Dc. Fernández Salguero Group

AhR has an important role in reprogramming, senescence, regeneration and carcinogenesis. The process of cell reprogramming is closely linked to an apparently antagonistic cellular event such as senescence, with both processes seeming to coexist under physiological and pathological conditions. In fact, recent studies have revealed that the reprogramming-senescence axis has an impact on major organ responses such as tissue repair and regeneration upon injury. Our group have already generated mouse lines expressing the OKSM reprogramming transgene in AhR wild type or AhR-null backgrounds in order to study such senescence-reprogramming interactions. Moreover, we are also studying AhR function in tissue repair, since partial hepatectomy-induced regeneration mainly involves a proliferative response in quiescent hepatocytes, while injury-induced regeneration involves both hepatocytes proliferation and the activation of liver stem cells. Our group have previously demonstrated how liver and lung regeneration upon acute tissue injury are more efficient in absence of AhR, with such responses involving the expansion of undifferentiated stem cell subpopulations. Therefore, our main research line is taking a multi-level approach by the integrated investigation of how the reprogramming-senescence balance impacts hepatic regeneration and hepatocarcinogenesis. This will allow the validation of prognostic markers and therapeutic targets for this disease, which are currently very limited.

Transcription factor aryl hydrocarbon receptor (AhR) has emerged as one of the main regulators involved both in physiological functions and tumor progression. In addition to its initially discovered functions in detoxification, this receptor exerts physiological and homeostatic functions in different tissues and organs including liver, skin, heart and immune system. A remarkable property of AhR is that its functions may be influenced by the phenotype of the target cell. Thus, it can promote or inhibit cell proliferation and tumor progression by acting as an oncogene or as a tumor suppressor. Therefore, a deregulation of AhR may have a causal role in contributing to tumor progression and spread. This receptor is particularly important in liver physiopathology, where transcriptomic studies have revealed that the absence of AhR alters gene expression patterns both in normal hepatocytes and hepatoma cells.

Currently we are characterizing, both at molecular and functional levels, in vitro and in vivo cell reprogramming upon the level of AhR expression. Moreover, we are investigating the crosstalk between reprogramming and cellular senescence in aged AhR +/+ and AhR -/- mice as well as in mouse and human liver tumors having different levels of AhR.  Overall, we aim to demonstrate that AhR is relevant in controlling the reprogramming-senescence balance that likely underlines liver regeneration. We are also analyzing reprogramming and senescence markers mentioned above in biopsies obtained from the first and second surgical procedures to determine if any of them can be used in the prognosis of liver regeneration in patients with such hepatocarcinomas. By combining all these different approaches, we want to determine the impact of the reprogramming-senescence axis in mouse liver regeneration and repair after acute injury or partial hepatectomy, and its correlation with the analysis of reprogramming and senescence markers in regenerated livers from human hepatocarcinoma patients.