Growth Differentiation Factor 11 Promotes Neurovascular Recovery After Stroke in Mice

Mouse models, so you'll have to see if your doctor contacts these researchers doing human testing.  And no real hurry to get it done.
https://www.frontiersin.org/articles/10.3389/fncel.2018.00205/full?

Lu Lu, Xiaofei Bai, Yongliang Cao, Haiyu Luo, Xing Yang, Lijing Kang, Mei-Juan Shi, Wenying Fan^* and Bing-Qiao Zhao^*

• Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, China

Background: Growth differentiation factor 11 (GDF11), a member of transforming growth factor-β (TGF-β) superfamily, was shown to rejuvenate cardiac and skeletal muscle function and to improve cerebral vasculature and neurogenesis in old mice. However, recent experimental data reported that raising GDF11 levels inhibited skeletal muscle regeneration and had no effect on cardiac hypertrophy. Our aim was to investigate the effects of GDF11 on brain repair during the recovery phase after stroke.

Methods: Mice were subjected to distal middle cerebral artery occlusion, and recombinant GDF11 (rGDF11) was injected intraperitoneally once a day during days 7–13 after stroke. Neuronal precursor cells (NPCs) proliferation and angiogenesis were assayed at 14 days. Neuronal regeneration was assayed at 42 days. The beam-walking test and CatWalk were used to evaluate behavioral functions. Downstream pathways of GDF11 were also investigated.

Results: GDF11 was upregulated in the ipsilateral peri-infarct cortex and subventricular zone (SVZ) at 14 days after stroke. Treatment with rGDF11 enhanced the number of newborn NPCs and endothelial cells, microvascular length and area, and brain capillary perfusion. Western blots showed that rGDF11 upregulated brain-derived neurotrophic factor (BDNF) and increased the levels of proangiogenic factor angiopoietin-2 (Ang-2) and phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2). We also found that rGDF11 upregulated the transcription factors Smad2 and Smad3 phosphorylation, but these activations were blocked by a TGF-β receptor inhibitor SB431542. Moreover, rGDF11-induced angiogenic remodeling and NPCs proliferation were reversed by injection of SB431542, suggesting that GDF11 may exert its effect via the TGF-β/Smad2/3 signaling pathway. Finally, treating mice with rGDF11 resulted in a significant increase in neuronal regeneration and functional recovery.

Conclusion: GDF11 promoted neurogenesis and angiogenesis and contributed to functional recovery after stroke in mice.

Introduction

Stroke is the leading cause of disability around the world (Murray et al., 2012). However, currently there is no effective treatment to facilitate the recovery in stroke patients. Stroke triggers the proliferation of the neural progenitor cells (NPCs) in the subventricular zone (SVZ) and the subgranular zone (SGZ) and the migration of NPCs toward the stroke areas (Arvidsson et al., 2002; Teng et al., 2008; Osman et al., 2011). Recent studies have suggested that stroke also induces angiogenesis in the peri-infarct region (Jiang et al., 2016). In stroke patients, there is a significant correlation between the vessel density in the brain and delayed mortality, suggesting that the angiogenesis is important for stroke recovery (Krupinski et al., 1993; Krupinski, 1994). Furthermore, angiogenic vessels were reported to release growth factors and chemokines to promote the migration of neuroblasts and the survival of new neurons, indicating that angiogenesis is highly linked with neurogenesis (Tsai et al., 2006). Therefore, therapeutic approaches to promote both neurogenesis and angiogenesis process may provide promising opportunities for stroke recovery.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, participates various biological processes in mammals. GDF11 has been identified as a rejuvenation factor which could reverse age-related cardiac hypertrophy and improve muscle and brain function (Loffredo et al., 2013; Katsimpardi et al., 2014; Sinha et al., 2014). The major findings of these studies were that circulating levels of GDF11 decreased with aging and recombinant GDF11 injection could improve the vascular remodeling and increase neurogenesis in aging mice (Katsimpardi et al., 2014). However, a recent report questioned the conclusion and suggested that circulating GDF11 levels increased with age and reduced muscle regeneration (Egerman et al., 2015). Another study also demonstrated a negative effect of GDF11 on age-related cardiac hypertrophy (Smith et al., 2015). Furthermore, in vitro experiments found that GDF11 treatment could increase the peripheral blood endothelial progenitor cells migration and the sprout formation (Finkenzeller et al., 2015), while showed no significant effect on the human umbilical vein endothelial cells proliferation and migration (Zhang et al., 2016).

In this study, we investigated the role of GDF11 on stroke recovery in a mouse model of distal occlusion of middle cerebral artery. We found that delayed treatment with recombinant GDF11 (rGDF11) at 7 days after stroke promoted neurogenesis and angiogenesis and improved behavioral outcome by regulating the TGF-β/Smad2/3 signaling pathway.