Lung regeneration after toxic injury is improved in absence of dioxin receptor

Abstract

Recent experimental evidences from cellular systems and from mammalian and non-mammalian animal models highlight novel functions for the aryl hydrocarbon/dioxin receptor (AhR) in maintaining cell differentiation and tissue homeostasis. Notably, AhR depletion stimulates an undifferentiated and pluripotent phenotype likely associated to a mesenchymal transition in epithelial cells and to increased primary tumorigenesis and metastasis in melanoma. In this work, we have used a lung model of epithelial regeneration to investigate whether AhR regulates proper tissue repair by adjusting the expansion of undifferentiated stem-like cells. AhR-null mice developed a faster and more efficient repair of the lung bronchiolar epithelium upon naphthalene injury that required increased cell proliferation and the earlier activation of stem-like Clara, Basal and neuroepithelial cells precursors. Increased basal content in multipotent Sca1/CD31/CD4 cells and in cells expressing pluripotency factors NANOG and OCT4 could also improve re-epithelialization in AhR-null lungs. The reduced response of AhR-deficient lungs to Sonic Hedgehog (Shh) repression shortly after injury may also help their improved bronchiolar epithelium repair. These results support a role for AhR in the regenerative response against toxins, and open the possibility of modulating its activation level to favor recovery from lesions caused by environmental contaminants.

The Aryl Hydrocarbon Receptor Promotes Differentiation During Mouse Preimplantational Embryo Development

“…As cleavage of the early zygote takes place, central pluripotency factors increase their expression to produce totipotent cells that will proliferate and differentiate to generate a complete organism. We have first found that zygotes from AhR -/- mice have basal overexpression of well-known pluripotency factors Oct4, Nanog and Sox2 , in agreement with our previous studies showing that AhR-null mice have an increased ability to regenerate lung (Morales-Hernandez et al, 2017) and liver (Moreno-Marin et al, 2017) and a higher potential to sustain undifferentiation of human embryionic carcinoma cells (Morales-Hernandez et al, 2016). The apparent global role of AhR in controlling differentiation was also reported by its ability to regulate ovarian follicular development through piRNA-associated proteins, piRNAs and retrotransposons (Rico-Leo et al, 2016).…”

“…AhR promotes cell differentiation through the inhibition of pluripotency genes. As a result, AhR deficiency originates an undifferentiated phenotype not only in cell lines but also in tissue regeneration in mice (Morales-Hernandez, Gonzalez-Rico et al 2016, Morales-Hernandez, Nacarino-Palma et al 2017, Moreno-Marin, Barrasa et al 2017). However, our knowledge about the role of AhR in embryo differentiation is still very limited, in particular with respect to the molecular intermediates that, been dependent on AhR, may be involved.…”

“…Previous work from our laboratory using human NTERA-2 cells revealed that AhR supports cell differentiation through the transcriptional repression of retrotransposable Alu elements located in the promoter region of pluripotency genes Oct4 and Nanog (Morales-Hernandez et al, 2016). On the contrary, receptor deficiency in mice produces a more undifferentiated phenotype improving the regenerative potential of the lung (Morales-Hernandez et al, 2017) and the liver (Moreno-Marin et al, 2017) upon acute damage.…”

A potential role for AHR in SARS-CoV-2 pathology

“…Our studies also suggest that AHR signaling associated to coronavirus infection affects lung basal cells, which give rise to stem cells involved in lung repair in multiple contexts including influenza virus infection 29 – 31 . Of note, AHR-deficient mice show enhanced repair of the lung bronchiolar epithelium following naphthalene injury 32 , concomitant with the increase proliferation and the earlier activation of basal cells. Taken together, these findings suggest that AHR signaling associated to coronavirus infection may interfere with the activity of basal cells, contributing to the lung pathogenesis associated to SARS-CoV-1, MERS-CoV and SARS-CoV-2 infection.…”

Old Receptor, New Tricks—The Ever-Expanding Universe of Aryl Hydrocarbon Receptor Functions. Report from the 4th AHR Meeting, 29–31 August 2018 in Paris, France

“…He found that the AHR, in that context, improves regeneration but inhibits cell differentiation. With elegant kinetic AHR knockdown experiments, he could demonstrate that the AHR is only needed at the start of re-differentiation, i.e., for the activation of stem cells [ 10 , 11 ]. The underlying mechanisms involve pluripotency factors such as the well-recognized octamer-binding transcription factor 4 (OCT-4) or the homeobox protein NANOG.…”