AICAR Induces Astroglial Differentiation of Neural Stem Cells via Activating the JAK/STAT3 Pathway Independently of AMP-activated Protein Kinase

Abstract

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.Neural stem cell differentiation is controlled by intrinsic regulators and the extracellular environment. In many cases, these factors act in concert to confer potent change in cell lineages.

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

“…AICAR-enhanced differentiation of progenitor cells placed in specific differentiation medium has been reported. 58,59 Some percentage of stem cells isolated from aged hearts, when subjected to AICAR in serum-free medium, differentiated into myofibroblasts ( Figure 5B), which suggests that AICAR activation can bypass serum-dependent pathways necessary for myofibroblast maturation.…”

Resveratrol Inhibits the Proliferation of Neural Progenitor Cells and Hippocampal Neurogenesis

“…For example, AMPK activation mediates the inhibition of cell growth in mouse embryonic fibroblasts under conditions of reduced energy availability (49). Furthermore, the AMPK activator AICAR reduces the proliferation of NPCs and cancer cells (50,(53)(54)(55)(56). We therefore suggest that, with regards to NPCs, resveratrolinduced AMPK activation can have beneficial effects in a back-ground of a metabolic disorder or disease state, but may adversely affect these cells under normal conditions.…”

Physalin B not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in human colon cancer cells in vitro

“…The microtubules were observed using an immunocytochemistry assay [25] . Briefly, the cells were grown on glass coverslips for 24 h, treated with 10 µmol/L physalin B for 12 h, fixed using 4% paraformaldehyde for 20 min, incubated with 0.1% Triton X-100 for 10 min, blocked with 5% BSA for 1 h at room temperature, and incubated with a monoclonal β-tubulin antibody overnight at 4 °C.…”