title: STAT3 modulation to enhance motor neuron differentiation in human neural stem cells.
abstract: Spinal cord injury or amyotrophic lateral sclerosis damages spinal motor neurons and forms a glial scar, which prevents neural regeneration. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in astrogliogenesis and scar formation, and thus a fine modulation of STAT3 signaling may help to control the excessive gliogenic environment and enhance neural repair. The objective of this study was to determine the effect of STAT3 inhibition on human neural stem cells (hNSCs). In vitro hNSCs primed with fibroblast growth factor 2 (FGF2) exhibited a lower level of phosphorylated STAT3 than cells primed by epidermal growth factor (EGF), which correlated with a higher number of motor neurons differentiated from FGF2-primed hNSCs. Treatment with STAT3 inhibitors, Stattic and Niclosamide, enhanced motor neuron differentiation only in FGF2-primed hNSCs, as shown by increased homeobox gene Hb9 mRNA levels as well as HB9+ and microtubule-associated protein 2 (MAP2)+ co-labeled cells. The increased motor neuron differentiation was accompanied by a decrease in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes. Interestingly, Stattic and Niclosamide did not affect the level of STAT3 phosphorylation; rather, they perturbed the nuclear translocation of phosphorylated STAT3. In summary, we demonstrate that FGF2 is required for motor neuron differentiation from hNSCs and that inhibition of STAT3 further increases motor neuron differentiation at the expense of astrogliogenesis. Our study thus suggests a potential benefit of targeting the STAT3 pathway for neurotrauma or neurodegenerative diseases.
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Rajalaxmi
authors.initials: R
authors.lastname: Natarajan
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Vinamrata
authors.initials: V
authors.lastname: Singal
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Benes
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Junling
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Hoi
authors.initials: H
authors.lastname: Chan
authors.affiliation: Department of Pharmacology & Toxicology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Haijun
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Yongjia
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pharmacology & Toxicology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D009046:Motor Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009534:Niclosamide / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D003499:Cyclic S-Oxides; D005904:Glial Fibrillary Acidic Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C517409:stattic; D016222:Fibroblast Growth Factor 2; D019000:Phosphotyrosine; D009534:Niclosamide