Adipose-derived mesenchymal stem cells transplantation facilitate experimental peritoneal fibrosis repair by suppressing epithelial–mesenchymal transition

Wakabayashi, Keiichi; Hamada, Chikuma; Kanda, Reo; Nakano, Takanori; Io, Hiroaki; Horikoshi, Satoshi; Tomino, Yasuhiko

doi:10.1007/s40620-014-0133-5

Cited by 29 publications

(19 citation statements)

References 30 publications

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“…It is accepted that activated myofibroblasts that accumulate in fibrotic tissues may derive from different sources [27][28][29]. At least five possible origins for peritoneal activated fibroblasts have been described: (1) activation of resident fibroblasts or stem cells; (2) circulating fibrocytes from the bone marrow; (3) endothelial-to-mesenchymal transition (EndMT); (4) adipose-derived progenitor cells; and (5) the mesenchymal conversion of MCs via MMT [12,[30][31][32][33][34][35][36][37]. The first two mechanisms have been widely implicated in the pathogenesis of adhesions [1,6,14].…”

Section: Discussionmentioning

confidence: 99%

Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

et al. 2016

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Peritoneal adhesions (PAs) are fibrotic bands formed between bowel loops, solid organs, and the parietal peritoneum, which may appear following surgery, infection or endometriosis. They represent an important health problem with no effective treatment. Mesothelial cells (MCs) line the peritoneal cavity and undergo a mesothelial-to-mesenchymal transition (MMT) under pathological conditions, transforming into myofibroblasts, which are abundant in peritoneal fibrotic tissue. The aim of this study was to investigate if peritoneal MCs undergo a MMT contributing to the formation of post-surgical adhesions. Biopsies from patients with PAs were analysed by immunohistochemistry, immunofluorescence, and quantitative RT-PCR. A mouse model of PAs based on ischaemic buttons was used to modulate MMT by blocking the transforming growth factor-beta (TGF-β) pathway. The severity of adhesions and MMT-related marker expression were studied. We observed myofibroblasts derived from the conversion of MCs in submesothelial areas of patients with PAs. In addition, MMT-related markers were dysregulated in adhesion zones when compared to distant normal peritoneal tissue of the same patient. In animal experiments, blockage of TGF-β resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the adhesions. These data indicate for the first time that MMT is involved in PA pathogenesis. This finding opens new therapeutic strategies to interfere with adhesion formation by modulating MMT with a wide range of pharmacological agents.

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Section: Discussionmentioning

confidence: 99%

Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

et al. 2016

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“…ADSCs also presented an anti-fibrotic effect in muscle injury [ 47 ]. The therapeutic effects of ADSC transplantation on peritoneal fibrosis are facilitated by suppressing epithelial-mesenchyme transition, and modulating inflammation and angiogenesis during the early phase of tissue repair [ 48 ]. Further studies have revealed ADSCs could downregulate pulmonary fibrosis induced by repetitive bleomycin administration [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway

Zhang

Gao

et al. 2016

Stem Cell Res Ther

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BackgroundHypertrophic scars (HS) generally occur after injury to the deep layers of the dermis, resulting in functional deficiency for patients. Growing evidence has been identified that the supernatant of adipose tissue-derived stem cells (ADSCs) significantly ameliorates fibrosis of different tissues, but limited attention has been paid to its efficacy on attenuating skin fibrosis. In this study, we explored the effect and possible mechanism of ADSC-conditioned medium (ADSC-CM) on HS.MethodReal-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of collagen I (Col1), collagen III (Col3), and α-smooth muscle actin (α-SMA) after fibroblasts and cultured HS tissues were stimulated with ADSC-CM and p38 inhibitor/activator. Immunofluorescence staining was performed to test the expression of α-SMA. Masson’s trichrome staining, hematoxylin and eosin (H&E) staining, and immunohistochemistry staining were carried out to assess the histological and pathological change of collagen in the BALB/c mouse excisional model. All data were analyzed by using SPSS17.0 software. Statistical analysis was performed by Student’s t tests.ResultsThe in vitro and ex vivo study revealed ADSC-CM decreased the expression of Col1, Col3, and α-SMA. Together, thinner and orderly arranged collagen was manifested in HS tissues cultured with ADSC-CM. Dramatically, the assessed morphology showed an accelerated healing rate, less collagen deposition, and col1- and col3-positive cells in the ADSC-CM treated group. Importantly, the protein level of p-p38 was downregulated in a concentration-dependent manner in HS-derived fibroblasts with ADSC-CM treatment, which further decreased the expression of p-p38 after the application of its inhibitor, SB203580. SB203580 led to an obvious decline in the expression of Col1, Col3, and α-SMA in fibroblasts and cultured HS tissues and presented more ordered arrangement and thinner collagen fibers in BALB/c mice. Lastly, anisomycin, an agonist of p38, upregulated the expression of fibrotic proteins and revealed more disordered structure and denser collagen fibers.ConclusionThis study demonstrated that ADSC-CM could decrease collagen deposition and scar formation in in vitro, ex vivo and in vivo experiments. The regulation of the p38/MAPK signaling pathway played an important role in the process. The application of ADSC-CM may provide a novel therapeutic strategy for HS treatment, and the anti-scarring effect can be achieved by inhibition of the p38/MAPK signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0356-6) contains supplementary material, which is available to authorized users.

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“…Numerous studies have demonstrated that ADSCs may repair injured tissues by inhibiting inflammation ( 24 , 52 ), and may also inhibit transforming growth factor (TGF)-β1 signaling in animal models of experimental peritoneal fibrosis ( 52 ). Notably, inflammatory cytokines, such as TGF-β and epidermal growth factor, may stimulate EMT of tumor cells ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

3D-cultured adipose tissue-derived stem cells inhibit liver cancer cell migration and invasion through suppressing epithelial-mesenchymal transition

et al. 2017

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Abstract. adipose tissue-derived stem cells (adScs) are considered promising candidates for stem cell therapy; however, the tumorigenicity of adScs remains controversial. the present study aimed to investigate the association between adScs and liver cancer cells, and to determine whether culture methods could influence the effects of ADSCs on liver cancer cell growth in vitro. liver cancer cells were treated with adScs-conditioned medium (cm) that was collected using the two-dimensional (2d) culture method, sphere culture method, or three-dimensional (3d) culture method. after that, cell viability and apoptosis were measured using ccK-8 and annexin V-fitc assay, respectively; the cell motility and adhesive capacity were analyzed by scratch wound healing and cell adhesion assay, respectively; the cell migration and invasion were examined by transwell units; and the molecular mechanisms of adScs on effecting epithelial mesenchymal transition signaling pathway were further analyzed. the results demonstrated that adScs-cm was able to inhibit the growth of liver cancer cells by inhibiting cell proliferation and promoting cell apoptosis, as well as by suppressing cell motility, adhesive capacity, migration and invasion. in addition, adScs-cm was able to suppress cell growth via the downregulation of epithelial-mesenchymal transition signaling. notably, the enhanced inhibitory effects of adScs on liver cancer cell growth could be achieved after cultu ring using a 3d approach. these findings suggested that adScs may provide a novel promising therapeutic approach for the treatment of patients with liver cancer, and the 3d culture method may provide a novel approach to explore the association between adScs and cancer.

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Adipose-derived mesenchymal stem cells transplantation facilitate experimental peritoneal fibrosis repair by suppressing epithelial–mesenchymal transition

Abstract: ASC transplantation facilitates peritoneal repair by suppressing EMT and modulating inflammation and angiogenesis during the early phase of tissue repair in experimental PF.

Cited by 29 publications

References 30 publications

Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway

3D-cultured adipose tissue-derived stem cells inhibit liver cancer cell migration and invasion through suppressing epithelial-mesenchymal transition

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