Effects of mycophenolic acid on human fibroblast proliferation, migration and adhesion in vitro and in vivo

Mycophenolic acid (MPA) is a potent inhibitor of the inosine monophosphate dehydrogenase and commonly used as an immunosuppressive drug in transplantation. MPA inhibits proliferation of both T- and B-lymphocytes by guansoin depletion. Since fibroblasts rely on the de novo synthesis of guanosin nucleotides, it is assumed that MPA interacts with fibroblasts causing an increased frequency of wound healing problems. We show a downregulation of the cytoskeletal proteins actin, vinculin and tubulin in human dermal fibroblasts exposed to pharmacologic doses of MPA using microarray technology and western blot. This reduction in protein content is accompanied by a substantial derangement of the cytoskeleton in MPA-treated fibroblasts as documented by confocal microscopy. The dysfunctional fibroblast growth was validated by scratch test documenting impaired migrational capacity. The results of the cultured dermal fibroblasts were applied to skin biopsies of renal transplant recipients. Skin biopsies of patients treated with MPA expressed less tubulin and actin as compared to control biopsies which could explain potential wound healing problems post transplantation. The perspective of MPA-induced cytoskeletal dysfunction may go beyond wound healing disturbances and has potential beneficial effects on (renal) allografts with respect to scarring. Keywords: Timecourse and MPA and/or Guanosin response Human fibroblast are treated with Guanin and or Mycophenolic Acid (MPA). Samples were taken at different timepoints (20min, 1h, 12h,36h). Samples were amplified and hybridised against amplified RNA of Control human fibroblasts in dye-swaps to Human Oligo arrays. For GPR file names with _1, the test sample is labeled with Cy3. For GPR file names with _1, the test sample is labeled with Cy3.