Abstract
Liver ischemia reperfusion injury (IRI) is inevitable during transplantation and resection and is characterized by hepatocellular injury. Therapeutic strategies to reduce IRI and accelerate regeneration could offer major benefits. Mesenchymal stem cells (MSC) are reported to have anti-inflammatory and regeneration promoting properties. We investigated the effect of MSC in a model of combined IRI and partial resection in the mouse. Hepatic IRI was induced by occlusion of 70% of the blood flow during 60 minutes, followed by 30% hepatectomy. 2 × 105 MSC or PBS were infused 2 hours before or 1 hour after IRI. Six, 48, and 120 hours postoperatively mice were sacrificed. Liver damage was evaluated by liver enzymes, histology, and inflammatory markers. Regeneration was determined by liver/body weight ratio, proliferating hepatocytes, and TGF-β levels. Fate of MSC was visualized with 3D cryoimaging. Infusion of 2 × 105 MSC 2 hours before or 1 hour after IRI and resection showed no beneficial effects. Tracking revealed that MSC were trapped in the lungs and did not migrate to the site of injury and many cells had already disappeared 2 hours after infusion. Based on these findings we conclude that intravenously infused MSC disappear rapidly and were unable to induce beneficial effects in a clinically relevant model of IRI and resection.
Highlights
The liver has the unique ability of regeneration as a response to liver injury
Six hours after reperfusion and partial hepatectomy (PH), serum alanine aminotransferase (ALAT) (7400 ± 1392 U/L) and aspartate aminotransferase (ASAT) (7529±1202 U/L) levels were significantly lower in mice infused with Mesenchymal stem cells (MSC) 2 hours before ischemia reperfusion injury (IRI) and PH compared with their PBS controls (ALAT 13271 ± 1644 U/L) (ASAT 13207 ± 1131 U/L) (P = 0.015, Figure 1(a)) (P = 0.005, Figure 1(b))
Mice infused with MSC 1 hour after reperfusion and PH showed no significant difference compared with their PBS control group (Figures 1(a) and 1(b)). 48 hours after reperfusion and PH, there were no significant differences in transaminases between mice infused with MSC 2 hours before or 1 hour after reperfusion and PH compared to the mice infused with PBS (Figures 1(c) and 1(d))
Summary
In healthy individuals the liver can compensate an acute loss of 70% and return to its original mass within 30 days of resection [1]. Thanks to this remarkable feature and advances in surgical techniques, large (oncologic) liver resections as well as split and living donor liver transplantation are possible. Ischemia reperfusion injury (IRI), caused by interruptions of the hepatic blood flow, is inevitable during LTx and liver resection. Liver IRI is the leading cause of hepatocellular injury causing morbidity and mortality after LTx and may negatively affect liver regeneration after both postmortal and living donor LTx [12,13,14]. Potential therapeutic strategies to reduce hepatic IRI and
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