Topical transplantation of mesenchymal stem cells accelerates gastric ulcer healing in rats

2008 ◽  
Vol 294 (3) ◽  
pp. G778-G786 ◽  
Author(s):  
Yujiro Hayashi ◽  
Shingo Tsuji ◽  
Masahiko Tsujii ◽  
Tsutomu Nishida ◽  
Shuji Ishii ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Gastric Ulcer ◽  
Growth Factor ◽  
Ulcer Healing ◽  
Gastric Wall ◽  
Female Rats ◽  
Male Rats ◽  
Gastric Ulcers ◽  
Gastric Ulcer Healing

Mesenchymal stem cells (MSCs), a subpopulation of adult somatic stem cells, are an attractive stem cell source in regenerative medicine because of their multipotentiality. We examined the effects of MSC transplantation on gastric ulcer healing. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in culture, were characterized by flow cytometry and reverse transcription-polymerase chain reaction. Gastric ulcers were induced by serosal application of acetic acid on the anterior wall of the stomach in female rats. Either MSCs (labeled with PKH67; 1×107 cells) or vehicle was injected into the gastric wall surrounding the ulcer. The healing process of the ulcer and the influence of anti-vascular endothelial growth factor (VEGF) antibody were examined. CD29-positive, CD90-positive, CD34-negative, and CD45-negative MSCs expressed mRNAs for VEGF and hepatocyte growth factor (HGF). The MSCs were transplantable to the gastric tissue surrounding the ulcer, where a majority of the engrafted cells were positive for vimentin. The transplantation significantly accelerated gastric ulcer healing compared with controls. The engrafted MSCs also expressed VEGF and HGF. Administration of anti-VEGF neutralizing antibody dose dependently reduced the MSC-induced promotion of ulcer healing. In conclusion, MSC transplantation accelerated gastric ulcer healing, possibly through the induction of angiogenesis in the gastric mucosa via the secretion of VEGF. The beneficial effects of MSCs might be mediated not only by their differentiation into gastric interstitial cells, but also by their ability to supply angiogenic factors.

scholarly journals Gastric ulcer healing in the rat: kinetics and localisation of de novo procollagen synthesis

Gut ◽  
1997 ◽  
Vol 41 (2) ◽  
pp. 187-194 ◽  
Author(s):  
M Shahin ◽  
A Gillessen ◽  
T Pohle ◽  
C Weber ◽  
D Schuppan ◽  
...  
Keyword(s):  
Gastric Ulcer ◽  
Ulcer Healing ◽  
De Novo ◽  
Gastric Wall ◽  
In Situ Hybridisation ◽  
Muscularis Propria ◽  
Gastric Ulcers ◽  
Type I ◽  
Gastric Ulcer Healing ◽  
Transcript Levels

Background and aims—To gain further insight into the role of the extracellular matrix during healing of peptic ulcers, sequential changes of procollagen expression were studied over 30 days of ulcer healing.Materials and methods—Procollagens α1(I), α1(III), and α1(IV) RNA and their polypeptides were assessed in acetic acid induced rat gastric ulcers by in situ hybridisation and immunohistochemistry.Results—Three days after ulcer induction, intense hybridisation signals were obtained with all probes, with procollagen α1(I) showing the highest transcript levels. Procollagen gene expression remained elevated up to day 15, but was reduced to initial low levels on day 30. Immunohistochemical staining documented increased deposition of the three procollagen types parallel to their respective transcript levels, again with type I showing the earliest and the most prominent deposits. The highest procollagen transcript levels were found in the intact submucosa surrounding the ulcer margins, followed by the muscularis propria and the serosa, with the lamina propria exhibiting the lowest transcript levels.Conclusion—The procollagens studied are regulated differentially at the transcriptional and post-transcriptional levels. The early onset and long duration of procollagen expression as well as the involvement of all layers of the gastric wall points to their central structural and functional role in gastric ulcer healing.

Bacterial colonization and healing of gastric ulcers: the effects of epidermal growth factor

2000 ◽  
Vol 278 (1) ◽  
pp. G105-G112 ◽  
Author(s):  
Susan N. Elliott ◽  
J. L. Wallace ◽  
W. McKnight ◽  
D. G. Gall ◽  
J. A. Hardin ◽  
...  
Keyword(s):  
Gastric Ulcer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Ulcer Healing ◽  
Bacterial Colonization ◽  
Neutrophil Infiltration ◽  
Gastric Ulcers ◽  
Gastric Ulcer Healing ◽  
Epidermal Growth

.—Experimental gastric ulcers are rapidly colonized by various bacteria, resulting in significantly impaired healing. Epidermal growth factor (EGF) is capable of preventing bacterial colonization of the healthy intestinal mucosa. In this study, we examined the possibility that EGF accelerates gastric ulcer healing by reducing bacterial colonization of the ulcer. Gastric ulcers were induced by serosal application of acetic acid. The effect of daily administration of EGF on ulcer healing and bacterial colonization was assessed and compared with the effect of daily treatment with broad-spectrum antibiotics. EGF administration reduced colonization levels and accelerated ulcer healing as effectively as the antibiotic treatment. EGF was without effect on acid secretion or neutrophil infiltration into the ulcer. Bacterial growth was not inhibited in the presence of EGF in vitro. These results demonstrate that EGF reduces bacterial colonization during an established infection of a compromised mucosal surface. This effect may contribute to the ability of EGF to accelerate gastric ulcer healing. This effect is acid independent and not due to an anti-inflammatory effect or to direct bactericidal actions.

S1624 Mesenchymal Stem Cells Transplantation Accelerates Gastric Ulcer Healing in Rats

2008 ◽  
Vol 134 (4) ◽  
pp. A-237
Author(s):  
Yujiro Hayashi ◽  
Shingo Tsuji ◽  
Masahiko Tsujii ◽  
Tsutomu Nishida ◽  
Shuji Ishii ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Gastric Ulcer ◽  
Ulcer Healing ◽  
Gastric Ulcer Healing ◽  
Stem Cells Transplantation

Annexin-1 modulates repair of gastric mucosal injury

2008 ◽  
Vol 294 (3) ◽  
pp. G764-G769 ◽  
Author(s):  
Gary R. Martin ◽  
Mauro Perretti ◽  
Roderick J. Flower ◽  
John L. Wallace
Keyword(s):  
Gastric Ulcer ◽  
Ulcer Healing ◽  
Mucosal Injury ◽  
Formyl Peptide Receptor ◽  
Gastric Mucosal Damage ◽  
Gastric Ulcers ◽  
Wild Type ◽  
Gastric Ulcer Healing ◽  
Annexin 1 ◽  
Deficient Mice

Annexin-1 is a glucocorticoid-inducible protein that plays an important effector role in the resolution of inflammation and has recently been shown to contribute to the resistance of the stomach to injury. Using an integrated genetic and pharmacological approach, we have tested the hypothesis that annexin-1 contributes to the healing of mucosal injury, given that such injury is accompanied by an inflammatory response, which is often associated with an overexpression of annexin-1 expression. Gastric ulcers were induced in mice through serosal application of acetic acid. Annexin-1 expression during the healing of the ulcers was examined. The effects on gastric ulcer healing of treatment with an annexin-1 mimetic (Ac2-26), an antagonist of the annexin-1 receptor (Boc2), or a glucocorticoid (dexamethasone) were examined. Finally, susceptibility to and healing of indomethacin-induced gastric lesions were compared in wild-type and annexin-1-deficient mice. Expression of annexin-1 was significantly increased in the gastric ulcer margin throughout the healing process. Treatment with an annexin-1 mimetic (Ac2-26) significantly enhanced gastric ulcer healing. In contrast, both dexamethasone and an formyl peptide receptor-like-1 (FPRL-1) antagonist impaired the early phase of ulcer healing. Annexin-1-deficient mice exhibited the same susceptibility as wild-type mice to indomethacin-induced gastric damage, but the healing of that damage was impaired in the former. These data support the hypothesis that annexin-1 contributes significantly to the process of healing of gastric mucosal damage.

Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors

2006 ◽  
Vol 290 (5) ◽  
pp. G1041-G1050 ◽  
Author(s):  
Tsutomu Nishida ◽  
Shingo Tsuji ◽  
Arata Kimura ◽  
Masahiko Tsujii ◽  
Syuji Ishii ◽  
...  
Keyword(s):  
Gastric Ulcer ◽  
Ulcer Healing ◽  
Angiogenic Factors ◽  
Gastric Epithelium ◽  
Gastric Ulcers ◽  
Ulcer Formation ◽  
Peptic Ulcers ◽  
Converting Enzyme ◽  
Potent Inducer ◽  
Gastric Ulcer Healing

Endothelin (ET)-1 is a potent inducer of peptic ulcers. The roles of ET-1 in ulcer healing, however, have remained unclear, and these were investigated in mice. Gastric ulcers were induced in mice by serosal application of acetic acid. Three days later, mice were given a neutralizing ET-1 antibody or nonimmunized serum. The ulcer size, amount of fibrosis and myofibroblasts, and localization of ET-1 and ETA/B receptors were analyzed. To elucidate the mechanisms underlying the effects of ET-1, we examined the proliferation, migration, and release of growth and angiogenic factors in gastric myofibroblasts with or without ET-1. The expression of prepro-ET-1 (an ET-1 precursor) and ET-converting enzyme-1 was examined in gastric myofibroblasts using RT-PCR. Immunoneutralization of ET-1 delayed gastric ulcer healing. The areas of fibrosis and myofibroblasts were smaller in the anti-ET-1 antibody group than in the control. ET-1 was expressed in the gastric epithelium, myofibroblasts, and other cell types. ETA receptors, but not ETB receptors, were present in myofibroblasts. ET-1 increased proliferation and migration of gastric myofibroblasts. ET-1 stimulated the release of hepatocyte growth factor, VEGF, PGE2, and IL-6 from gastric myofibroblasts. mRNA for prepro-ET-1 and ET-converting enzyme-1 was also expressed. ET-1 promotes the accumulation of gastric myofibroblasts and collagen fibrils at gastric ulcers. ET-1 also stimulates migration and proliferation of gastric myofibroblasts and enhances the release of growth factors, angiogenic factors, and PGE2. Thus ET-1 has important roles not only in ulcer formation but also in ulcer healing via mobilizing myofibroblasts and inducing production of stroma-derived factors.

Mesenchymal stem cells promote healing of nonsteroidal anti-inflammatory drug-related peptic ulcer through paracrine actions in pigs

2019 ◽  
Vol 11 (516) ◽  
pp. eaat7455 ◽  
Author(s):  
Xianfeng Xia ◽  
Kai Fung Chan ◽  
Gerald Tsz Yau Wong ◽  
Peng Wang ◽  
Liu Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Peptic Ulcer ◽  
Gastric Ulcer ◽  
Stem Cell ◽  
Protein Kinase ◽  
Ulcer Healing ◽  
Cell Phenotype ◽  
Submucosal Injection ◽  
Anti Inflammatory

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most important causes of peptic ulcer disease in high-income countries. Proton pump inhibitors are the current standard treatment; however, safety and long-term adverse effects of using these drugs are attracting more and more concerns in recent years. Using a porcine model of NSAID-related gastric ulcer, we herein show that adipose-derived mesenchymal stem cells (ADMSCs) delivered by endoscopic submucosal injection promoted ulcer healing with less inflammatory infiltration and enhanced reepithelization and neovascularization at day 7 and day 21 when compared with the controls (saline injection). However, only few engrafted ADMSCs showed myofibroblast and epithelial cell phenotype in vivo, suggesting the ulcer healing process might be much less dependent on the stem cell transdifferentiation. Further experiment with submucosal injection of MSC-derived secretome revealed a therapeutic efficacy comparable to that of stem cell transplantation. Profiling analysis showed up-regulation of genes associated with inflammation, granulation formation, and extracellular matrix remodeling at day 7 after injection of MSC-derived secretome. In addition, the extracellular signal–regulated kinase/mitogen-activated protein kinase and the phosphoinositide-3-kinase/protein kinase B pathways were activated after injection of ADMSCs or MSC-derived secretome. Both signaling pathways were involved in mediating the major events critical to gastric ulcer healing, including cell survival, migration, and angiogenesis. Our data suggest that endoscopic submucosal injection of ADMSCs serves as a promising approach to promote healing of NSAID-related peptic ulcer, and the paracrine effectors released from stem cells play a crucial role in this process.

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