCl(4) treated mice receiving single or double hAEC doses showed a significant but similar decrease in liver fibrosis area associated with decreased activation of collagen-producing hepatic stellate cells and decreased hepatic protein levels of the pro-fibrogenic cytokine, transforming growth factor-beta1. CCl(4) administration caused hepatic T cell infiltration that decreased significantly following hAEC transplantation. Hepatic macrophages play a crucial role in both fibrogenesis and fibrosis resolution. Mice exposed to CCl(4) demonstrated increased numbers of hepatic macrophages compared to normal mice; the number of macrophages decreased significantly in CCl(4) treated mice given hAEC. These mice had significantly lower hepatic protein levels of the chemokine monocyte chemoattractant protein-1 than mice given CCl(4) alone. Alternatively activated M2 macrophages are associated with fibrosis resolution. CCl(4) treated mice given hAEC showed increased expression of genes associated with M2 macrophages including YM-1, IL-10 and CD206. We provide novel data showing that hAEC transplantation induces a wound healing M2 macrophage phenotype associated with reduction of established hepatic fibrosis that justifies further investigation of this potential cell-based therapy for advanced hepatic fibrosis.

SUBMITTER: Manuelpillai U

PROVIDER: S-EPMC3375296 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis.

Manuelpillai Ursula U Lourensz Dinushka D Vaghjiani Vijesh V Tchongue Jorge J Lacey Derek D Tee Jing-Yang JY Murthi Padma P Chan James J Hodge Alexander A Sievert William W

PloS one 20120614 6

Chronic hepatic inflammation from multiple etiologies leads to a fibrogenic response that can progress to cirrhosis and liver failure. Transplantation of human amniotic epithelial cells (hAEC) from term delivered placenta has been shown to decrease mild to moderate hepatic fibrosis in a murine model. To model advanced human liver disease and assess the efficacy of hAEC therapy, we transplanted hAEC in mice with advanced hepatic fibrosis. Immunocompetent C57BL/6 mice were administered carbon tetr ...[more]

PMID: 22719909

Similar Datasets

Project description:BACKGROUND & AIMS:De novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH. METHODS:We analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastography measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy. RESULTS:A relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P = .004 vs placebo), 23% given GS-0976 5 mg (P = .43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P = .002). Changes in magnetic resonance elastography-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was observed in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were observed in patients given GS-0976. CONCLUSIONS:In a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555.

Project description:As a featured ocular inflammatory disease, autoimmune uveitis is the major cause of blindness in the clinic. Although current immunosuppressive regimens can alleviate the progression of autoimmune uveitis, they have serious side effects. Therefore, an alternative therapeutic strategy is urgently required. The present study investigated the therapeutic efficacy of human amniotic epithelial cells (hAECs) on autoimmune uveitis in a rat model. Herein, experimental autoimmune uveitis (EAU) was induced in rats via a subcutaneous injection of interphotoreceptor retinoid-binding protein. EAU rats were treated with hAECs or the vehicle solution via a subretinal injection on day 0 and day 6 after immunization, and rats were sacrificed on day 12 and day 18 for further analysis. The pathological development of EAU was evaluated by slit lamp microscopy. Immune cell infiltration and retinal structure damage were examined by histological examination of hematoxylin and eosin (H&E) and immunofluorescence staining. T-cell subsets were detected by flow cytometry, and the levels of inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). hAEC treatment ameliorated the pathological progression of EAU and preserved the retinal structure organization and thickness, especially in the preventive group that received a subretinal injection on day 0. Moreover, hAECs inhibited the retinal infiltration of macrophages and T-cells. Mechanistically, hAECs modulated the balance of T-cell subsets by downregulating T helper (Th)17 cells and upregulating T regulatory (Treg) cells, as confirmed by decreased interleukin (IL)-17 and increased IL-10 levels in the spleens and lymph nodes of EAU rats. Furthermore, hAECs improved the local cytokine environment in EAU rats by suppressing the monocyte chemoattractant protein (MCP)-1, IL-17 and interferon (IFN)-? levels and enhancing the IL-10 in the aqueous humor. Therefore, subretinal transplantation of hAECs in EAU rats ameliorated ocular inflammation, preserved the retinal structure and coordinated the immune balance. The current study provides a novel therapeutic strategy for autoimmune uveitis and related ocular inflammatory diseases in the clinic.

Dataset Information

Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis.

Publications

Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets