The anti-aging factor GDF11 has both direct and indirect effects on mouse neural stem cells (P5.089)

Objective: Determine the direct and indirect effects of the anti-aging factor GDF11 on neural stem cells and endothelial cells. Background: Aging is the number one risk factor for the development of Alzheimer’s disease and Parkinson’s disease. Data from parabiosis experiments, in which old and young mice are surgically joined to share circulation, demonstrate that systemic circulating factors are able to reverse certain aspects of aging. GDF11, a TGFβ family member, has been proposed as one of the circulating factors responsible for the anti-aging effects of parabiosis. Accordingly, injection of recombinant GDF11 into old mice improves vasculature and increases neural stem cell (NSC) proliferation (Katsimpardi et. al. 2014). A better understanding of the mechanism of this effect, and of cross-talk between circulating factors, the vasculature, and NSCs, will provide insight into new therapeutic approaches for age-related neurodegenerative diseases. Design/Methods: We used an in vitro system of mouse subventricular zone-derived neurospheres and brain endothelial cells to study the direct and indirect effects of GDF11 and interactions between the vasculature and NSCs. We examined GDF11 effects on NSC proliferation and differentiation using size quantitation of neurospheres and immunocytochemistry for markers of differentiation. Transwell assays were performed to assess the indirect effects of GDF11-stimulated endothelial cells on co-cultured neurospheres. Results: Neurosphere derived cells activate downstream signaling components upon GDF11 treatment. Direct treatment of neurospheres with GDF11 alters the size of spheres produced. GDF11 treatment of vascular endothelial cells indirectly increases neurosphere production in a coculture system. GDF11 influences differentiation of neurospheres by decreasing the amount of neurons produced. Conclusions: GDF11 influences both NSC and progenitor expansion and resultant differentiation based on the direct effects observed in vitro . Additionally, endothelial cells may play an important role in mediating the indirect effects of GDF11 on neural stem cells, as coculture of endothelial cells with neurospheres further stimulates growth. Study Supported by: NIH NINDS R25 program Harvard University, Blavatnik Biomedical Accelerator Program Rainwater Charitable Foundation Disclosure: Dr. Krolewski has nothing to disclose. Dr. Buchanan has nothing to disclose. Dr. Rubin has received personal compensation for activities with Denali, Alkahest, ReNeuron, Q-State, Pharma Arava, and Yumanity. Dr. Rubin has received research support from Nikon, Biogen, and Pharma Arava.