title: PTEN inhibition enhances neurite outgrowth in human embryonic stem cell-derived neuronal progenitor cells.
abstract: We investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during neurite outgrowth of human embryonic stem cell (hESC)-derived neuronal progenitors. PTEN inhibits phosphoinositide 3-kinase (PI3K)/Akt signaling, a common and central outgrowth and survival pathway downstream of neuronal growth factors. It is known that PTEN inhibition, by either polymorphic mutation or gene deletion, can lead to the development of tumorigenesis (Stambolic et al., ; Tamura et al., ). However, temporary inhibition of PTEN, through pharmacological manipulation, could regulate signaling events such as the PI3K/Akt signaling pathway, leading to enhanced recovery of central nervous system (CNS) injury and disease. We demonstrate that pharmacological inhibition of PTEN in hESC-derived neuronal progenitors significantly increased neurite outgrowth in vitro in a dose- and time-dependent manner. Our results indicate that inhibition of PTEN augments neurite outgrowth beyond that of traditional methods such as elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, and depends on upregulation of the PI3K/Akt signaling pathway and its downstream effectors, such as mammalian target of rapamycin (mTOR). PTEN inhibition also rescued neurite outgrowth over an inhibitory substrate in vitro. These findings indicate a remarkable impact on hESC-derived neuronal progenitor plasticity through PTEN inhibition. Overall, these findings identify a novel therapeutic strategy for neurite outgrowth in CNS injury and disease.
authors.affiliation: Department of Anatomy and Neurobiology, Sue and Bill Gross Stem Cell Research Center, Reeve-Irvine Research Center, School of Medicine, University of California at Irvine, Irvine, California, 92697-4292.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Wyatt
authors.forename: Marie T
authors.initials: MT
authors.lastname: Filbin
authors.forename: Hans S
authors.initials: HS
authors.lastname: Keirstead
mesh_terms: D000818:Animals; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D003412:Cricetulus / Q000502:physiology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D009942:Organometallic Compounds; D038601:Ribosomal Protein S6; D013873:Thionucleotides; C119540:oxodiperoxo(pyridine-2-carboxylate)vanadate(V); C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PTEN; axon; central nervous system; neuron; neuroregeneration