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Human Mesenchymal Stromal Cells Decrease Mortality Following Intestinal Ischemia and Reperfusion Injury
| Content Provider | Semantic Scholar |
|---|---|
| Author | Markel, Troy A. Crafts, Trevor D. Jensen, Amanda R. Hunsberger, Erin Bailey |
| Copyright Year | 2015 |
| Abstract | Background: Cellular therapy is a novel treatment option for intestinal ischemia. Bone Marrow Derived Mesenchymal Stromal Cells (BMSCs) have previously been shown to abate the damage caused by intestinal ischemia/reperfusion injury (I/R). We therefore hypothesized that 1) human BMSCs (hBMSCs) would produce more beneficial growth factors and lower levels of proinflammatory mediators compared to differentiated cells, 2) direct application of hBMSCs to ischemic intestine would decrease mortality following injury, and 3) decreased mortality would be associated with an altered intestinal and hepatic inflammatory response. Methods: Adult hBMSCs and keratinocytes were cultured on polystyrene flasks. For in vitro experiments, cells were exposed to TNF, LPS, or 2% oxygen for twenty-four hours. Supernatants were then analyzed for growth factors and chemokines by multiplex assay. For in vivo experiments, eight to twelve week old male C57Bl6J mice were anesthetized and underwent a midline laparotomy. Experimental groups were exposed to temporary superior mesenteric artery occlusion for 60 minutes. Immediately following ischemia, 2 x 106 hBMSCs or keratinocytes in PBS were placed into the peritoneal cavity. Animals were then closed and allowed to recover for 6 hours (molecular / histological analysis) or 7 days (survival analysis). Following 6 hour reperfusion, animals were euthanized. Intestines and livers were harvested and analyzed for inflammatory chemokines, growth factors, and histological changes. Results: hBMSCs expressed higher levels of human IL-6, IL-8, VEGF, and EGF, and lower levels of IL1, IL3, IL7, and GMCSF following stimulation. In vivo, I/R resulted in significant mortality (70% mortality), while application of hBMSCs following ischemia decreased mortality to 10% in a dose dependent fashion (p=0.004). Keratinocyte therapy offered no improvements in mortality above I/R. Histological profiles were equivalent between ischemic groups, regardless of application of hBMSCs or keratinocytes. Cellular therapy yielded significantly decreased murine intestinal levels of sALK-1, betacellulin and endothelin, while increasing levels of eotaxin, MIG, MCP-1, IL-6, GCSF and IP-10 from ischemia were appreciated. hBMSC therapy yielded significantly higher expression of murine intestinal VEGF and lower levels of intestinal MIG compared to keratinocyte therapy. Application of hBMSCs following ischemia yielded significantly lower murine levels of hepatic MIG, IP-10, and GCSF compared to keratinocyte therapy. Conclusion: Human BMSCs produce multiple beneficial growth factors. Direct application of hBMSCs to the peritoneal cavity following intestinal I/R decreased mortality by sixty percent. Improved outcomes with hBMSC therapy were not associated with improved histological profiles in this model. hBMSC therapy was associated with higher VEGF in intestines, and lower levels of proinflammtory MIG, IP-10, and GCSF in liver tissue following ischemia, suggesting that reperfusion with hBMSC therapy may alter survival by modulating the systemic inflammatory response to ischemia. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://scholarworks.iupui.edu/bitstream/handle/1805/9465/markel-2015-human.pdf;sequence=1 |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
