Plasticidad fisiológica de las células madre del cuerpo carotídeo adultocaracterización del linaje mesectodérmico

Abstract

We have described a novel neurogenic niche in the adult carotid body (CB), an oxygen-sensing organ derived from the neural crest that is able to adapt to chronic hypoxemia by increasing the number of chemosensory neuronal cells and vascular cells. These neurogenesis and angiogenesis depend on the activity of a resident population of neural progenitors, which are also able to form neurospheres (NS) in vitro. Gene expression analysis comparing NS cultures enriched in undifferentiated versus differentiated cells displayed CD10 as a candidate marker for CB progenitor cells. CD10 is a metalloendopeptidase that inactivates signalling peptides, modifying the extracellular environment. In parallel, CD10 protein has an intracellular domain that mediates proliferation, endothelial differentiation and migration processes, by direct protein-protein associations. In the CB, CD10 expression partially co-localizes with Nestin and/or GFAP, and a cell-fate mapping analysis has confirmed that CD10+ cells lie within the CB progenitor lineage. Sorting for CD10+ cells increases NS-forming efficiency. Interestingly, CD10+ progenitors can differentiate into smooth muscle (SMA+) or endothelial (GSA I+) cells, but are not able to convert into neuronal (TH+) cells, indicating a mesectodermal commitment in these cells. Since a profound angiogenesis occurs in the CB in response to hypoxia and it is described that CD10 is a key regulator of angiogenesis, we have tested whether CD10 is having a role in regulating this process. Our functional study revealed that CD10 protein controls endothelial differentiation of the CD10+ progenitor subpopulation, likely through the catalytic activity of CD10. One of the typical molecules cleaved by CD10 is the pro-angiogenic peptide endothelin-1 (ET-1). ET-1 significantly increases CD10 expression and the amount of CD10+ cells in vitro, and gene expression analysis shows that ET-1 induces an increase in mesectodermal differentiation of CBSCs. Taking together, our results suggest that GFAP+ stem cells give rise to mesectoderm-committed CD10+ progenitors, and that CD10 could have a functional role cleaving peptides such as ET-1, regulating the angiogenesis that accompany the neurogenesis suffered in hypoxemia. A deeper knowledge of the molecular mechanisms governing CB progenitor cell fate decisions will improve our understanding of the physiology of this important chemoreceptor organ.