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Novel regenerative peptide TP508 mitigates radiation-induced gastrointestinal damage by activating stem cells and preserving crypt integrity.

ABSTRACT: In recent years, increasing threats of radiation exposure and nuclear disasters have become a significant concern for the United States and countries worldwide. Exposure to high doses of radiation triggers a number of potentially lethal effects. Among the most severe is the gastrointestinal (GI) toxicity syndrome caused by the destruction of the intestinal barrier, resulting in bacterial translocation, systemic bacteremia, sepsis, and death. The lack of effective radioprotective agents capable of mitigating radiation-induced damage has prompted a search for novel countermeasures that can mitigate the effects of radiation post exposure, accelerate tissue repair in radiation-exposed individuals, and prevent mortality. We report that a single injection of regenerative peptide TP508 (rusalatide acetate, Chrysalin) 24?h after lethal radiation exposure (9?Gy, LD100/15) appears to significantly increase survival and delay mortality by mitigating radiation-induced intestinal and colonic toxicity. TP508 treatment post exposure prevents the disintegration of GI crypts, stimulates the expression of adherens junction protein E-cadherin, activates crypt cell proliferation, and decreases apoptosis. TP508 post-exposure treatment also upregulates the expression of DCLK1 and LGR5 markers of stem cells that have been shown to be responsible for maintaining and regenerating intestinal crypts. Thus, TP508 appears to mitigate the effects of GI toxicity by activating radioresistant stem cells and increasing the stemness potential of crypts to maintain and restore intestinal integrity. These results suggest that TP508 may be an effective emergency nuclear countermeasure that could be delivered within 24?h post exposure to increase survival and delay mortality, giving victims time to reach clinical sites for advanced medical treatment.

SUBMITTER: Kantara C

PROVIDER: S-EPMC4626368 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Novel regenerative peptide TP508 mitigates radiation-induced gastrointestinal damage by activating stem cells and preserving crypt integrity.

Kantara Carla C Moya Stephanie M SM Houchen Courtney W CW Umar Shahid S Ullrich Robert L RL Singh Pomila P Carney Darrell H DH

Laboratory investigation; a journal of technical methods and pathology 20150817 11

In recent years, increasing threats of radiation exposure and nuclear disasters have become a significant concern for the United States and countries worldwide. Exposure to high doses of radiation triggers a number of potentially lethal effects. Among the most severe is the gastrointestinal (GI) toxicity syndrome caused by the destruction of the intestinal barrier, resulting in bacterial translocation, systemic bacteremia, sepsis, and death. The lack of effective radioprotective agents capable o ...[more]

PMID: 26280221

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Project description:BackgroundNuclear accidents and terrorism presents a serious threat for mass casualty. While bone-marrow transplantation might mitigate hematopoietic syndrome, currently there are no approved medical countermeasures to alleviate radiation-induced gastrointestinal syndrome (RIGS), resulting from direct cytocidal effects on intestinal stem cells (ISC) and crypt stromal cells. We examined whether bone marrow-derived adherent stromal cell transplantation (BMSCT) could restitute irradiated intestinal stem cells niche and mitigate radiation-induced gastrointestinal syndrome.Methodology/principal findingsAutologous bone marrow was cultured in mesenchymal basal medium and adherent cells were harvested for transplantation to C57Bl6 mice, 24 and 72 hours after lethal whole body irradiation (10.4 Gy) or abdominal irradiation (16-20 Gy) in a single fraction. Mesenchymal, endothelial and myeloid population were characterized by flow cytometry. Intestinal crypt regeneration and absorptive function was assessed by histopathology and xylose absorption assay, respectively. In contrast to 100% mortality in irradiated controls, BMSCT mitigated RIGS and rescued mice from radiation lethality after 18 Gy of abdominal irradiation or 10.4 Gy whole body irradiation with 100% survival (p<0.0007 and p<0.0009 respectively) beyond 25 days. Transplantation of enriched myeloid and non-myeloid fractions failed to improve survival. BMASCT induced ISC regeneration, restitution of the ISC niche and xylose absorption. Serum levels of intestinal radioprotective factors, such as, R-Spondin1, KGF, PDGF and FGF2, and anti-inflammatory cytokines were elevated, while inflammatory cytokines were down regulated.Conclusion/significanceMitigation of lethal intestinal injury, following high doses of irradiation, can be achieved by intravenous transplantation of marrow-derived stromal cells, including mesenchymal, endothelial and macrophage cell population. BMASCT increases blood levels of intestinal growth factors and induces regeneration of the irradiated host ISC niche, thus providing a platform to discover potential radiation mitigators and protectors for acute radiation syndromes and chemo-radiation therapy of abdominal malignancies.

Project description:Determining a representative microbial signature from any given location is dependent on robust sample collection and handling. Different sampling locations and hence sample properties can vary widely; for example, soil would be collected and handled differently compared to liquid samples. In the event that sample material has a low concentration of biomass, large quantities need to be collected for microbial community analysis. This is certainly the case when investigating the microbiology of oilfield systems, wherein produced water (PW) is one of the most common sources for microbial sampling. As the detrimental effects of microbial metabolism within these industrial milieus are becoming increasingly well-established, the characterization of microbial community composition using molecular biological analyses is becoming more commonplace for accurate monitoring. As this field continues to develop, the importance for standardized operating protocols cannot be understated, so that industry can make the most informed operational decisions possible. Accurately identifying oilfield microbial communities is paramount, as improper preservation and storage following sample collection is known to lead to erroneous microbial identifications. Preserving oilfield PW can be challenging, as many locations are remote, requiring lengthy periods of time before samples can be processed and analyzed. While previous studies have characterized the effects of various preservatives on concentrated, filtered, or purified microbial samples, to the best of our knowledge, no such study has been undertaken on low biomass liquid samples. To this end, we investigated the effectiveness of nine different preservation conditions on PW collected from the same sampling location within a heavy-oil producing field, and monitored how the microbial community changed over the period of a month. Our results reveal that the choice of preservative drastically affects microbial community, and should be selected with careful consideration before sampling occurs.

Dataset Information

Novel regenerative peptide TP508 mitigates radiation-induced gastrointestinal damage by activating stem cells and preserving crypt integrity.

Publications

Novel regenerative peptide TP508 mitigates radiation-induced gastrointestinal damage by activating stem cells and preserving crypt integrity.

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