Neural stem cells (NSCs) that reside in the adult mammalian hippocampus are capable of proliferation and differentiation into new neurons and glia throughout adulthood, a process that is associated with learning and memory. Reductionist approaches to recapitulate the NSC’s <i>in vivo</i> niche could provide valuable insight on the cell’s developmental process. To date, numerous biochemical cues from the endogenous NSC niche have been identified to play a role in NSC development. However, the combinatorial nature of the niche warrants investigation into how these cues act in combination with one another; various stem cell systems have revealed unintuitive cell response to combinations of stimuli that could not be predicted from the activity of the individual stimuli in isolation.<br/>To probe this, we have adapted a novel high-throughput microculture system to conduct systematic full factorial analyses of relevant niche cues, and employed traditional and data driven approaches to extract patterns from the large data set. ANOVA and factor analysis of neuronal and glial immunofluorescence measurements after 6 days “on-chip” reveals significant interactions among numerous pairwise and higher order combinations of stimuli. Unsupervised clustering, bivariate analysis, and partial least squares regression modeling suggest that the majority of variation in the endpoint population phenotype can be attributed to less than half of the soluble cues present in the full factorial analysis. This study provides early evidence for AHNSC signaling pathway crosstalk and contributes to further elucidation of the molecular mechanisms guiding stem cell fate choice.

Full factorial analyses via novel high-throughput microculture platform reveal numerous interactions among stimuli within adult hippocampal neural stem cell niche

253rd National Meeting (2017)

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