Mitochondrial biogenesis and neural differentiation of human iPSC is modulated by idebenone in a developmental stage-dependent manner

J Augustyniak,J Lenart,L Buzanska,P P Stepien,M Zychowicz

doi:10.1007/s10522-017-9718-4

J Augustyniak, J Lenart + Show 3 more

Open Access

https://doi.org/10.1007/s10522-017-9718-4

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Abstract

Idebenone, the synthetic analog of coenzyme Q10 can improve electron transport in mitochondria. Therefore, it is used in the treatment of Alzheimer’s disease and other cognitive impairments. However, the mechanism of its action on neurodevelopment is still to be elucidated. Here we demonstrate that the cellular response of human induced pluripotent stem cells (hiPSC) to idebenone depends on the stage of neural differentiation. When: neural stem cells (NSC), early neural progenitors (eNP) and advanced neural progenitors (NP) have been studied a significant stimulation of mitochondrial biogenesis was observed only at the eNP stage of development. This coexists with the enhancement of cell viability and increase in total cell number. In addition, we report novel idebenone properties in a possible regulation of neural stem cells fate decision: only eNP stage responded with up-regulation of both neuronal (MAP2), astrocytic (GFAP) markers, while at NSC and NP stages significant down-regulation of MAP2 expression was observed, promoting astrocyte differentiation. Thus, idebenone targets specific stages of hiPSC differentiation and may influence the neural stem cell fate decision.

Highlights

Human induced pluripotent stem cells can generate neural stem cells, as well as neural and glial progenitors (Choi et al 2014)
We present results showing the response of neural stem/progenitor cells generated from human induced pluripotent stem cells (hiPSC) to idebenone exposition at three different stages of neural differentiation: neural stem cells (NSC); early neural progenitors and neural progenitors (NP)
Neural stem cells are multipotent cells characterized by self-renewal, the ability to proliferate without a limit and the capacity to produce neural progenitors which can be differentiated into neurons, astrocytes and oligodendrocytes (Clarke et al 2000)

Summary

Introduction

Human induced pluripotent stem cells (hiPSC) can generate neural stem cells, as well as neural and glial progenitors (Choi et al 2014). Differentiation of hiPSC into neural progenitors is associated with the metabolic switch from glycolysis to oxidative phosphorylation (OXPHOS) and is correlated with an increase in the number of mitochondria (Zheng et al 2016). Manipulation of the activity and number of mitochondria is an interesting therapeutic option for age-related neurodegenerative diseases (Reddy 2009, Luo et al 2015). In the process of reprogramming (Takahashi et al 2007) somatic cells are converted into induced pluripotent stem cells. During differentiation, which is a process opposed to reprogramming, mitochondria plays a leading role as well (Wanet et al 2015). A participation of mitochondria in reprogramming and differentiation is important in therapy and regenerative medicine but is crucial for understanding stem cell biology

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