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Inhibition of glycogen synthase kinase 3 increased subventricular zone stem cells proliferation
Narges Pachenari1, Sahar Kiani2, Mohammad Javan3
1Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Abstract:
The effects of Wnt signaling modifiers on cell proliferation, seem to be cell specific. Enhancing the proliferation of subventricular zone (SVZ) progenitors has been in the focus of research in recent years. Here we investigate the effect of CHIR99021, a Glycogen Synthase Kinase 3 (GSk-3) inhibitor, on SVZ progenitor's proliferation both in vivo and in vitro. Neural stem cells were extracted from the adult C57bl/6 by mincing and trypsin treatment followed by culturing in specific medium. Sphere cells formed within about 7-10days and were characterized by immunostaining. Number of spheres and their size was assessed following exposure to different concentration of CHIR99021 or vehicle. For in vivo studies, animals received intracerebroventricular (i.c.v.) injection of CHIR99021 or vehicle for four days. A subgroup of animals, after 4days treatment with CHIR99021 received intranasal kainic acid to induce local neurodegeneration in CA3 area of hippocampus. Inhibition of GSk-3 by CHIR99021 increased neural progenitor proliferation and the effect of CHIR99021 was long lasting so that the treated cells showed higher proliferation even after CHIR99021 removal. In vivo administration of CHIR99021 increased the number of neural progenitors at the rims of lateral ventricles especially when the treatment was followed by kainic acid administration which induces neural insult. Results showed that direct administration of CHIR99021 into the culture medium or animal brain increased the number of SVZ progenitors, especially when a neural insult was induced in the hippocampus.
Insights
Glycogen Synthase Kinase 3 (GSk-3) inhibition with CHIR99021 enhances subventricular zone (SVZ) progenitor proliferation in vitro and in vivo. This effect is long-lasting and particularly pronounced following neural insult, suggesting therapeutic potential.
Area of Science:
- Neuroscience
- Cell Biology
- Regenerative Medicine
Background:
- Subventricular zone (SVZ) progenitor proliferation is crucial for neural repair.
- Wnt signaling pathway modifiers can influence cell proliferation in a cell-specific manner.
- Glycogen Synthase Kinase 3 (GSk-3) is a key regulator in cellular signaling pathways.
Purpose of the Study:
- To investigate the effect of CHIR99021, a GSk-3 inhibitor, on SVZ progenitor proliferation.
- To assess the in vitro and in vivo impact of CHIR99021 on neural stem cells.
- To determine if CHIR99021 enhances progenitor proliferation following induced neural insult.
Main Methods:
- Neural stem cells were isolated and cultured from adult C57bl/6 mice.
- Cells were treated with varying concentrations of CHIR99021 or vehicle.
- In vivo studies involved intracerebroventricular (i.c.v.) CHIR99021 administration, with a subgroup receiving intranasal kainic acid.
- Sphere formation, size, and progenitor cell counts were assessed.
Main Results:
- CHIR99021 significantly increased SVZ progenitor proliferation in vitro, with a sustained effect even after drug removal.
- In vivo administration of CHIR99021 boosted neural progenitor numbers in the lateral ventricles.
- Combined CHIR99021 treatment and kainic acid-induced neurodegeneration led to a notable increase in progenitor cells.
Conclusions:
- Inhibition of GSk-3 by CHIR99021 is an effective method to enhance SVZ progenitor proliferation.
- CHIR99021 demonstrates potential for promoting neural regeneration, especially in contexts of neural injury.
- The findings support the role of GSk-3 inhibition in boosting endogenous neural repair mechanisms.
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