scholarly journals Cathelicidin-WA Protects Against LPS-Induced Gut Damage Through Enhancing Survival and Function of Intestinal Stem Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Sisi Wang ◽  
Lixia Kai ◽  
Luoyi Zhu ◽  
Bocheng Xu ◽  
Nana Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Critical Role ◽  
Intestinal Barrier ◽  
Intestinal Stem Cells ◽  
Intestinal Barrier Function ◽  
Intestinal Damage ◽  
Epithelial Regeneration ◽  
Gut Damage ◽  
And Function ◽  
Lps Treatment

Preservation of intestinal stem cells (ISCs) plays a critical role in initiating epithelial regeneration after intestinal injury. Cathelicidin peptides have been shown to participate in regulating intestinal damage repair. However, it is not known how exactly Cathelicidin-WA (CWA) exert its function after tissue damage. Using a gut injury model in mice involving Lipopolysaccharide (LPS), we observed that CWA administration significantly improved intestinal barrier function, preserved ISCs survival, and augmented ISCs viability within the small intestine (SI) under LPS treatment. In addition, CWA administration effectively prevented proliferation stops and promoted the growth of isolated crypts. Mechanistically, our results show that the appearance of γH2AX was accompanied by weakened expression of SETDB1, a gene that has been reported to safeguard genome stability. Notably, we found that CWA significantly rescued the decreased expression of SETDB1 and reduced DNA damage after LPS treatment. Taken together, CWA could protect against LPS-induced gut damage through enhancing ISCs survival and function. Our results suggest that CWA may become an effective therapeutic regulator to treat intestinal diseases and infections.

scholarly journals Qingchang Wenzhong Decoction Accelerates Intestinal Mucosal Healing Through Modulation of Dysregulated Gut Microbiome, Intestinal Barrier and Immune Responses in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhongmei Sun ◽  
Junxiang Li ◽  
Wenting Wang ◽  
Yuyue Liu ◽  
Jia Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gut Microbiota ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Mucosal Healing ◽  
Intestinal Stem Cells ◽  
Mucosal Inflammation ◽  
Protective Effects ◽  
Fecal Microbiome ◽  
Epithelial Regeneration

Inflammatory bowel disease (IBD), a group of multifactorial and inflammatory infirmities, is closely associated with dysregulation of gut microbiota and host metabolome, but effective treatments are currently limited. Qingchang Wenzhong Decoction (QCWZD) is an effective and classical traditional herbal prescription for the treatment of IBD and has been proved to attenuate intestinal inflammation in a model of acute colitis. However, the role of QCWZD in recovery phase of colitis is unclear. Here, we demonstrated that mice treated with QCWZD showed a faster recovery from dextran sulfate sodium (DSS)-induced epithelial injury, accompanied by reduced mucosal inflammation and attenuated intestinal dysbiosis using bacterial 16S rRNA amplicon sequencing compared to those receiving sterile water. The protective effects of QCWZD are gut microbiota dependent, as demonstrated by fecal microbiome transplantation and antibiotics treatment. Gut microbes transferred from QCWZD-treated mice displayed a similar role in mucosal protection and epithelial regeneration as QCWZD on colitis in mice, and depletion of the gut microbiota through antibiotics treatments diminished the beneficial effects of QCWZD on colitis mice. Moreover, metabolomic analysis revealed metabolic profiles alternations in response to the gut microbiota reprogrammed by QCWZD intervention, especially enhanced tryptophan metabolism, which may further accelerate intestinal stem cells-mediated epithelial regeneration to protect the integrity of intestinal mucosa through activation of Wnt/β-catenin signals. Collectively, our results suggested that orally administrated QCWZD accelerates intestinal mucosal healing through the modulation of dysregulated gut microbiota and metabolism, thus regulating intestinal stem cells-mediated epithelial proliferation, and hold promise for novel microbial-based therapies in the treatment of IBD.

Epithelial Regeneration after Doxorubicin Arises Primarily from Early Progeny of Active Intestinal Stem Cells

2020 ◽  
Author(s):  
Breanna Sheahan ◽  
Ally N. Freeman ◽  
Theresa M. Keeley ◽  
Linda C. Samuelson ◽  
Jatin Roper ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intestinal Stem Cells ◽  
Epithelial Regeneration

scholarly journals Inflammation- and Gut-Homing Macrophages, Engineered to De Novo Overexpress Active Vitamin D, Promoted the Regenerative Function of Intestinal Stem Cells

2021 ◽  
Vol 22 (17) ◽  
pp. 9516
Author(s):  
Yi Xu ◽  
David J. Baylink ◽  
Huynh Cao ◽  
Jeffrey Xiao ◽  
Maisa I. Abdalla ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vitamin D ◽  
De Novo ◽  
Chronic Inflammatory Disease ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Active Vitamin ◽  
Gut Inflammation ◽  
Epithelial Regeneration ◽  
Active Vitamin D

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Available drugs aim to suppress gut inflammation. These drugs have significantly delayed disease progression and improved patients’ quality of life. However, the disease continues to progress, underscoring the need to develop novel therapies. Aside from chronic gut inflammation, IBD patients also experience a leaky gut problem due to damage to the intestinal epithelial layer. In this regard, epithelial regeneration and repair are mediated by intestinal stem cells. However, no therapies are available to directly enhance the intestinal stem cells’ regenerative and repair function. Recently, it was shown that active vitamin D, i.e., 1,25-dihydroxyvitamin D or 1,25(OH)2D, was necessary to maintain Lgr5+ intestinal stem cells, actively cycling under physiological conditions. In this study, we used two strategies to investigate the role of 1,25(OH)2D in intestinal stem cells’ regenerative function. First, to avoid the side effects of systemic high 1,25(OH)2D conditions, we used our recently developed novel strategy to deliver locally high 1,25(OH)2D concentrations specifically to inflamed intestines. Second, because of the Lgr5+ intestinal stem cells’ active cycling status, we used a pulse-and-chase strategy via 5-bromo-2′-deoxyuridine (BrdU) labeling to trace the Lgr5+ stem cells through the whole epithelial regeneration process. Our data showed that locally high 1,25(OH)2D concentrations enhanced intestinal stem cell migration. Additionally, the migrated cells differentiated into mature epithelial cells. Our data, therefore, suggest that local delivery of high 1,25(OH)2D concentrations is a promising strategy to augment intestinal epithelial repair in IBD patients.

scholarly journals The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells

2011 ◽  
Vol 208 (2) ◽  
pp. 285-294 ◽  
Author(s):  
Shuichiro Takashima ◽  
Masanori Kadowaki ◽  
Kazutoshi Aoyama ◽  
Motoko Koyama ◽  
Takeshi Oshima ◽  
...  
Keyword(s):  
Stem Cells ◽  
Graft Versus Host Disease ◽  
Intestinal Epithelium ◽  
Critical Role ◽  
Intestinal Stem Cells ◽  
Allogeneic Bone ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Bmt

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.

scholarly journals Use of organoids to study regenerative responses to intestinal damage

2019 ◽  
Vol 317 (6) ◽  
pp. G845-G852 ◽  
Author(s):  
Sarah E. Blutt ◽  
Ophir D. Klein ◽  
Mark Donowitz ◽  
Noah Shroyer ◽  
Chandan Guha ◽  
...  
Keyword(s):  
Stem Cells ◽  
Parasitic Infection ◽  
Genetically Modify ◽  
Intestinal Wall ◽  
Intestinal Damage ◽  
Therapeutic Modalities ◽  
Epithelial Regeneration ◽  
Vitro Model ◽  
Induced Pluripotent

Intestinal organoid cultures provide an in vitro model system for studying pathways and mechanisms involved in epithelial damage and repair. Derived from either embryonic or induced pluripotent stem cells or adult intestinal stem cells or tissues, these self-organizing, multicellular structures contain polarized mature cells that recapitulate both the physiology and heterogeneity of the intestinal epithelium. These cultures provide a cutting-edge technology for defining regenerative pathways that are induced following radiation or chemical damage, which directly target the cycling intestinal stem cell, or damage resulting from viral, bacterial, or parasitic infection of the epithelium. Novel signaling pathways or biological mechanisms identified from organoid studies that mediate regeneration of the epithelium following damage are likely to be important targets of preventive or therapeutic modalities to mitigate intestinal injury. The evolution of these cultures to include more components of the intestinal wall and the ability to genetically modify them are key components for defining the mechanisms that modulate epithelial regeneration.

scholarly journals Role for diet in normal gut barrier function: developing guidance within the framework of food-labeling regulations

2019 ◽  
Vol 317 (1) ◽  
pp. G17-G39 ◽  
Author(s):  
Michael Camilleri ◽  
Barbara J. Lyle ◽  
Karen L. Madsen ◽  
Justin Sonnenburg ◽  
Kristin Verbeke ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Normal Function ◽  
Model Systems ◽  
Intestinal Barrier Function ◽  
Dietary Interventions ◽  
Labeling Regulations ◽  
Gut Barrier Function ◽  
And Function

A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, as it facilitates passage of injurious factors such as lipopolysaccharide, peptidoglycan, whole bacteria, and other toxins to traverse the barrier to damage the intestine or enter the portal circulation. Currently available evidence in animal models and in vitro systems has shown that certain dietary interventions can be used to reinforce the intestinal barrier to prevent the development of disease. The relevance of these studies to human health is unknown. Herein, we define the components of the intestinal barrier, review available modalities to assess its structure and function in humans, and review the available evidence in model systems or perturbations in humans that diet can be used to fortify intestinal barrier function. Acknowledging the technical challenges and the present gaps in knowledge, we provide a conceptual framework by which evidence could be developed to support the notion that diet can reinforce human intestinal barrier function to restore normal function and potentially reduce the risk for disease. Such evidence would provide information on the development of healthier diets and serve to provide a framework by which federal agencies such as the US Food and Drug Administration can evaluate evidence linking diet with normal human structure/function claims focused on reducing risk of disease in the general public.

The Enteric Microbiota Regulates Paneth Cell Number and Function Without Affecting Intestinal Stem Cells

2017 ◽  
Vol 152 (5) ◽  
pp. S13 ◽  
Author(s):  
Alexi A. Schoenborn ◽  
Richard von Furstenberg ◽  
Smrithi Valsaraj ◽  
Farah S. Hussain ◽  
Molly Stein ◽  
...  
Keyword(s):  
Stem Cells ◽  
Paneth Cell ◽  
Cell Number ◽  
Intestinal Stem Cells ◽  
And Function

scholarly journals Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

2021 ◽  
Author(s):  
Emelyne Lécuyer ◽  
Tiphaine Le Roy ◽  
Aurélie Gestin ◽  
Amélie Lacombe ◽  
Catherine Philippe ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Metabolic Diseases ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Low Grade ◽  
Obesity And Diabetes ◽  
Tolerogenic Dendritic Cells ◽  
Tolerogenic Function ◽  
And Function

Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes. <p>The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DC<sup>hBcl-2</sup> mice) are challenged with a high-fat diet.</p> <p>Those mice display resistance to DIO and metabolic alterations. The DIO-resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DC<sup>hBcl-2</sup> DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses.</p> <p>Microbiota composition and function analyses reveal that the DC<sup>hBcl-2</sup> mice microbiota is characterized by lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic disease management.</p>

scholarly journals Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

2020 ◽  
Author(s):  
Emelyne Lécuyer ◽  
Tiphaine Le Roy ◽  
Aurélie Gestin ◽  
Amélie Lacombe ◽  
Catherine Philippe ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Metabolic Diseases ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Low Grade ◽  
Obesity And Diabetes ◽  
Tolerogenic Dendritic Cells ◽  
Tolerogenic Function ◽  
And Function

ABSTRACTExcess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes.The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice), are challenged with a high fat diet.Those mice display resistance to DIO and metabolic alterations. The DIO resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses.Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by a lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic diseases management.

scholarly journals Linker histone H1.2 and H1.4 affect the neutrophil lineage determination

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Gabriel Sollberger ◽  
Robert Streeck ◽  
Falko Apel ◽  
Brian Edward Caffrey ◽  
Arthur I Skoultchi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Critical Role ◽  
Human Cell Line ◽  
Linker Histone ◽  
High Turnover ◽  
Hematopoietic Stem ◽  
Murine Bone Marrow ◽  
A Genome ◽  
And Function

Neutrophils are important innate immune cells that tackle invading pathogens with different effector mechanisms. They acquire this antimicrobial potential during their maturation in the bone marrow, where they differentiate from hematopoietic stem cells in a process called granulopoiesis. Mature neutrophils are terminally differentiated and short-lived with a high turnover rate. Here, we show a critical role for linker histone H1 on the differentiation and function of neutrophils using a genome-wide CRISPR/Cas9 screen in the human cell line PLB-985. We systematically disrupted expression of somatic H1 subtypes to show that individual H1 subtypes affect PLB-985 maturation in opposite ways. Loss of H1.2 and H1.4 induced an eosinophil-like transcriptional program, thereby negatively regulating the differentiation into the neutrophil lineage. Importantly, H1 subtypes also affect neutrophil differentiation and the eosinophil-directed bias of murine bone marrow stem cells, demonstrating an unexpected subtype-specific role for H1 in granulopoiesis.

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