Human mesenchymal stromal cells decrease mortality after intestinal ischemia and reperfusion injury

Markel, Troy A.; Crafts, Trevor D.; Jensen, Amanda R.; Hunsberger, E. Bailey; Yoder, Mervin C.

doi:10.1016/j.jss.2015.06.060

Cited by 35 publications

(39 citation statements)

References 32 publications

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“…We have previously demonstrated that MSCs protect the intestines following I/R injury and promote survival [6]. In this study, we observed a distinct survival advantage with the use several MSC lines when compared to differentiated cellular control cells.…”

Section: Discussionmentioning

confidence: 49%

“…The abdominal fascia and skin were then closed in a two layer fashion using silk suture. Prior to complete abdominal closure, 250μL PBS vehicle, or 2 × 10 6 of BMSCs, USCs, or keratinocytes re-suspended in 250μL of PBS were injected into the intraperitoneal cavity based on our previously reported dose response curves [6]. Triple antibiotic ointment was applied to the abdominal incision following complete closure andanalgesia (1mg/kg buprenorphine and 5 mg/kg caprofen) was injected subcutaneously.…”

Section: Methodsmentioning

confidence: 99%

“…Paraffin-embedded sections were prepared and stained with hematoxylin and eosin. Histological scoring of the depth of tissue injury was performed as previously described: 0, no damage; 1, subepithelial space at the villous tip; 2, loss of mucosal lining of the villous tip; 3, loss of less than half of the villous structure; 4, loss of more than half of the villous structure; and 5 transmural necrosis [6, 8]. Sections were evaluated blindly by two observers with all scores averaged.…”

Section: Methodsmentioning

confidence: 99%

“…To date however, there have been no innovative treatment modalities aimed at recovering the infarcted bowel. Recent studies in the literature have demonstrated reversal of ischemia-reperfusion (I/R) injury and recovery of bowel function with use of bone marrow-derived mesenchymal stromal cells (BMSCs) following I/R injury in animal models [6] [7] [8] [9] [10]. BMSCs have also been shown to decrease the inflammatory response through down-regulation of inflammatory chemokines [11, 12] and mitigation of oxidative stress [13].…”

Section: Introductionmentioning

confidence: 99%

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Harvest tissue source does not alter the protective power of stromal cell therapy after intestinal ischemia and reperfusion injury

Jensen

Manning

Khaneki³

et al. 2016

Journal of Surgical Research

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Background Transplantation of mesenchymal stromal cells (MSCs) may be a novel treatment for intestinal ischemia. The optimal stromal cell source that could yield maximal protection following injury, however, has not been identified. We hypothesized that: 1) MSCs would increase survival and mesenteric perfusion, preserve intestinal histological architecture, and limit inflammation following intestinal ischemia and reperfusion injury (I/R), and 2) MSCs harvested from different sources of tissue would have equivalent protective properties to the intestine following I/R. Methods Adult male mice were anesthetized and a midline laparotomy performed. The intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using Laser Doppler Imaging (LDI). Intestinal ischemia was established by temporarily occluding the superior mesenteric artery for 60 minutes with a non-crushing clamp. Following ischemia, the clamp was removed and the intestines were allowed to recover. Prior to abdominal closure, 2 × 106 human umbilical (USCs), bone-marrow (BMSCs) derived MSCs, or keratinocytes in 250μl of phosphate-buffered saline (PBS) vehicle were injected into the peritoneum. Animals were allowed to recover for 12 or 24 hours (perfusion, histology, inflammatory studies), or 7 days (survival studies). Survival data was analyzed using log rank test. Perfusion was expressed as percentage of baseline and 12 and 24 hour data was analyzed using one way ANOVA and student’s t-test. Non parametric data was compared using Mann-Whitney-U test. A p-value of less than 0.05 was significant. Results All MSCs increased seven day survival following I/R and were superior to vehicle or keratinocytes (P<0.05). All MSCs increased mesenteric perfusion above vehicle at 12 and 24 hours following injury (P<0.05). All MSCs provided superior perfusion compared to keratinocytes at 24 hours post-injury (P<0.05). Administration of each MSC line improved intestinal histology after I/R (P<0.05). Multiple pro-inflammatory chemokines were down-regulated following application of MSCs suggesting a decreased inflammatory response following MSC therapy. Conclusion Transplantation of MSCs following intestinal I/R, irrespective of source tissue, significantly increases survival and mesenteric perfusion while limiting intestinal damage and inflammation. Further studies are needed to identify the mechanism that these cells utilize to promote improved outcomes following injury.

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Section: Discussionmentioning

confidence: 49%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Harvest tissue source does not alter the protective power of stromal cell therapy after intestinal ischemia and reperfusion injury

Jensen

Manning

Khaneki³

et al. 2016

Journal of Surgical Research

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“…Male C57BL/6 mice aged 8-10 weeks were purchased from Jackson Laboratories. Intestinal I/R was induced similar to previous reports [20,21]. In brief, mice were placed under isoflurane anesthesia, their abdomens shaved and prepped with betadine and alcohol, and lower midline laparotomy was performed.…”

Section: Animal Modelmentioning

confidence: 99%

Ischemia/Reperfusion Injury Alters Sphingolipid Metabolism in the Gut

Hoehn

Seitz

Jernigan

et al. 2016

Cell Physiol Biochem

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Background: Intestinal ischemia/reperfusion injury (I/R) is a significant cause of morbidity and mortality in surgical patients. Ceramide is a mediator of apoptosis and has been implicated as increasing bacterial infection susceptibility. The metabolite of ceramide, sphingosine, was recently shown to play an important role in the cell-autonomous, innate immune response of the upper respiratory tract by killing bacterial pathogens. The role of ceramide and/or sphingosine after mesenteric I/R is unknown. We investigated the specific effects of intestinal I/R on tissue ceramide and sphingosine concentration and resulting susceptibility to bacterial invasion. Methods: To simulate intestinal I/R, C57BL/6 mice underwent 30 minutes of vascular clamp-induced occlusion of the superior mesenteric artery followed by variable reperfusion times. Jejunum segments and intraluminal contents were analyzed for ceramide, sphingosine and bacteria using immunohistochemistry. Jejunum samples were also homogenized and cultured to quantify bacterial presence in the proximal intestine. Results: We hypothesized that I/R induces an increase of ceramide in the intestine resulting in increased permeability, while a concomitant decrease of sphingosine may permit bacterial overgrowth. Control mice had no measurable bacteria in their proximal jejunum as measured by tissue culture and immunohistochemistry. After I/R, bacterial counts in the jejunum increased in a time-dependent manner, reaching a peak at 12 hours after reperfusion. Immunohistochemical analysis revealed a marked increase in ceramide in the vasculature of jejunal villi. In contrast, while ceramide concentrations in the epithelial cells decreased after I/R, sphingosine levels appeared to remain unchanged. Surprisingly, bacteria present in the jejunal lumen following I/R contained a ceramide coat. Conclusion: These data indicate that intestinal I/R leads to small intestine bacterial overgrowth as well as ceramide formation in the jejunal vasculature, which may contribute to the gut permeability associated with this injury. Moreover, our novel finding of ceramide in bacterial membranes represents a new opportunity to investigate the dynamic pathogenicity of the gut microbiome. The hypothesis that a decrease of sphingosine after I/R permits bacterial overgrowth in the intestine was not confirmed.

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Age disparities in intestinal stem cell quantities: a possible explanation for preterm infant susceptibility to necrotizing enterocolitis

Hosfield

Shelley²,

Mesfin³

et al. 2022

Pediatr Surg Int

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Human mesenchymal stromal cells decrease mortality after intestinal ischemia and reperfusion injury

Cited by 35 publications

References 32 publications

Harvest tissue source does not alter the protective power of stromal cell therapy after intestinal ischemia and reperfusion injury

Harvest tissue source does not alter the protective power of stromal cell therapy after intestinal ischemia and reperfusion injury

Ischemia/Reperfusion Injury Alters Sphingolipid Metabolism in the Gut

Age disparities in intestinal stem cell quantities: a possible explanation for preterm infant susceptibility to necrotizing enterocolitis

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