Discovery of a Small Molecule that Enhances Astrocytogenesis by Activation of STAT3, SMAD1/5/8, and ERK1/2 via Induction of Cytokines in Neural Stem Cells.
Identification of small molecules that direct neural stem cells (NSCs) into specific cell types would be helpful to understand the molecular mechanisms involved in regulation of NSC fate, and facilitate the development of therapeutic applications. In the current study, we developed and screened small molecules that can modulate the fate of NSCs that are derived from rat fetal cortex. Among these compounds, compounds 5 and 6 successfully differentiated NSCs into astrocytes and neurons, respectively. Compound 5 induced astrocytogenesis by increasing expression of interleukin-6, bone morphogenetic protein 2 and leukemia inhibitory factor and through consequent phosphorylation of signal transducer and activator of transcription 3 and Sma- and Mad-related protein 1/5/8 in NSCs. In addition, compound 5 increased the expression of fibroblast growth factor (FGF) 2 and FGF8 which may regulate the branching and morphology of astrocytes. Taken together, our results suggest that these small molecules can serve as a useful tool to study cell fate determination in NSCs and be used as an inexpensive alternative to cytokines to study mechanisms of astrocytogenesis.
College of Pharmacy, Chung-Ang University , Seoul 156-756, Korea.
Ha-Rim
HR
Lee
GVK Bioscience Pvt Ltd, Hyderabad-500076, India.
Farhanullah
College of Pharmacy, Chung-Ang University , Seoul 156-756, Korea.
JiSoo
J
Lee
GVK Bioscience Pvt Ltd, Hyderabad-500076, India.
Rahul
R
Jajoo
College of Pharmacy, Chung-Ang University , Seoul 156-756, Korea.
Sun-Young
SY
Kong
College of Pharmacy, Chung-Ang University , Seoul 156-756, Korea.
Jae-Yeon
JY
Shin
Laboratory Science Division, International Vaccine Institute , Seoul 151-919, Korea.
Jae-Ouk
JO
Kim
Department of Global Medical Science, Sungshin University , Seoul 142-732, Korea.
Jiyoun
J
Lee
College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
Jeewoo
J
Lee
College of Pharmacy, Chung-Ang University , Seoul 156-756, Korea.
Hyun-Jung
HJ
Kim
D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D002452:Cell Count; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004622:Embryo, Mammalian; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D038081:Organogenesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism*; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D051904:Smad8 Protein / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D050796:STAT3 Transcription Factor; D051896:Smad Proteins, Receptor-Regulated; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D048052:Mitogen-Activated Protein Kinase 3
Astrocytogenesis; differentiation; neural stem cells; neurodegeneration; neurological agents; structure−activity relationships