TNF-α respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma.
Bone marrow-derived human mesenchymal stem cells (hMSCs) have become valuable candidates for cell-based therapeutical applications including neuroregenerative and anti-tumor strategies. Yet, the molecular mechanisms that control hMSC trans-differentiation to neural cells and hMSC tropism toward glioma remain unclear. Here, we demonstrate that hMSCs incubated with 50 ng/ml tumor necrosis factor alpha (TNF-α) acquired astroglial cell morphology without affecting proliferation, which was increased at 5 ng/ml. TNF-α (50 ng/ml) upregulated expression of numerous genes important for neural cell growth and function including LIF (leukemia inhibitory factor), BMP2 (bone morphogenetic protein 2), SOX2 (SRY box 2), and GFAP (glial fibrillary acidic protein), whereas NES (human nestin) transcription ceased suggesting a premature neural phenotype in TNF-α-differentiated hMSCs. Studies on intracellular mitogen-activated protein kinase (MAPK) signaling revealed that inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity abolished the TNF-α-mediated regulation of neural genes in hMSCs. In addition, TNF-α significantly enhanced expression of the chemokine receptor CXCR4 (CXC motive chemokine receptor 4), which facilitated the chemotactic invasiveness of hMSCs toward stromal cell-derived factor 1 (SDF-1) alpha. TNF-α-pretreated hMSCs not only exhibited an increased ability to infiltrate glioma cell spheroids dependent on matrix metalloproteinase activity in vitro, but they also showed a potentiated tropism toward intracranial malignant gliomas in an in vivo mouse model. Taken together, our results provide evidence that culture-expansion of hMSCs in the presence of TNF-α triggers neural gene expression and functional capacities, which could improve the use of hMSCs in the treatment of neurological disorders including malignant gliomas.
Division of Clinical Chemistry and Clinical Biochemistry, Surgical Department, Ludwig-Maximilians University, Nussbaumstrasse 20, Munich, Germany.
V
V
Egea
L
L
von Baumgarten
C
C
Schichor
B
B
Berninger
T
T
Popp
P
P
Neth
R
R
Goldbrunner
Y
Y
Kienast
F
F
Winkler
M
M
Jochum
C
C
Ries
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000235:genetics; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D019718:Receptors, CXCR4 / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C527276:CXCR4 protein, human; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D019718:Receptors, CXCR4; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases