Dataset Information

Mesenchymal stem cells overexpressing hepatocyte nuclear factor-4 alpha alleviate liver injury by modulating anti-inflammatory functions in mice.

ABSTRACT:

Background

Mesenchymal stem cells (MSCs) can migrate to tissue injury sites where they can induce multipotential differentiation and anti-inflammation effects to treat tissue injury. When traditional therapeutic methods do not work, MSCs are considered to be one of the best candidates for cell therapy. MSCs have been used for treating several injury- and inflammation-associated diseases, including liver cirrhosis. However, the therapeutic effect of MSCs is limited. In some cases, the anti-inflammatory function of naïve MSCs is not enough to rescue tissue injury.

Methods

Carbon tetrachloride (CCl₄) was used to establish a mouse liver cirrhosis model. Enhanced green fluorescence protein (EGFP) and hepatocyte nuclear factor-4? (HNF-4?) overexpression adenoviruses were used to modify MSCs. Three weeks after liver injury induction, mice were injected with bone marrow MSCs via their tail vein. The mice were then sacrificed 3?weeks after MSC injection. Liver injury was evaluated by measuring glutamic-pyruvic transaminase (ALT) and glutamic oxalacetic transaminase (AST) levels. Histological and molecular evaluations were performed to study the mechanisms.

Results

We found that HNF-4?-overexpressing MSCs had a better treatment effect than unmodified MSCs on liver cirrhosis. In the CCl₄-induced mouse liver injury model, we found that HNF-4?-MSCs reduced inflammation in the liver and alleviated liver injury. In addition, we found that HNF-4? promoted the anti-inflammatory effect of MSCs by enhancing nitric oxide synthase (iNOS) expression, which was dependent on the nuclear factor kappa B (NF-?B) signalling pathway.

Conclusions

MSCs overexpressing HNF-4? exerted good therapeutic effects against mouse liver cirrhosis due to an enhanced anti-inflammatory effect. Gene modification is likely a promising method for improving the effects of cell therapy.

SUBMITTER: Ye Z

PROVIDER: S-EPMC6537220 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Mesenchymal stem cells overexpressing hepatocyte nuclear factor-4 alpha alleviate liver injury by modulating anti-inflammatory functions in mice.

Ye Zhenxiong Z Lu Wenfeng W Liang Lei L Tang Min M Wang Yunfeng Y Li Zhen Z Zeng Heping H Wang Aili A Lin Moubin M Huang Lei L Wang Hui H Hu Hai H

Stem cell research & therapy 20190527 1

<h4>Background</h4>Mesenchymal stem cells (MSCs) can migrate to tissue injury sites where they can induce multipotential differentiation and anti-inflammation effects to treat tissue injury. When traditional therapeutic methods do not work, MSCs are considered to be one of the best candidates for cell therapy. MSCs have been used for treating several injury- and inflammation-associated diseases, including liver cirrhosis. However, the therapeutic effect of MSCs is limited. In some cases, the ant ...[more]

PMID: 31133062

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Project description:UnlabelledMesenchymal stem cells (MSCs) exhibit immunosuppressive efficacy and significantly inhibit the formation of the atherosclerosis (AS) plaque in apolipoprotein E-knockout (apoE(-/-)) mice. Of note, the largest lymphoid organ, the skin, provides a readily accessible and ideal source of tissue for the isolation of MSCs: skin-derived MSCs (S-MSCs). However, the effect and the mechanism of the therapeutic properties of S-MSCs in the progression of AS are unclear. We therefore investigated a direct effect of S-MSC treatment in the formation of atherosclerotic plaque in apoE(-/-) mice. Fifty apoE(-/-) mice were divided into four groups: the control group (AS), the S-MSC treatment group (S-MSC treatment), the nuclear factor-κB (NF-κB)(-/-)-S-MSC treatment group (KO-S-MSC treatment), and the additional S-MSC migration group. Brachiocephalic artery ultrasound biomicroscope (UBM) analysis showed that S-MSC treatment significantly reduced lesion size compared with the control groups (p < .01). Histological studies demonstrated that the plaque area of the mouse aortic arch was significantly decreased after S-MSC treatment. All alterations were dependent on NF-κB activation. After tail-vein injection, S-MSCs were capable of migrating to atherosclerotic plaque and selectively taking up residence near macrophages. S-MSC treatment reduced the release of the proinflammatory cytokine tumor necrosis factor (TNF)-α and increased the expression of the anti-inflammatory factor interleukin (IL)-10 in the atherosclerotic plaque, which was also dependent on NF-κB activation. In vitro, we found lipopolysaccharide (LPS) induced NF-κB-dependent expression of cyclooxygenase-2 (COX-2) in S-MSCs. Prostaglandin E2 (PGE2) expression was markedly increased after LPS-stimulated S-MSCs were cocultured with macrophages. LPS-stimulated macrophages produced less TNF-α/IL-1β and more IL-10 when cultured with S-MSCs, and although both were dependent upon NF-κB, the release of IL-10 was diminished if the S-MSCs were pretreated with a COX-2 inhibitor or an EP2/EP4 antagonist. Our data demonstrated that S-MSCs inhibited the formation of the atherosclerotic plaque in apoE(-/-) mice by modulating the functionality of macrophages, suggesting that S-MSCs may potentially have a role in stem cell-based therapy for AS.SignificanceA combination of in vitro and in vivo experiments showed that skin-derived mesenchymal stem cells (S-MSCs) can attenuate the plaque size of atherosclerosis. This is probably because S-MSCs beneficially modulate the response of macrophages through an increased release of prostaglandin E2 acting on the EP2 and EP4 receptors of the macrophages, stimulating the production and release of the anti-inflammatory cytokine interleukin-10, and decreasing the production of proinflammatory cytokine tumor necrosis factor-α. S-MSCs inhibited the formation of the atherosclerotic plaque in apolipoprotein E-knockout mice by modulating the functionality of macrophages, and the suppressive property of S-MSCs is dependent on NF-κB signaling. This study provides direct evidence that S-MSCs have a potent immunosuppressive effect in the development of atherosclerosis in mice, suggesting that S-MSCs can easily be cultured and have similar function to bone marrow-derived MSCs, a promising cell source for stem cell-based therapies of atherosclerosis, and possibly also in transplantation.

Project description:HNF4α is a nuclear receptor regulating the transcription of genes involved mainly in development, cell differentiation and metabolism. Opposite functions for the two classes of P1 and P2 isoforms of HNF4α have recently been highlighted. These classes include 12 variants of HNF4α that can be expressed by the use of two promoters and by alternative splicing. Until now, the characterization of this transcription factor has ignored this diversity and has remained confined to the study of a fraction of the isoforms. We therefore wanted to clarify the situation by specifically characterizing the transcriptional functions of the 12 isoforms of HNF4α. We have generated for this purpose stable lines expressing each isoform of HNF4α in HCT 116 cells. We analyzed the whole transcriptome associated with each isoform by sequencing RNA, as well as their proteome by a BioID approach coupled to quantitative mass spectrometry. We noted major differences in the transcriptional function of the 12 isoforms. The α4, α5 and α6 isoforms have been characterized for the first time, and show a greatly reduced transcriptional potential. We have shown that these isoforms are unable to recognize the consensus response element of HNF4α. The α1 and α2 isoforms are the most potent regulators of gene expression, while the α3 isoform exhibits significantly reduced activity. Several transcription factors and coregulators have been identified as potential specific partners for certain HFH4α isoforms. The IRF-2BP2 co-repressor interacts specifically with isoforms which include the long form of the F domain of HNF4α. This specific interaction could explain the large number of genes modulated negatively by α1 and α2 compared to α3. The analysis integrating the vast amount of transcriptomic and proteomic data allows the identification of transcriptional regulatory mechanisms specific to certain isoforms, demonstrating the importance of considering all isoforms which can have diverse functions.

Dataset Information

Mesenchymal stem cells overexpressing hepatocyte nuclear factor-4 alpha alleviate liver injury by modulating anti-inflammatory functions in mice.

Background

Methods

Results

Conclusions

Publications

Mesenchymal stem cells overexpressing hepatocyte nuclear factor-4 alpha alleviate liver injury by modulating anti-inflammatory functions in mice.

Similar Datasets

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