Mesenchymal Stem Cell (MSC)-derived humoral factors promote survival of insulin producing pancreatic β-cells during intrinsic cellular stress via Akt and ERK1/2 signalling

MSC are of interest for cell therapy since they secrete factors with tissue regenerative properties such as immunomodulation and restoration of local microenvironment. Own previous results demonstrated that human telomerase immortalized MSC (hMSC-TERT) also directly support survival of cocultured rat insulinoma-derived INS-1E beta cells and rodent islets during intrinsic cellular stress by alloxan (ALX) and streptozotocin. Here we investigated the protective potential of hMSC-TERT-induced p-Akt and p-ERK1/2 signalling in INS-1E beta cells during ALX exposure. In some experiments, p-Akt and p-ERK1/2 signalling were depleted by pretreatment with the inhibitors MK-2206 and U0126, respectively. Exposure of INS-1E beta cells to 6.6 mM ALX results in approximately 50% loss of viability. hMSC-TERT maintained p-Akt levels and induced p-ERK1/2 levels during ALX exposure in cocultured INS-1E beta cells. Inhibition of either p-Akt or p-ERK1/2 increased ALX-induced loss of viability but did not abolish relative protection by hMSC-TERT. Upregulation of the respective non-inhibited pathway due to release of cross-inhibition indicates the possibility that one pathway compensates for the other. Cross-inhibition was also observed in mouse islets since ALX-induced depletion of p-Akt results in upregulation of p-ERK1/2. hMSC-TERT protected p-Akt in ALX-treated mouse islets was further associated with maintained levels of anti-apoptotic p-BAD. In contrast to insulinoma-derived INS-1E beta cells, hMSC-TERT did not upregulate p-ERK1/2 in primary mouse islets. We conclude that MSC-derived factors mediate reduction of intrinsic beta cell apoptosis basically by preservation of p-Akt and downstream p-BAD but further involve p-ERK1/2 in certain conditions such as loss of p-Akt signalling or insulinoma background.