mTOR Pathway Inhibition Alters Proliferation as Well as Differentiation of Neural Stem Cells

Authors

Nataliya Romanyuk, Department of Neuroregeneration, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.
Kristyna Sintakova, Department of Neuroregeneration, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.
Ivan Arzhanov, Department of Neuroregeneration, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.
Martin Horak, Department of Neurochemistry, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.
Chirag Gandhi, Department of Neurosurgery, New York Medical College, Valhalla, NY, United States.Follow
Meena Jhanwar-Uniyal, Department of Neurosurgery, New York Medical College, Valhalla, NY, United States.
Pavla Jendelova, Department of Neuroregeneration, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.

Author Type(s)

Faculty

DOI

10.3389/fncel.2024.1298182

Journal Title

Frontiers in Cellular Neuroscience

First Page

1298182

Document Type

Article

Publication Date

1-1-2024

Department

Neurosurgery

Abstract

INTRODUCTION: Neural stem cells (NSCs) are essential for both embryonic development and adult neurogenesis, and their dysregulation causes a number of neurodevelopmental disorders, such as epilepsy and autism spectrum disorders. NSC proliferation and differentiation in the developing brain is a complex process controlled by various intrinsic and extrinsic stimuli. The mammalian target of rapamycin (mTOR) regulates proliferation and differentiation, among other cellular functions, and disruption in the mTOR pathway can lead to severe nervous system development deficits. In this study, we investigated the effect of inhibition of the mTOR pathway by rapamycin (Rapa) on NSC proliferation and differentiation. METHODS: The NSC cultures were treated with Rapa for 1, 2, 6, 24, and 48 h. The effect on cellular functions was assessed by immunofluorescence staining, western blotting, and proliferation/metabolic assays. RESULTS: mTOR inhibition suppressed NSC proliferation/metabolic activity as well as S-Phase entry by as early as 1 h of Rapa treatment and this effect persisted up to 48 h of Rapa treatment. In a separate experiment, NSCs were differentiated for 2 weeks after treatment with Rapa for 24 or 48 h. Regarding the effect on neuronal and glial differentiation (2 weeks post-treatment), this was suppressed in NSCs deficient in mTOR signaling, as evidenced by downregulated expression of NeuN, MAP2, and GFAP. We assume that the prolonged effect of mTOR inhibition is realized due to the effect on cytoskeletal proteins. DISCUSSION: Here, we demonstrate for the first time that the mTOR pathway not only regulates NSC proliferation but also plays an important role in NSC differentiation into both neuronal and glial lineages.

Recommended Citation

Romanyuk, N., Sintakova, K., Arzhanov, I., Horak, M., Gandhi, C., Jhanwar-Uniyal, M., & Jendelova, P. (2024). mTOR Pathway Inhibition Alters Proliferation as Well as Differentiation of Neural Stem Cells. Frontiers in Cellular Neuroscience, 18, 1298182. https://doi.org/10.3389/fncel.2024.1298182