Topographical Analysis of the Subependymal Zone Neurogenic Niche

Ana Mendanha Falcão,Nuno Sousa,Joana Almeida Palha,Fernanda Marques,Ana Catarina Ferreira,João Carlos Sousa,Domingos Henrique

doi:10.1371/journal.pone.0038647

Abstract

The emerging model for the adult subependymal zone (SEZ) cell population indicates that neuronal diversity is not generated from a uniform pool of stem cells but rather from diverse and spatially confined stem cell populations. Hence, when analysing SEZ proliferation, the topography along the anterior-posterior and dorsal-ventral axes must be taken into account. However, to date, no studies have assessed SEZ proliferation according to topographical specificities and, additionally, SEZ studies in animal models of neurological/psychiatric disorders often fail to clearly specify the SEZ coordinates. This may render difficult the comparison between studies and yield contradictory results. More so, by focusing in a single spatial dimension of the SEZ, relevant findings might pass unnoticed. In this study we characterized the neural stem cell/progenitor population and its proliferation rates throughout the rat SEZ anterior-posterior and dorsal-ventral axes. We found that SEZ proliferation decreases along the anterior-posterior axis and that proliferative rates vary considerably according to the position in the dorsal-ventral axis. These were associated with relevant gradients in the neuroblasts and in the neural stem cell populations throughout the dorsal-ventral axis. In addition, we observed spatially dependent differences in BrdU/Ki67 ratios that suggest a high variability in the proliferation rate and cell cycle length throughout the SEZ; in accordance, estimation of the cell cycle length of the neuroblasts revealed shorter cell cycles at the dorsolateral SEZ. These findings highlight the need to establish standardized procedures of SEZ analysis. Herein we propose an anatomical division of the SEZ that should be considered in future studies addressing proliferation in this neural stem cell niche.

Highlights

The subependymal zone (SEZ), generally described as a thin layer of proliferative cells lining the lateral wall of the lateral brain ventricles, is a major source of multipotent neural stem cells (NSCs) in the adult brain [1,2]
Analysis of the SEZ cell proliferation rate along the anteriorposterior axis, as defined in the material and methods section and in Figure 1, revealed that the anterior SEZ displays the highest number of Ki67 positive cells per mm2 (6.4060.276103) that comparatively decreases 48% and 52% at the intermediate and posterior SEZ divisions, respectively (Figure 2A)
Analysis of proliferation with BrdU revealed that at the intermediate and posterior levels of the SEZ, BrdU incorporation was 45% and 34% lower than in the anterior division (2.8660.296103 BrdU positive cells/mm2) (Figure 2A). These results showed that the SEZ cell proliferation rate is higher in the anterior division than in the intermediate and posterior divisions and that the latter two display very similar proliferation patterns

Summary

Introduction

The subependymal zone (SEZ), generally described as a thin layer of proliferative cells lining the lateral wall of the lateral brain ventricles, is a major source of multipotent neural stem cells (NSCs) in the adult brain [1,2]. Alterations in the proliferative and migratory profile of the SEZ NSC population are extensively described for several animal models of neurological disorders, such as Alzheimer’s and Parkinson’s diseases, stroke and epilepsy [7]. Such studies have raised expectations for the development of endogenous regenerative therapies based on the manipulation of the SEZ neurogenic niche. To fully explore the regenerative potential of the SEZ stem cell niche, a better knowledge of how the niche is maintained and regulated, both in physiological and pathological conditions, is needed

Methods

Results

Conclusion