An NSC-progeny relationship that shifts between linear and variab

An NSC-progeny relationship that shifts between linear and variable is inconsistent with the current model of adult hippocampal neurogenesis. Similar to the biology of resident stem cells in other organs, NSC division is currently thought to result in a transit amplifying IP cell and another NSC. The IP is then thought to divide symmetrically multiple times before differentiating into its terminal fates and has been termed a “transit-amplifying cell” (Fuchs, 2009,

Jones et al., 2007 and Zhao et al., 2008). Unlike other stem cells, resident stem cells in the epidermis were recently shown to follow lineage expansion with a linear stoichiometry by which each intermediate progenitor cell divides to produce one intermediate progenitor and one terminally differentiated cell (Clayton Screening Library et al., 2007).

Mathematical modeling suggests that expansion with linear stoichiometry is inconsistent with transit amplification (Clayton et al., 2007 and Jones et al., 2007). While linear expansion was reported for epidermal differentiation, expansion through a transit amplifier is observed in models of epidermal injury (Ghazizadeh and Taichman, 2001). These seemingly paradoxical findings have generated a controversy www.selleckchem.com/products/tariquidar.html about the homeostasis underlying stem cell differentiation (Jones et al., 2007). Our results indicate that exposure to different environments can influence the proclivity of NSCs for proliferation versus neurogenesis. This interpretation is most dramatically supported by the results of the X-irradiation experiment where disruption of the NSC niche prevented neurogenesis, but permitted NSC proliferation. Furthermore, we observed a homeostatic shift from Ergoloid linear to a variable NSC-neuronal relationship after more naturalistic environmental manipulations or with a more restricted anatomic analysis of animals exposed to standard laboratory housing. In order to place our

findings into the context of reports describing tissue homeostasis in other organs, we propose a new model for adult hippocampal neurogenesis (Figure 8). Our results are most consistent with an intermediate progenitor that can divide to produce neurons or NSCs, or undergo multiple symmetric divisions acting as a transit-amplifying cell. The mode of lineage expansion is dictated by the structural (anatomic) niche and functional changes in the niche resulting from the animals’ experiences. More neurogenesis would be expected under conditions in which symmetric amplification of an IP and terminal differentiation were favored, while less neurogenesis would be associated with accumulation of NSCs. Interestingly, one recent report found that intermediate progenitors can function as transit amplifying cells during spermatogenesis, but produce germ stem cells after stem cell depletion (Nakagawa et al., 2007).

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