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

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 and underlying mechanisms of GDF11 on C17.2 neural stem cells. GDF11 induced differentiation and apoptosis, and suppressed migration of C17.2 neural stem cells. Besides, GDF11 slightly increased cell viability after 24h 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 level 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 pharmacologic blockade.

Retracted: Lipopolysaccharides‐mediated injury to chondrogenic ATDC5 cells can be relieved by Sinomenine via downregulating microRNA‐192

“…GDF11, a key member of TGF‐β superfamily, is closely associated with inflammatory response. Previous findings reported GDF11 as an anti‐inflammatory gene via repressing NF‐κB and MAPK signaling pathways (Wang, Duo, et al, ; Wang, Qu, et al, ). Herein, GDF11 was found to be a target gene of miR‐192.…”

Interleukin‑35 sensitizes monocytes from patients with asthma to glucocorticoid therapy by regulating p38 MAPK

“…Second, the present results suggested that IL-35 alone significantly decreased p-p38 MAPK expression in monocytes stimulated by LPS, but did not increase MKP-1 protein expression and GR binding to GRE. Several previous studies have reported that multiple signaling pathways regulate p-p38 MAPK activation at the epigenetic, transcriptional and post-transcriptional levels (32,33). Therefore, IL-35 may inhibit p-p38 MAPK activation via a variety of pathways, thus further research is required.…”

The influence of GDF11 on brain fate and function

“…In contrast, in the developing spinal cord, newly born neurons transiently express Gdf11, which triggers adjacent progenitor cells to exit the cell cycle and differentiate into neurons (Shi and Liu 2011), indicating that GDF11 is also capable of facilitating developmental neurogenesis in distinct contexts. Functional neuronal morphology and identity may also be influenced by GDF11 (Hocking et al 2008;Augustin et al 2017;Lo and Frasch 1999;Awasaki et al 2011;Wang et al 2018). Immature neurons may require extrinsic signals for dendritic initiation and maturationmaturation, and work by Hocking and colleagues suggests that GDF11, as well as other TGFβ superfamily ligands, extrinsically influence neuronal differentiation.…”

“…Mammalian cell culture experiments also support GDF11 as a regulator of functional neuronal morphology. A study of C17.2 neural stem cell identity and behavior indicated that concentration and temporal kinetics of GDF11 treatment highly influence its effects (Wang et al 2018). Treatment of neural stem cells with GDF11 induced differentiation, including neurite outgrowth, and increased protein levels of neuronal and astrocytic lineage markers (Wang et al 2018).…”