Abstract
The role of resveratrol (RV), a natural polyphenol, is well documented, although its role on neurogenesis is still controversial and poorly understood. Therefore, to decipher the cellular insights of RV on neurogenesis, we investigated the potential effects of the compound on the survival, proliferation, and neuronal differentiation of human cord blood-derived mesenchymal stem cells (hCBMSCs). For neuronal differentiation, purified and characterized hCBMSCs were exposed to biological safe doses of RV (10 μM) alone and in combination with nerve growth factor (NGF-50 ng). The cells exposed only to NGF (50 ng/mL) served as positive control for neuronal differentiation. The genes showing significant involvement in the process of neuronal differentiation were further funneled down at transcriptional and translational level. It was observed that RV promotes PKA-mediated neuronal differentiation in hCBMSCs by inducing canonical pathway. The studies with pharmacological inhibitors also confirmed that PKA significantly induces β-catenin expression via GSK3β induction and stimulates CREB phosphorylation and pERK1/2 induction. Besides that, the studies also revealed that RV additionally possesses the binding sites for molecules other than PKA and GSK3β, with which it interacts. The present study therefore highlights the positive impact of RV over the survival, proliferation, and neuronal differentiation in hCBMSCs via PKA-mediated induction of GSK3β, β catenin, CREB, and ERK1/2.
Similar content being viewed by others
References
Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70(4):687–702
Sun AY et al (2010) Resveratrol as a therapeutic agent for neurodegenerative diseases. Mol Neurobiol 41(2–3):375–383
Timmers S, Auwerx J, Schrauwen P (2012) The journey of resveratrol from yeast to human. Aging 4(3):146–158
Quincozes-Santos A, Gottfried C (2011) Resveratrol modulates astroglial functions: neuroprotective hypothesis. Ann N Y Acad Sci 1215(1):72–78
Singh N, Agrawal M, Doré S (2013) Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models. ACS Chem Neurosci 4(8):1151–1162
Das KP, Freudenrich TM, Mundy WR (2004) Assessment of PC12 cell differentiation and neurite growth: a comparison of morphological and neurochemical measures. Neurotoxicol Teratol 26(3):397–406
Perry T et al (2002) A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther 300(3):958–966
Sanchez S et al (2004) A cAMP-activated pathway, including PKA and PI3K, regulates neuronal differentiation. Neurochem Int 44(4):231–242
Sofroniew MV, Howe CL, Mobley WC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 24(1):1217–1281
York RD et al (1998) Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392(6676):622–626
Stork PJ, Schmitt JM (2002) Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 12(6):258–266
Segal RA, Greenberg ME (1996) Intracellular signaling pathways activated by neuropathic factors. Annu Rev Neurosci 19(1):463–489
Chang F et al (2003) Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 17(7):1263–1293
Jahan S et al (2017) Neurotrophic factor mediated neuronal differentiation of human cord blood mesenchymal stem cells and their applicability to assess the developmental neurotoxicity. Biochem Biophys Res Commun 482(4):961–967
Tang N et al (2009) BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/β-catenin signalling. J Cell Mol Med 13(8b):2448–2464
Clevers H (2006) Wnt/β-catenin signaling in development and disease. Cell 127(3):469–480
Baksh D, Song L, Tuan R (2004) Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 8(3):301–316
Forde JA, Dale TC (2007) Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci 64(15):1930–1944
Ikeda S et al (1998) Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β and β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J 17(5):1371–1384
Ginty DD et al (1991) Nerve growth factor-induced neuronal differentiation after dominant repression of both type I and type II cAMP-dependent protein kinase activities. J Biol Chem 266(23):15325–15333
Frödin M, Peraldi P, Van Obberghen E (1994) Cyclic AMP activates the mitogen-activated protein kinase cascade in PC12 cells. J Biol Chem 269(8):6207–6214
Kao HT et al (2002) A protein kinase A–dependent molecular switch in synapsins regulates neurite outgrowth. Nat Neurosci 5(5):431–437
Impey S et al (1998) Cross talk between ERK and PKA is required for Ca 2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21(4):869–883
Delghandi MP, Johannessen M, Moens U (2005) The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells. Cell Signal 17(11):1343–1351
Lee OK et al (2004) Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 103(5):1669–1675
Tojima T, Kobayashi S, Ito E (2003) Dual role of cyclic AMP-dependent protein kinase in neuritogenesis and synaptogenesis during neuronal differentiation. J Neurosci Res 74(6):829–837
Montminy M (1997) Transcriptional regulation by cyclic AMP. Annu Rev Biochem 66(1):807–822
Marambaud P, Dreses-Werringloer U, Vingtdeux V (2009) Calcium signaling in neurodegeneration. Mol Neurodegener 4(20):6–5
Greer PL, Greenberg ME (2008) From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59(6):846–860
Kutcher III, LW (2003) The Importance Of Subcellular Localization Of Ca2+/Calmodulin Dependent Protein Kinase Ii In Neuronal Differentiation. University of Cincinnati
Tresguerres M, Levin LR, Buck J (2011) Intracellular cAMP signaling by soluble adenylyl cyclase. Kidney Int 79(12):1277–1288
Gutierrez H, Davies AM (2011) Regulation of neural process growth, elaboration and structural plasticity by NF-κB. Trends Neurosci 34(6):316–325
Becker EB, Bonni A (2004) Cell cycle regulation of neuronal apoptosis in development and disease. Prog Neurobiol 72(1):1–25
West AE et al (2001) Calcium regulation of neuronal gene expression. Proc Natl Acad Sci 98(20):11024–11031
Imitola J (2007) Prospects for neural stem cell-based therapies for neurological diseases. Neurotherapeutics 4(4):701–714
Barzilay R et al (2008) Induction of human mesenchymal stem cells into dopamine-producing cells with different differentiation protocols. Stem Cells Dev 17(3):547–554
Parr AM, Tator CH, Keating A (2007) Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 40(7):609–619
Ling L, Nurcombe V, Cool SM (2009) Wnt signaling controls the fate of mesenchymal stem cells. Gene 433(1):1–7
Ortiz-Gonzalez XR et al (2004) Neural induction of adult bone marrow and umbilical cord stem cells. Curr Neurovasc Res 1(3):207–213
Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B: Biol Sci 361(1473):1545–1564
Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309
Pyle AD, Lock LF, Donovan PJ (2006) Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnol 24(3):344–350
Sariola H (2001) The neurotrophic factors in non-neuronal tissues. Cell Mol Life Sci CMLS 58(8):1061–1066
Reznichenko L et al (2005) Green tea polyphenol (−)-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem 93(5):1157–1167
Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116(7):1175–1186
Schmidt-Ott KM, Barasch J (2008) WNT/β-catenin signaling in nephron progenitors and their epithelial progeny. Kidney Int 74(8):1004–1008
Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13(12):767–779
Maurer MH et al (2007) Glycogen synthase kinase 3β (GSK3β) regulates differentiation and proliferation in neural stem cells from the rat subventricular zone. J Proteome Res 6(3):1198–1208
Gribkoff VK et al (2001) Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nat Med 7(4):471–477
Arundine M, Tymianski M (2003) Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34(4):325–337
Oliveria SF, Dell’Acqua ML, Sather WA (2007) AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca 2+ channel activity and nuclear signaling. Neuron 55(2):261–275
Nagase H et al (2005) Mechanism of neurotrophic action of nobiletin in PC12D cells. Biochemistry 44(42):13683–13691
Kamenetsky M et al (2006) Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol 362(4):623–639
Stessin AM et al (2006) Soluble adenylyl cyclase mediates nerve growth factor-induced activation of Rap1. J Biol Chem 281(25):17253–17258
Young JJ et al (2008) “Soluble” adenylyl cyclase-generated cyclic adenosine monophosphate promotes fast migration in PC12 cells. J Neurosci Res 86(1):118–124
Jicha GA et al (1999) cAMP-dependent protein kinase phosphorylations on tau in Alzheimer’s disease. J Neurosci 19(17):7486–7494
Skalhegg B, Tasken K (2000) Specificity in the cAMP/PKA signaling pathway. Differential expression, regulation, and subcellular localization of subunits of PKA. Front Biosci 5(5):D678–D693
Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35(4):605–623
Wu G-Y, Deisseroth K, Tsien RW (2001) Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci 98(5):2808–2813
Daniel PB, Walker WH, Habener JF (1998) Cyclic AMP signaling and gene regulation. Annu Rev Nutr 18(1):353–383
Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134
Riccio A et al (2006) A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. Mol Cell 21(2):283–294
Peltier J, O’Neill A, Schaffer DV (2007) PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol 67(10):1348–1361
Acknowledgments
Financial support from Department of Science and Technology, Ministry of Science and Technology, Government of India, New Delhi, India [Grant No. SR/SO/Z 36/2007/91/10]; Department of Biotechnology, Ministry of Science and Technology, Government of India, New Delhi, India [Grant No. 102/IFD/SAN/3533/2014-15] and Council of Scientific and Industrial Research, Government of India, New Delhi, India [Grant No. BSC0111/INDEPTH/CSIR Network Project] is acknowledged.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Authors of this manuscript have no conflict of interest among them or anybody else regarding the scientific contents, financial matters, and otherwise.
Rights and permissions
About this article
Cite this article
Jahan, S., Singh, S., Srivastava, A. et al. PKA-GSK3β and β-Catenin Signaling Play a Critical Role in Trans-Resveratrol Mediated Neuronal Differentiation in Human Cord Blood Stem Cells. Mol Neurobiol 55, 2828–2839 (2018). https://doi.org/10.1007/s12035-017-0539-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-017-0539-x