AICAR induces astroglial differentiation of neural stem cells via activating the JAK/STAT3 pathway independently of AMP-activated protein kinase.
Neural stem cell differentiation and the determination of lineage decision between neuronal and glial fates have important implications in the study of developmental, pathological, and regenerative processes. Although small molecule chemicals with the ability to control neural stem cell fate are considered extremely useful tools in this field, few were reported. AICAR is an adenosine analog and extensively used to activate AMP-activated protein kinase (AMPK), a metabolic "fuel gauge" of the biological system. In the present study, we found an unrecognized astrogliogenic activity of AICAR on not only immortalized neural stem cell line C17.2 (C17.2-NSC), but also primary neural stem cells (NSCs) derived from post-natal (P0) rat hippocampus (P0-NSC) and embryonic day 14 (E14) rat embryonic cortex (E14-NSC). However, another AMPK activator, Metformin, did not alter either the C17.2-NSC or E14-NSC undifferentiated state although both Metformin and AICAR can activate the AMPK pathway in NSC. Furthermore, overexpression of dominant-negative mutants of AMPK in C17.2-NSC was unable to block the gliogenic effects of AICAR. We also found AICAR could activate the Janus kinase (JAK) STAT3 pathway in both C17.2-NSC and E14-NSC but Metformin fails. JAK inhibitor I abolished the gliogenic effects of AICAR. Taken together, these results suggest that the astroglial differentiation effect of AICAR on neural stem cells was acting independently of AMPK and that the JAK-STAT3 pathway is essential for the gliogenic effect of AICAR.
Zang
Yi
Y
National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Yu
Li-Fang
LF
Pang
Tao
T
Fang
Lei-Ping
LP
Feng
Xu
X
Wen
Tie-Qiao
TQ
Nan
Fa-Jun
FJ
Feng
Lin-Yin
LY
Li
Jia
J
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology*; D002454:Cell Differentiation / Q000187:drug effects*; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*
D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D053612:Janus Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide