Diabetologie und Stoffwechsel 2015; 10 - FV6
DOI: 10.1055/s-0035-1549512

The macrophage migration inhibitory factor (MIF)/CXCR4 axis regulates migration of bone marrow derived mesenchymal stem cells towards pancreatic ß-cells under lipotoxic conditions

B Mihic-Necic 1, S Taromi 2, C Liu 1, J Straetener 1, M Ihle 1, D Kriedemann 1, M Hille 1, AE Mehana 1, 3, K Laubner 1, N Perakakis 1, G Päth 1, J Seufert 1
  • 1Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany
  • 2Division of Hematology and Oncology, Department of Internal Medicine I, University Hospital of Freiburg, Freiburg, Germany
  • 3Department of Zoology, Faculty of Science, Suez Canal University, Ismailia, Egypt

Background and aim: Mesenchymal stem cells (MSCs) bare the ability to home to sites of injury where they act by secreting angiogenic- and immunomodulatory factors. Previously we demonstrated that human telomerase-immortalised MSCs (hMSC-TERT) migrate towards injured INS-1E ß-cells, where they preserve cellular viability. Here we identify macrophage migration inhibitory factor (MIF) secreted by injured ß-cells as chemotactic factor that supports migration of MSCs.

Materials and methods: Chemotaxis assay was performed using microchemotaxis system ChemoTx. hMSC-TERT were allowed to migrate through 8-µm pore size membrane towards conditioned medium of (palmitate-treated-) INS-1E. Blockade experiments in the chemotaxis system were done using MIF-specific inhibitor ISO-1 and CXCR4 receptor antagonist AMD3100 (functional receptor for MIF). Chemotactic potency of SDF-1 on hMSC-TERT (another ligand for CXCR4) was examined regardless of INS-1E-conditioned medium. MIF mRNA upregulation in palmitate-stimulated INS-1E was determined using qPCR. Upregulated MIF secretion by INS-1E in response to palmitate-mediated injury was confirmed by ELISA.

Results: Palmitate-treated-INS-1E-conditioned medium stimulated hMSC-TERT migration. 20-fold upregulated MIF mRNA expression in INS-1E was detected after 1h of palmitate treatment. ELISA confirmed upregulated MIF secretion by INS-1E in response to palmitate-mediated injury. MIF-specific inhibitor ISO-1 (50µM) inhibited 90% of hMSC-TERT migration towards palmitate-treated INS-1E-conditioned medium. In the presence of CXCR4 antagonist AMD3100 (1µM) hMSC-TERT migration was also inhibited by 90%. SDF-1 (100 ng/ml) didn't exhibit chemotactic effect on hMSC-TERT.

Conclusion: MIF secreted by injured ß-cells promotes MSC chemotaxis through CXCR4 receptor, suggesting an important role for MIF-CXCR4 signaling in MSC-mediated ß-cell protection under cellular stress.