Final Report Summary - CBSCS (Physiology of the adult carotid body stem cell niche)
The main goal of the project was to elucidate the molecular and cellular mechanisms underlying the functioning of the adult carotid body germinal niche. Thanks to the results obtained in the project, we know a lot more details about how these adult neural crest-derived carotid body stem cells (CBSCs) behave within the niche. We know they are not directly activated by hypoxia, the main physiological stimulus of the niche. Rather, progenitor cells have a special disposition within the niche, forming a synapse-like structure with neuronal cells. We have proven that it is the neuronal cells that communicate the hypoxic situation to the stem cells, and activate their proliferation through the niche factor endothelin-1 (ET-1). These findings constitute the first example of a stem cell behaviour regulated by neuronal activity in the peripheral nervous system, and we believe the story will have a strong impact in the field. Moreover, we also have obtained exciting data on the physiological plasticity of CBSCs, which are also able to differentiate into endothelial cells in addition to their role in neurogenesis. These are very relevant data to the field and we currently have this work in publication process. On top of that, we have also characterized the neuronal lineage of CBSCs by showing that these cells give rise to new neurons through intermediate stages of immature neuroblasts, which are ready for proliferation and terminal differentiation in the organ. Finally, we have also studied the dependence of CBSCs on oxidative metabolism, using dysfunctional mitochondria mutant mice, and have shown that these stem cells rely mainly on anaerobic metabolism. No relevant problems have incurred along the implementation of the project. We would like to mention also the new Objective that was added to the project. In order to increase the translational interest of the project, we added a new goal more related to everyday clinics. We have applied everything we learnt from the behaviour of CBSCs to halt the progress and development of cancer stem cells within Neuroblastoma pediatric tumors. Both stem cell populations have the same embryological origin, the sympathoadrenal lineage of the neural crest, and we have characterized for example that Neuroblastoma stem cells are also sensitive to ET-1 signalling. These findings might have a direct and fast application on the treatment of this devastating type of cancer. We have characterized these cancer stem cells within Neuroblastoma tumors, and have studied the molecular mechanisms by which these cells proliferate and differentiate. Hence, new therapeutical targets have been envisioned to try to halt this devastating disease. We are currently in the process of publishing our results with Neuroblastoma cells.