GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway.

Zongkui Wang,Pan Sun,Fengjuan Liu,Fangzhao Lin,Shengliang Ye,Haijun Cao,Peng Jiang,Changqing Li,Li Ma,Miaomiao Dou,Na Su,Rong Zhang,Xi Du

doi:10.7717/peerj.5524

Zongkui Wang, Pan Sun + Show 11 more

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https://doi.org/10.7717/peerj.5524

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Abstract

GDF11, a member of TGF-β superfamily, has recently received widespread attention as a novel anti-ageing/rejuvenation factor to reverse age-related dysfunctions in heart and skeletal muscle, and to induce angiogenesis and neurogenesis. However, these positive effects of GDF11 were challenged by several other studies. Furthermore, the mechanism is still not well understood. In the present study, we evaluated the effects of GDF11 on C17.2 neural stem cells. GDF11 induced differentiation and apoptosis, and suppressed migration of C17.2 neural stem cells. In addition, GDF11 slightly increased cell viability after 24 h treatment, showed no effects on proliferation for about 10 days of cultivation, and slightly decreased cumulative population doubling for long-term treatment (p < 0.05). Phospho-proteome profiling array displayed that GDF11 significantly increased the phosphorylation of 13 serine/threonine kinases (p < 0.01), including p-p38, p-ERK and p-Akt, in C17.2 cells, which implied the activation of MAPK pathway. Western blot validated that the results of phospho-proteome profiling array were reliable. Based on functional analysis, we demonstrated that the differentially expressed proteins were mainly involved in signal transduction which was implicated in cellular behavior. Collectively, our findings suggest that, for neurogenesis, GDF11 might not be the desired rejuvenation factor, but a potential target for pharmacological blockade.

Highlights

Growth differentiation factor 11 (GDF11), known as bone morphogenetic protein 11 (BMP11), is a secreted glycoprotein belonging to the transforming growth factor β (TGF-β) superfamily (Pepinsky et al, 2017; Walker et al, 2016)
We focused on the effects of GDF11 on the cellular behavior of C17.2 neural stem cells, the changes in the phospho-proteome and the corresponding signaling pathways
We found that GDF11 was an important regulator of neural stem cell

Summary

Introduction

Growth differentiation factor 11 (GDF11), known as bone morphogenetic protein 11 (BMP11), is a secreted glycoprotein belonging to the transforming growth factor β (TGF-β) superfamily (Pepinsky et al, 2017; Walker et al, 2016). Egerman and colleagues (2015) showed that GDF11 supplementation inhibited muscle regeneration and decreased satellite cell expansion in mice, and suggested that GDF11 was not a rejuvenation factor but a potential target for pharmacologic blockade to treat age-related diseases. Hinken et al (2016) suggested GDF11 wasn’t a rejuvenator of aged murine skeletal muscle satellite cells. Others reported restoring GDF11 in old mice had no effect on cardiac structure or function (Smith et al, 2015). These conflicting studies offer compelling evidence that the effects of GDF11 are contradictory and demonstrate that the effects of GDF11 on neurogenesis are still not completely understood. We require an indepth knowledge of the effects and potential mechanism of action of GDF11 on regulating neural stem cells

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