Inhibition of platelet-derived growth factor receptor signaling regulates Oct4 and Nanog expression, cell shape, and mesenchymal stem cell potency.
Defining the signaling mechanisms that regulate the fate of adult stem cells is an essential step toward their use in regenerative medicine. Platelet-derived growth factor receptor (PDGFR) signaling plays a crucial role in specifying mesenchymal stem cell (MSC) commitment to mesenchymal lineages. Based on the hypothesis that selective inhibition of signaling pathways involved in differentiation may increase stem cell potency, we examined the role of PDGFR signaling in controlling the fate of human MSCs. Using a small molecular PDGFR inhibitor that induced MSCs toward a more rounded shape, expression of Oct4 and Nanog were markedly upregulated. In these PDGFR inhibitor-treated MSCs, Oct4 and Nanog expression and cell shape were regulated by janus kinase (JAK), MAPK kinase (MEK), and epidermal growth factor receptor (EGFR) signaling. Under defined differentiation conditions, these PDGFR-inhibited MSCs expressed definitive endodermal, ectodermal, and mesodermal markers. We also confirmed that depletion of individual PDGF receptors upregulated expression of Oct4A and Nanog. This study identifies PDGFR signaling as a key regulator of Oct4 and Nanog expression and of MSC potency. Thus, inhibiting these specific receptor tyrosine kinases, which play essential roles in tissue formation, offers a novel approach to unlock the therapeutic capacity of MSCs.
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK.
Stephen G
SG
Ball
Adrian
A
Shuttleworth
Cay M
CM
Kielty
D000205:Actomyosin / Q000378:metabolism; D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D053145:Cell Nucleus Size / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology*; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
C505208:(6,7-dimethoxy-2,4-dihydroindeno(1,2-c)pyrazol-3-yl)(3-fluorophenyl)amine; D018398:Homeodomain Proteins; D007189:Indans; C529896:Ki11502; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000205:Actomyosin; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D053612:Janus Kinases; D016315:Proto-Oncogene Proteins c-abl; D020930:MAP Kinase Kinase Kinases