scholarly journals Hyaluronan Accelerates Intestinal Mucosal Healing through Interaction with TSG-6

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1074 ◽  
Author(s):  
Giusy Sammarco ◽  
Mohammad Shalaby ◽  
Sudharshan Elangovan ◽  
Luciana Petti ◽  
Giulia Roda ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Wound Repair ◽  
Mucosal Healing ◽  
Mucosal Inflammation ◽  
Intestinal Epithelial ◽  
Beneficial Effects ◽  
Distal Ulcerative Colitis ◽  
Epithelial Regeneration

Hyaluronan (HA) has proven to be beneficial in the treatment of several diseases. Recently, it has been shown that the local application of HA (IBD98E) improves endoscopic and clinical outcomes in subjects with active distal ulcerative colitis (UC). However, the mechanisms by which this polysaccharide exerts its beneficial effects are unclear. Here, we demonstrated that HA treatment in vitro and in vivo improved mucosal healing by accelerating intestinal epithelial regeneration. Indeed, mice treated with HA showed a faster recovery from colitis and reduced endoscopic signs of mucosal inflammation compared to those receiving saline. Furthermore, histological analysis revealed less ulcerated mucosa in mice treated with HA, characterized by re-epithelialized areas. TSG-6, the secreted product of TNF-stimulated gene-6, is an HA-binding protein shown previously to have tissue-protective properties and promote wound healing. Mucosal levels of TSG-6 increased in UC patients compared to the healthy controls and also after wounding in mice. TSG-6 deletion prevented the beneficial properties of HA in mucosal wound repair, suggesting that the interaction of HA with TSG-6 is crucial for intestinal epithelial regeneration. Overall these results are consistent with HA having a therapeutic effect via the promotion of mucosal healing in patients with ulcerative colitis.

scholarly journals Interleukin-10 Expands Transit-Amplifying Cells While Depleting Lgr5+ Stem Cells via Inhibition of Wnt and Notch Signaling

2020 ◽  
Author(s):  
Fan Deng ◽  
Jingjuan Hu ◽  
Xiao Yang ◽  
Yifan Wang ◽  
Kexuan Liu
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Interleukin 10 ◽  
Mucosal Healing ◽  
Mucosal Barrier ◽  
Inflammatory Factor ◽  
Epithelial Regeneration ◽  
Immune Mediated

Abstract Background & Aims: Epithelial regeneration is essential for homeostasis and mucosal barrier repair. In infectious and immune-mediated intestinal diseases, interleukin (IL)-10 is thought to enhance these processes. We aimed to define the mechanism by which IL-10 played in mucosal healing or injury.Methods: Intestinal stem cells (ISCs) cultures and mice were treated with recombinant mice IL-10 (rmIL-10). The level of cell proliferation, differentiation, death and related signaling pathways for self-renewal of ISCs were measured in vitro and in vivo.Results: It was uncovered that rmIL-10 increased the size and death, but reduced the total number of organoids. In addition, rmIL-10 depleted Lgr5+ ISCs and reduced epithelial proliferation, but enhanced the differentiation of epithelial cells and expanded numbers of transit-amplifying (TA) cells. These changes are related to the decrease of Wnt and Notch signals in vivo and in vitro. Meanwhile, increased expression of Paneth cells and decreased expression of enteroendocrine cells and goblet cells were induced by rmIL-10.Conclusions: IL-10 reduces the survival of Lgr5+ ISCs and proliferation of epithelial cells by inhibiting Notch and Wnt signaling, but promotes enhanced the differentiation of epithelial cells and expanded numbers of TA cells. Therefore, IL-10 acts as an anti-inflammatory factor, but may damage intestinal mucosa repair and maybe a potential target for the treatment of intestinal injury.

scholarly journals Platelet-Rich Plasma-Derived Exosomal USP15 Promotes Cutaneous Wound Healing via Deubiquitinating EIF4A1

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Yan Xu ◽  
Ze Lin ◽  
Lei He ◽  
Yanzhen Qu ◽  
Liu Ouyang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Repair ◽  
Platelet Rich Plasma ◽  
Healing Process ◽  
Cell Counting ◽  
Wound Healing Process ◽  
Hacat Cells ◽  
Epithelial Regeneration

Epithelial regeneration is an essential wound healing process, and recent work suggests that different types of exosomes (Exos) can improve wound repair outcomes by promoting such epithelial regeneration. Platelet-rich plasma (PRP) is known to facilitate enhanced wound healing, yet the mechanisms underlying its activity are poorly understood. To explore these mechanisms, we first isolated PRP-derived Exos (PRP-Exos). Using immortalized keratinocytes (HaCaT cells) treated with PBS, PRP, or PRP-Exos, we conducted a series of in vitro Cell Counting Kit-8 (CCK-8), EdU, scratch wound, and transwell assays. We then established a wound defect model in vivo in mice and assessed differences in the mRNA expression within these wounds to better understand the basis for PRP-mediated wound healing. The functions of PRP-Exos and USP15 in the context of wound healing were then confirmed through additional in vitro and in vivo experiments. We found that PRP-Exos effectively promoted the in vitro proliferation, migration, and wound healing activity of HaCaT cells. USP15 was further identified as a key mediator through which these PRP-Exos were able to promote tissue repair both in vitro and in vivo. At a mechanistic level, USP15 enhanced the functional properties of HaCaT cells by promoting EIF4A1 deubiquitination. Thus, PRP-Exos and USP15 represent promising tools that can promote wound healing via enhancing epithelial regeneration.

Adhesion of Dairy Propionibacteria to Intestinal Epithelial Tissue In Vitro and In Vivo

2002 ◽  
Vol 65 (3) ◽  
pp. 534-539 ◽  
Author(s):  
GABRIELA ZÁRATE ◽  
VILMA I. MORATA de AMBROSINI ◽  
ADRIANA PEREZ CHAIA ◽  
SILVIA N. GONZÁLEZ
Keyword(s):  
Surface Characteristics ◽  
Epithelial Tissue ◽  
Intestinal Epithelial ◽  
Adhesive Properties ◽  
Bacterial Surface ◽  
Beneficial Effects ◽  
Adhesion Ability ◽  
Dairy Propionibacteria

Adhesion to the intestinal mucosa is a desirable property for probiotic microorganisms and has been related to many of their health benefits. In the present study, 24 dairy Propionibacterium strains were assessed with regard to their hydrophobic characteristics and their autoaggregation and hemagglutination abilities, since these traits have been shown to be indicative of adherence in other microorganisms. Six strains were further tested for their capacity to adhere to ileal epithelial cells in vitro and in vivo. The results of the study showed that propionibacteria were highly hydrophilic, and hemagglutination and autoaggregation were properties not commonly found among these microorganisms. No relationship was found between surface characteristics and adhesion ability, since hemagglutinating, autoaggregating, and nonautoaggregating bacteria were able to adhere to intestinal cells both in vitro and in vivo. Microscopic examination revealed that autoaggregating cells adhered in clusters, with adhesion being mediated by only a few bacteria, whereas the hemagglutinating and nonautoaggregating strains adhered individually or in small groups making contact with each epithelial cell with the entire bacterial surface. The in vitro assessment of adhesion was a good indication of the in vivo association of propionibacteria with the intestinal epithelium. Therefore, the in vitro method presented here should be valuable in screening routinely adhesive properties of propionibacteria for probiotic purposes. The adhesion ability of dairy propionibacteria would prolong their maintenance in the gut and increase the duration of their provision of beneficial effects in the host, supporting the potential of Propionibacterium in the development of new probiotic products.

scholarly journals Inflammation-induced, 3′UTR-dependent translational inhibition of Hsp70 mRNA impairs intestinal homeostasis

2009 ◽  
Vol 296 (5) ◽  
pp. G1003-G1011 ◽  
Author(s):  
Shien Hu ◽  
Xiaorong Zhu ◽  
Joseph R. Triggs ◽  
Yun Tao ◽  
Yunwei Wang ◽  
...  
Keyword(s):  
Mucosal Inflammation ◽  
Luciferase Reporter ◽  
Hsp70 Expression ◽  
Intestinal Epithelial ◽  
Intestinal Homeostasis ◽  
Hsp70 Mrna ◽  
Translational Inhibition

Although the inducible heat shock protein 70 (Hsp70) is essential for maintaining intestinal homeostasis in colitis, it is translationally downregulated in inflamed colonic mucosa, paradoxically rendering the gut more susceptible to injury. We examined the basis for this process by analyzing the role of untranslated regions (UTR) of Hsp70 mRNA in inflammation-associated downregulation in vitro and in vivo. Using luciferase-reporter assays in young adult mouse intestinal epithelial cells, we determined that cytokine-induced translational inhibition of Hsp70 mRNA was mediated by the 3′UTR, but not 5′UTR. In vivo, dextran sodium sulfate (DSS) colitis was induced in wild-type (WT) and villin-promoter regulated “UTR-less” Hsp70 transgenic (TG) mice, the latter exhibiting intestinal epithelial-specific transgene expression. Progressive downregulation of colonic Hsp70 protein expression was observed in WT, but not in TG, mice with increasing severity of mucosal inflammation, confirming the essential role of the 3′UTR in mediating inflammation-associated downregulation of Hsp70. Hsp70 TG mice demonstrated significantly lower endoscopic and histological inflammation scores in DSS-induced colitis than WT. In conclusion, downregulation of Hsp70 expression in inflamed mucosa is mediated by translational inhibition requiring the 3′UTR, resulting in increased mucosal injury. By forcing intestinal epithelial-specific Hsp70 expression in vivo, the severity of experimentally induced colitis was significantly reduced.

scholarly journals The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring

2016 ◽  
Vol 4 ◽  
pp. 1-12 ◽  
Author(s):  
M. Mehta ◽  
O. A. Branford ◽  
K. J. Rolfe
Keyword(s):  
Wound Repair ◽  
Standard Treatment ◽  
Epigallocatechin Gallate ◽  
Potential Mechanism ◽  
Clinical Therapeutics ◽  
Beneficial Effects ◽  
Thermal Injuries ◽  
No Gold Standard

Abstract Though survival rate following severe thermal injuries has improved, the incidence and treatment of scarring have not improved at the same speed. This review discusses the formation of scars and in particular the formation of hypertrophic scars. Further, though there is as yet no gold standard treatment for the prevention or treatment of scarring, a brief overview is included. A number of natural therapeutics have shown beneficial effects both in vivo and in vitro with the potential of becoming clinical therapeutics in the future. These natural therapeutics include both plant-based products such as resveratrol, quercetin and epigallocatechin gallate as examples and includes the non-plant-based therapeutic honey. The review also includes potential mechanism of action for the therapeutics, any recorded adverse events and current administration of the therapeutics used. This review discusses a number of potential ‘treatments’ that may reduce or even prevent scarring particularly hypertrophic scarring, which is associated with thermal injuries without compromising wound repair.

scholarly journals Fusobacterium nucleatum Promotes the Development of Ulcerative Colitis by Inducing the Autophagic Cell Death of Intestinal Epithelial

2020 ◽  
Vol 10 ◽  
Author(s):  
Wenhao Su ◽  
Yongyu Chen ◽  
Pan Cao ◽  
Yan Chen ◽  
Yuanmei Guo ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Cell Death ◽  
Epithelial Cell ◽  
Clinical Characteristics ◽  
Intestinal Epithelial Cell ◽  
Fusobacterium Nucleatum ◽  
Autophagic Cell Death ◽  
Intestinal Epithelial

There is a growing body of evidence which suggests that intestinal microbiota, especially Fusobacterium nucleatum (F. nucleatum), are associated with intestinal immune disease such as ulcerative colitis (UC). The mechanism by which F. nucleatum promotes intestinal epithelial cell (IEC) death remained undefined. Here, we investigated the potential mechanisms about how F. nucleatum aggravates IEC death in UC. We first detected the abundance of F. nucleatum in UC tissues and analyzed its relationship with the clinical characteristics of UC. Next, we explored whether F. nucleatum promotes intestinal epithelial cell death in vitro and in vivo. Furthermore, we extracted lipopolysaccharide (LPS) of the F. nucleatum and examined whether F. nucleatum exacerbates UC via LPS. Our results indicated that F. nucleatum was abundant in UC tissues and was correlated with clinical characteristics. In addition, we demonstrated that F. nucleatum and its LPS aggravated IEC death by promoted IEC autophagy. Furthermore, autophagy inhibitors, chloroquine (CQ), 3-methyladenine (3-MA) or Atg5 silencing prevented IEC death mediated by F. nucleatum, which suggests F. nucleatum may contribute to UC by activating autophagic cell death. All our results uncover a vital role of F. nucleatum in autophagic cell death and UC, giving rise to a new sight for UC therapy by inhibiting excessive IEC autophagy and autophagic cell death.

scholarly journals Perturbation of neddylation-dependent NF-κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation

2016 ◽  
Vol 27 (23) ◽  
pp. 3687-3694 ◽  
Author(s):  
Stefan F. Ehrentraut ◽  
Valerie F. Curtis ◽  
Ruth X. Wang ◽  
Bejan J. Saeedi ◽  
Heidi Ehrentraut ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Significant Loss ◽  
Fine Tuning ◽  
Mucosal Inflammation ◽  
Luciferase Reporter ◽  
Intestinal Epithelial ◽  
Gene Target ◽  
Inflammatory Stimuli

Recent work has revealed a central role for neddylation (the conjugation of a Nedd8 moiety to Cullin proteins) in the fine-tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel Western blot, luciferase reporter, and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB. Subsequent studies revealed that MLN4924 potently induces epithelial apoptosis but only in the presence of additional inflammatory stimuli. In vivo administration of MLN4924 (3 mg/kg per day) in a TNBS-induced colitis model significantly accentuated disease severity. Indeed, MLN4924 resulted in worsened clinical scores and increased mortality early in the inflammatory response. Histologic analysis of the colon revealed that neddylation inhibition results in increased tissue damage and significantly increased mucosal apoptosis as determined by TUNEL and cleaved caspase-3 staining, which was particularly prominent within the epithelium. Extensions of these studies revealed that ongoing inflammation is associated with significant loss of deneddylase-1 (SENP8) expression. These studies reveal that intact Cullin-1 neddylation is central to resolution of acute inflammation.

scholarly journals Adrenomedullin Receptor Expression in Human Lung and in Pulmonary Tumors

1997 ◽  
Vol 45 (2) ◽  
pp. 159-164 ◽  
Author(s):  
Alfredo Martínez ◽  
Mae Jean Miller ◽  
Kevin J. Catt ◽  
Frank Cuttitta
Keyword(s):  
Wound Repair ◽  
Regulatory System ◽  
Receptor Expression ◽  
Respiratory Physiology ◽  
Basal Cells ◽  
Lung Carcinogenesis ◽  
Autocrine Loop ◽  
Epithelial Regeneration

Adrenomedullin (AM) is a multifunctional regulatory peptide that stimulates cyclic AMP production in many target tissues and is highly expressed in the lung. Analysis of the distribution of the recently cloned AM receptor (AM-R) by non-radioactive in situ hybridization revealed abundant expression in the basal cells of the airway epithelium and Type II pneumocytes. The expression of AM-R in the two cell types involved in epithelial regeneration of the lung suggests that AM may be relevant in such functions as organ development, wound repair, and epithelial turnover. AM-Rs are also synthesized in vivo and in vitro by a variety of tumor cells that also express the ligand, suggesting the existence of an autocrine loop that may be involved in tumor growth stimulation. The present findings suggest that the AM/AM-R regulatory system plays a major role in respiratory physiology and lung carcinogenesis and that new functions for AM remain to be identified.

scholarly journals Mucin degrader Akkermansia muciniphila accelerates intestinal epithelial regeneration and repairs damaged intestinal mucosa

2020 ◽  
Author(s):  
Mi-Na Kweon ◽  
Seungil Kim ◽  
Tae-Young Kim ◽  
Yeji Kim ◽  
Yong-Soo Lee ◽  
...  
Keyword(s):  
Intestinal Epithelial ◽  
Akkermansia Muciniphila ◽  
Epithelial Regeneration ◽  
Epithelial Development ◽  
Degrading Bacteria ◽  
Pre Treatment ◽  
Gut Damage ◽  
G Protein Coupled

Abstract Background: Mucin-degrading bacteria are densely populated in the intestinal epithelium; however, their interaction with intestinal stem cells (ISCs) and their progeny has not been elucidated. To determine whether mucin-degrading bacteria play a role in gut homeostasis, mice were treated with Akkermansia muciniphila, a specialized species that degrades mucin. A total of 32 fecal samples were obtained from healthy volunteers and A. muciniphila was isolated from 11 samples. Mechanism of A. muciniphila was observed in vivo and in vitro, and studied using organoids, histology, metagenomics, and whole genome sequencing.Results: We found that administration of A. muciniphila for 4 weeks accelerated theproliferation of Lgr5+ ISCs and promoted the differentiation of Paneth cells and goblet cells in the small intestine (SI). The levels of acetic and propionic acids were higher in the cecal contents of A. muciniphila-treated mice than in PBS-treated mice. SI organoids treated with cecal content supernatant obtained from A. muciniphila-treated mice were larger and could be diminished by treatment with G protein-coupled receptor (Gpr)41/43 antagonists. Pre- treatment of mice with A. muciniphila reduced gut damage caused by radiation and methotrexate. A novel isotype of A. muciniphila strain was isolated from heathy human feces that possessed improved functions for intestinal epithelial regeneration.Conclusions: These findings suggest that mucin-degrading bacteria (such as A. muciniphila)may play a crucial role in promoting ISC-mediated epithelial development and contribute to intestinal homeostasis maintenance.

scholarly journals P057 CRL4DCAF2 promotes cell proliferation and limits the development of colitis

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S163-S164
Author(s):  
C Wang ◽  
L Yao ◽  
Y Zhang ◽  
Q Cao
Keyword(s):  
Ulcerative Colitis ◽  
Epithelial Cells ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Sw480 Cell ◽  
Intestinal Epithelial ◽  
Rna Seq ◽  
Biopsy Specimens

Abstract Background Ulcerative colitis (UC) is an idiopathic intestinal inflammatory disease, which leads to chronic intestinal mucosal barrier damage. More and more evidences show that ubiquitination of proteins regulates the occurrence and development of intestinal inflammation. DCAF family proteins could form E3 ubiquitin ligase with CRL4-DDB1 to regulate cell growth, differentiation, apoptosis and other life activities. CRL4DCAF2 is a crucial regulator in cell cycle regulation, but there are few studies on its application in intestinal epithelium. This study aims to explore the specific mechanism of CRL4DCAF2 in regulating the proliferation and repairment of intestinal epithelial cells. Methods DSS - induced colitis in mice was used as the experimental model in vivo. HCT116 and SW480 cell lines were used as experimental models in vitro studies.The Cre-loxP system was used to construct a mouse model of intestinal epithelium-specific DCAF2 knockout. The intestinal mucosa biopsy specimens of 11 normal patients and 11 UC patients were collected. In addition, qRT-PCR, Western blot, RNA-seq and immunofluorescent staining were used to detect the expression levels of target genes in human colon biopsy specimens, mouse colon tissues, HCT116 or SW480 cells Results DCAF2 gene was highly expressed in the colon of mice. The occurrence and development of DSS-induced experimental colitis was accompanied by a significant down-regulation of DCAF2 protein expression in colon. DCAF2 mRNA level was significantly decreased in UC patients. Mouse with intestinal epithelial-specific knockout of DCAF2(i.e. DCAF2IEC-KO) suffered from embryonic death. Compared with wild-type adult C57BL/6J mice, DCAF2IEC-KD mouse showed more severe intestinal inflammation in DSS-induced colitis model. CCK-8 test, PI staining and EDU staining flow cytometry experiments showed that the proliferation of intestinal epithelial cells with DCAF2 overexpression was faster than that of the control (P < 0.05) in HCT116 and SW480 cell lines, while in knockdown of DCAF2 models, the opposite results were obtained. Its effect may be related to the ubiquitination of p21. At the same time, MLN4924 in vivo and in vitro experiments further verified our experimental results. Combined with RNA-seq and Western blot, we also found that DCAF2 may reduce the symptoms of colitis by maintaining the stability of autophagy. Conclusion DCAF2 is low expressed in patients with ulcerative colitis, which may promote the activation and proliferation of intestinal epithelial cells. It could maintain autophagy stability, and restore intestinal barrier, thus alleviate the development of ulcerative colitis

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