NIV Congres

Objectives Mesenchymal stem cells (MSC) and their secreted factors represent a potential new therapeutic strategy to stimulate liver regeneration in living-donor liver transplantation to prevent small-for-size syndrome. Our previous data showed increased liver weight gain and hepatocyte proliferation in mice treated with MSC-derived factors after 70% partial hepatectomy (PH). In the current study we investigated if MSC-derived factors protect mice against ischemia and reperfusion injury (IRI) alone or in combination with 50% PH.

Methods In the IRI alone model, C57BL/6 mice were subjected to IRI by clamping the median and left lateral liver lobes for 90 minutes. In the IRI+PH model, mice were subjected to 60 minutes of IRI after which a 50% PH was performed by ligation of the right lateral lobe, caudate lobes and the right part of the median lobe. In both groups, animals were treated immediately after surgery (and 24 hours later if sacrificed after 2 days) with serum-free concentrated conditioned culture medium of liver-derived MSC (MSC-CM). Concentrated unconditioned medium (UM) was used as vehicle control. Animals in the IRI group were sacrificed after 6 or 24 hours to investigate effects on serum transaminases and hepatocyte damage. Animals of the IRI+PH group were sacrificed after 48 hours to also investigate effects on hepatocyte proliferation.

Results In the IRI model, serum ALT and AST levels after 6 and 24 hours showed no differences between the MSC-CM and UM treatment group. Similar, in the IRI+PH model, ALT and AST levels were not significantly different between both treatment groups. In this combined group, however, a significant reduction in tissue damage after MSC-CM treatment was observed, accompanied by reduced inflammatory cell infiltration. The average damage score in the MSC-CM group was 0.63 versus 1.40 in the UM group (p=0.04). This was furthermore accompanied by a significant increase in hepatocyte proliferation in the MSC-CM group as compared to the UM group (13.5% vs. 5.0% BrdU-positive nuclei, p=0.002).

Conclusion This study shows that MSC-derived factors do not protect against the early effects of ischemia and reperfusion injury, but significantly stimulate hepatocyte proliferation and improve liver regeneration after liver resection, despite combined ischemia and reperfusion injury. MSC-derived factors therefore represent a promising strategy to expand options in living-donor liver transplantation.