Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor
Abstract The liver is among the few organs having the ability to self-regenerate in response to a severe damage compromising its functionality. The Aryl hydrocarbon receptor (Ahr) is a transcription factor relevant for the detoxification of xenobiotics but also largely important for liver developmen...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-19733-0 |
| _version_ | 1797995470663974912 |
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| author | Claudia M. Rejano-Gordillo Francisco J. González-Rico Beatriz Marín-Díaz Ana Ordiales-Talavero Ana Nacarino-Palma Ángel C. Román Jaime M. Merino Pedro M. Fernández-Salguero |
| author_facet | Claudia M. Rejano-Gordillo Francisco J. González-Rico Beatriz Marín-Díaz Ana Ordiales-Talavero Ana Nacarino-Palma Ángel C. Román Jaime M. Merino Pedro M. Fernández-Salguero |
| author_sort | Claudia M. Rejano-Gordillo |
| collection | DOAJ |
| description | Abstract The liver is among the few organs having the ability to self-regenerate in response to a severe damage compromising its functionality. The Aryl hydrocarbon receptor (Ahr) is a transcription factor relevant for the detoxification of xenobiotics but also largely important for liver development and homeostasis. Hence, liver cell differentiation is developmentally modulated by Ahr through the controlled expression of pluripotency and stemness-inducing genes. Here, 2/3 partial hepatectomy (PH) was used as a clinically relevant approach to induce liver regeneration in Ahr-expressing (Ahr +/+) and Ahr-null (Ahr −/−) mice. Ahr expression and activity were early induced after 2/3 PH to be gradually downmodulated latter during regeneration. Ahr −/− mice triggered liver regeneration much faster than AhR +/+ animals, although both reached full regeneration at the latest times. At initial stages after PHx, earlier regenerating Ahr −/− livers had upregulation of cell proliferation markers and increased activation of signalling pathways related to stemness such as Hippo-YAP and Wnt/β-catenin, concomitantly with the induction of pro-inflammatory cytokines TNFa, IL6 and p65. These phenotypes, together with the improved metabolic adaptation of Ahr −/− mice after PHx and their induced sustained cell proliferation, could likely result from the expansion of undifferentiated stem cells residing in the liver expressing OCT4, SOX2, KLF4 and NANOG. We propose that Ahr needs to be induced early during regeneration to fine-tune liver regrowth to physiological values. Since Ahr deficiency did not result in liver overgrowth, its transient pharmacological inhibition could serve to improve liver regeneration in hepatectomized and transplanted patients and in those exposed to damaging liver toxins and carcinogens. |
| first_indexed | 2024-04-11T10:01:56Z |
| format | Article |
| id | doaj.art-9c1c382cfec64853a9458bdb939a35a0 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T10:01:56Z |
| publishDate | 2022-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9c1c382cfec64853a9458bdb939a35a02022-12-22T04:30:24ZengNature PortfolioScientific Reports2045-23222022-09-0112111610.1038/s41598-022-19733-0Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptorClaudia M. Rejano-Gordillo0Francisco J. González-Rico1Beatriz Marín-Díaz2Ana Ordiales-Talavero3Ana Nacarino-Palma4Ángel C. Román5Jaime M. Merino6Pedro M. Fernández-Salguero7Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de ExtremaduraDepartamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de ExtremaduraDepartamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de ExtremaduraDepartamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de ExtremaduraDepartamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de ExtremaduraDepartamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de ExtremaduraDepartamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de ExtremaduraDepartamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de ExtremaduraAbstract The liver is among the few organs having the ability to self-regenerate in response to a severe damage compromising its functionality. The Aryl hydrocarbon receptor (Ahr) is a transcription factor relevant for the detoxification of xenobiotics but also largely important for liver development and homeostasis. Hence, liver cell differentiation is developmentally modulated by Ahr through the controlled expression of pluripotency and stemness-inducing genes. Here, 2/3 partial hepatectomy (PH) was used as a clinically relevant approach to induce liver regeneration in Ahr-expressing (Ahr +/+) and Ahr-null (Ahr −/−) mice. Ahr expression and activity were early induced after 2/3 PH to be gradually downmodulated latter during regeneration. Ahr −/− mice triggered liver regeneration much faster than AhR +/+ animals, although both reached full regeneration at the latest times. At initial stages after PHx, earlier regenerating Ahr −/− livers had upregulation of cell proliferation markers and increased activation of signalling pathways related to stemness such as Hippo-YAP and Wnt/β-catenin, concomitantly with the induction of pro-inflammatory cytokines TNFa, IL6 and p65. These phenotypes, together with the improved metabolic adaptation of Ahr −/− mice after PHx and their induced sustained cell proliferation, could likely result from the expansion of undifferentiated stem cells residing in the liver expressing OCT4, SOX2, KLF4 and NANOG. We propose that Ahr needs to be induced early during regeneration to fine-tune liver regrowth to physiological values. Since Ahr deficiency did not result in liver overgrowth, its transient pharmacological inhibition could serve to improve liver regeneration in hepatectomized and transplanted patients and in those exposed to damaging liver toxins and carcinogens.https://doi.org/10.1038/s41598-022-19733-0 |
| spellingShingle | Claudia M. Rejano-Gordillo Francisco J. González-Rico Beatriz Marín-Díaz Ana Ordiales-Talavero Ana Nacarino-Palma Ángel C. Román Jaime M. Merino Pedro M. Fernández-Salguero Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor Scientific Reports |
| title | Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor |
| title_full | Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor |
| title_fullStr | Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor |
| title_full_unstemmed | Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor |
| title_short | Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor |
| title_sort | liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor |
| url | https://doi.org/10.1038/s41598-022-19733-0 |
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