Deciphering application potentials and basic principles of neural stem cells - implications for BDNF and CB1
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Abstract
Stem cells have the remarkable potential to differentiate into multiple cell types during early embryogenesis and adulthood. Given their unique regenerative abilities, stem cells offer new potentials for treating neurodegenerative diseases, such as Huntington’s disease (HD). In addition, much work is also needed to detail mechanisms underlying the regulation of neural stem cells (NSCs) in the adult brain and to investigate neuropsychiatric diseases in the context of NSC regulation.
HD is characterized by fatal motoric failures induced by loss of striatal medium spiny neurons. Neuronal cell death has been linked to impaired expression and axonal transport of the neurotrophin BDNF (brain-derived neurotrophic factor). By transplanting embryonic stem cell-derived neural progenitors overexpressing BDNF, we combined cell replacement and BDNF supply as a potential HD therapy approach. Transplantation of purified neural progenitors was analyzed in a quinolinic acid (QA) induced and two genetic HD mouse models (R6/2 and N171-82Q) on the basis of distinct behavioral parameters, including CatWalk gait analysis. Explicit rescue of motor function by BDNF-overexpressing neural progenitors was found in QA-lesioned mice, whereas genetic mouse models displayed only minor improvements. Tumor formation was absent, and regeneration was attributed to enhanced striatal neuron differentiation. Additionally, adult neurogenesis was preserved in a BDNF-dependent manner. Our findings provide significant insight for establishing therapeutic strategies for HD to ameliorate neurodegenerative symptoms.
Adult born neurons in the subgranular zone (SGZ) of the dentate gyrus (DG) are continuously generated and incorporated in the hippocampal neuronal circuitry, yet the molecular mechanism of this process remains still unclear. Adult NSCs contain a functional endocannabinoid system. Endocannabinoids are endogenous lipids, which can bind to and activate the cannabinoid type 1 (CB1) receptor, thereby eliciting multiple cellular responses such as inhibition of neurotransmitter release and activation of different intracellular signaling cascades. To address the direct role of CB1 receptor expressing adult NSCs in vivo, we generated the triple-transgenic nestin-CreERT2/R26-STOP-YFP/CB1flox/flox mouse line. Tamoxifen injections induced deletion of the CB1 receptor and expression of yellow fluorescent protein (YFP) specifically in adult nestin-expressing stem cells and their progeny. We found that neural stem cell-specific deletion of the CB1 receptor led to a decrease in neural stem cell proliferation in the dentate gyrus as reflected by a decreased number of YFP+ and BrdU+ cells. In contrast, the differentiation potential of targeted NSCs was not shifted towards a specific neural lineage. By recording field excitatory postsynaptic potentials in the DG and cornu ammonis 1 (CA1) region, we found that mice with CB1 deficiency specifically in adult-born neurons displayed an impaired long-term potentiation. Furthermore, lack of functional CB1 receptor in NSCs led to a decrease in short-term spatial memory. Additionally, CB1-deficient animals showed an increase in depressive-like behavior. The present study shows that the proliferation of newborn neurons critically depends on CB1 receptor function, reflecting their importance in synaptic transmission processes and their involvement on the behavioral level.