AHR adjusts senescence and stemness: impact in tissue regeneration and tumor progression
Pedro M. Fernández Salguero
Universidad de Extremadura, Badajoz.
Cell reprogramming is greatly extending our understanding on how stemness operates in different cell types and tissues. Stemness is closely linked to the apparently antagonistic process of senescence and both, eventually, seem to coexist during tissue regeneration. Recent studies have shown that Ahr adjusts proliferation of embryonic and adult stem cells, and that receptor depletion favors the expansion of undifferentiated cells in injured liver and lung, likely by improving their regenerative competence. Moreover, Ahr deficiency greatly increased tumor growth upon in vivo reprogramming by a process involving stem cells buildup and enhanced senescence. Here, we will discuss our current studies revealing a regulatory role of Ahr in preserving physiological stemness during early embryo differentiation and in the regenerating liver following partial hepatectomy. Embryos lacking Ahr (Ahr-/-) had increased numbers of NANOG+ and OCT4/POU5F1+ cells and a sustained undifferentiated status that supports a pro-differentiation activity of Ahr needed to determine cell fate and embryonic development. In the adult liver, Ahr deficiency triggered a faster regenerative response upon hepatectomy that, at earlier stages, involved enhanced proliferation, upregulation of the stemness-related pathways Hippo-YAP and Wnt/b-Catenin and induction of pro-inflammatory cytokines TNFa and IL6. That phenotype was concomitant with the expansion of OCT4+, SOX2+ and NANOG+ cells. Moreover, aged Ahr-/- mice also had larger numbers of progenitor cells and an exacerbated senescence characterized by the expression of senescence-associated markers and the SASP phenotype. These altered conditions may contribute to the higher tumor burden found in aged Ahr-/- livers. Moreover, Ahr deficiency increased the pro-tumoral activity of the K-RasG12D oncogene in the lung by allowing expansion of cancer stem-like cells. We propose a systemic role of Ahr in regulating cell differentiation that could be relevant to modulate tissue regeneration and to control tumor progression.