Mécanismes de régulation de l’activité de la lignée neurale adulte
In the adult, neuron production is possible through neural stem cells (NSCs) that maintain neurogenesis throughout life. The proliferation of NSCs makes it possible to generate progenitors and new neuroblasts. The difficulty of intersecting functional and anatomical data poses a major problem. Several publications indicate that mitotic NSCs are ephemeral and disappear after division, which requires the presence of a reservoir of cells to succeed them. The hypothesis is that there are dormant NSCs that would be activated to replace them. Anatomically, quiescent cells, with same morphology and antigenic characteristics, are present alongside the mitotic NSCs, it has been postulated that they provide the cellular reservoir. Their transition, from quiescent state to active, and their activation mechanisms are unknow but represent a major issue to allow adult neurogenesis modulation. To understand activation mechanisms, we wanted to understand how extrinsic factors, with opposite effects, can be integrate by NSCs and progenitors. Thus, we chose to oppose a factor stimulating cell proliferation (EGF) to an anti-neurogenic (BMP). The results obtained in vitro demonstrated that BMP is dominant over all observed cellular behaviors including proliferation and differentiation. The dominance of BMP is not achieved by the inhibition of downstream signaling pathways of EGF, since Rapamycin, an inhibitor of mTOR, induces different effects on BMP. In vivo, BMP limits the proliferation induced by EGF. Using electroporation, approach which allow to specifically target astrocytic cells in the lateral wall, we showed that the inhibition of the SMAD pathway, which integrates the BMP factor, makes it possible to prime the NSCs. In this experiment, we realized that the majority of electroporated cells were quiescent, giving us an opportunity to define the biological properties of these dormant cells. This approach allowed us to show that the electroporated cells are largely quiescent and produce very few neurons. In addition, they do not allow the regeneration of the subventricular zone nor the production of neurospheres, which implies that they are difficult to activate. However, activation of the EGF pathway can prime them and allow them to enter the cell cycle. Our results suggest that electroporated cells contribute only marginally to adult neurogenesis and mitotic NSC production. With these data, we can suppose that there exists a heterogeneity of the astrocytic cells in contact with the cerebrospinal fluid of which only some iv populations contribute to neurogenesis or that the mitotic NSCs are generated from another cell population.
cellule souche neurale adulte activation EGF BMP adult neural stem cell neurogenesis subventricular zone proliferation activation electroporation