Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengths
Abstract Telomeres are terminal protective chromosome structures. Genetic variants in genes coding for proteins required for telomere maintenance cause rare, life-threatening Telomere Biology Disorders (TBDs) such as dyskeratosis congenita, aplastic anemia or pulmonary fibrosis. The more frequently...
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Nature Portfolio
2025-02-01
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| author | Rosa Guerrero-López Cristina Manguán-García Carlos Carrascoso-Rubio M. Luz Lozano Marta Toldos-Torres Laura García-Castro Rebeca Sánchez-Dominguez Omaira Alberquilla Isabel Sánchez-Pérez Maria Molina-Molina Juan A. Bueren Guillermo Guenechea Rosario Perona Leandro Sastre |
| author_facet | Rosa Guerrero-López Cristina Manguán-García Carlos Carrascoso-Rubio M. Luz Lozano Marta Toldos-Torres Laura García-Castro Rebeca Sánchez-Dominguez Omaira Alberquilla Isabel Sánchez-Pérez Maria Molina-Molina Juan A. Bueren Guillermo Guenechea Rosario Perona Leandro Sastre |
| author_sort | Rosa Guerrero-López |
| collection | DOAJ |
| description | Abstract Telomeres are terminal protective chromosome structures. Genetic variants in genes coding for proteins required for telomere maintenance cause rare, life-threatening Telomere Biology Disorders (TBDs) such as dyskeratosis congenita, aplastic anemia or pulmonary fibrosis. The more frequently used mice strains have telomeres much longer than the human ones which question their use as in vivo models for TBDs. One mice model with shorter telomeres based on the CAST/EiJ mouse strain carrying a mutation in the Terc gene, coding for the telomerase RNA component, has been studied in comparison with C57BL/6J mice, carrying the same mutation and long telomeres. The possible alterations produced in lungs and the haematopoietic system, frequently affected in TBD patients, were determined at different ages of the mice. Homozygous mutant mice presented a very shortened life span, more notorious in the short-telomeres CAST/EiJ strain. The lungs of mutant mice presented a transitory increase in fibrosis and a significant decrease in the relative amount of the alveolar epithelial type 2 cells from six months of age. This decrease was larger in mutant homozygous animals but was also observed in heterozygous animals. On the contrary the expression of the senescence-related protein P21 increased from six months of age in mutant mice of both strains. The analysis of the haematopoietic system indicated a decrease in the number of megakaryocyte-erythroid progenitors in homozygous mutants and an increase in the clonogenic potential of bone marrow and LSK cells. Bone marrow cells from homozygous mutant animals presented decreasing in vitro expansion capacity. The alterations observed are compatible with precocious ageing of lung alveolar cells and the bone marrow cells that correlate with the alterations observed in TBD patients. The alterations seem to be more related to the genotype of the animals that to the basal telomere length of the strains although they are more pronounced in the short-telomere CAST/EiJ-derived strain than in C57BL/6J animals. Therefore, both animal models, at ages over 6–8 months, could represent valuable and convenient models for the study of TBDs and for the assay of new therapeutic products. |
| format | Article |
| id | doaj-art-2fab38698a5147d9ba9482cb14ee42c8 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-2fab38698a5147d9ba9482cb14ee42c82025-08-20T03:10:50ZengNature PortfolioScientific Reports2045-23222025-02-0115111810.1038/s41598-025-90246-2Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengthsRosa Guerrero-López0Cristina Manguán-García1Carlos Carrascoso-Rubio2M. Luz Lozano3Marta Toldos-Torres4Laura García-Castro5Rebeca Sánchez-Dominguez6Omaira Alberquilla7Isabel Sánchez-Pérez8Maria Molina-Molina9Juan A. Bueren10Guillermo Guenechea11Rosario Perona12Leandro Sastre13Instituto de Investigaciones Biomedicas Sols/Morreale, CSIC-UAM. Arturo DuperierInstituto de Investigaciones Biomedicas Sols/Morreale, CSIC-UAM. Arturo DuperierHematopoietic Innovative Therapies Division, Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT)) and Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM)Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT)) and Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM)Instituto de Investigaciones Biomedicas Sols/Morreale, CSIC-UAM. Arturo DuperierInstituto de Investigaciones Biomedicas Sols/Morreale, CSIC-UAM. Arturo DuperierCentro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)Instituto de Investigaciones Biomedicas Sols/Morreale, CSIC-UAM. Arturo DuperierILD Unit, Pneumatology Department, University Hospital of Bellvitge, IDIBELL. University of BarcelonaCentro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)Instituto de Investigaciones Biomedicas Sols/Morreale, CSIC-UAM. Arturo DuperierAbstract Telomeres are terminal protective chromosome structures. Genetic variants in genes coding for proteins required for telomere maintenance cause rare, life-threatening Telomere Biology Disorders (TBDs) such as dyskeratosis congenita, aplastic anemia or pulmonary fibrosis. The more frequently used mice strains have telomeres much longer than the human ones which question their use as in vivo models for TBDs. One mice model with shorter telomeres based on the CAST/EiJ mouse strain carrying a mutation in the Terc gene, coding for the telomerase RNA component, has been studied in comparison with C57BL/6J mice, carrying the same mutation and long telomeres. The possible alterations produced in lungs and the haematopoietic system, frequently affected in TBD patients, were determined at different ages of the mice. Homozygous mutant mice presented a very shortened life span, more notorious in the short-telomeres CAST/EiJ strain. The lungs of mutant mice presented a transitory increase in fibrosis and a significant decrease in the relative amount of the alveolar epithelial type 2 cells from six months of age. This decrease was larger in mutant homozygous animals but was also observed in heterozygous animals. On the contrary the expression of the senescence-related protein P21 increased from six months of age in mutant mice of both strains. The analysis of the haematopoietic system indicated a decrease in the number of megakaryocyte-erythroid progenitors in homozygous mutants and an increase in the clonogenic potential of bone marrow and LSK cells. Bone marrow cells from homozygous mutant animals presented decreasing in vitro expansion capacity. The alterations observed are compatible with precocious ageing of lung alveolar cells and the bone marrow cells that correlate with the alterations observed in TBD patients. The alterations seem to be more related to the genotype of the animals that to the basal telomere length of the strains although they are more pronounced in the short-telomere CAST/EiJ-derived strain than in C57BL/6J animals. Therefore, both animal models, at ages over 6–8 months, could represent valuable and convenient models for the study of TBDs and for the assay of new therapeutic products.https://doi.org/10.1038/s41598-025-90246-2TercTelomere biology disordersTelomeresPulmonary fibrosisAplastic anemiaCAST/EiJ |
| spellingShingle | Rosa Guerrero-López Cristina Manguán-García Carlos Carrascoso-Rubio M. Luz Lozano Marta Toldos-Torres Laura García-Castro Rebeca Sánchez-Dominguez Omaira Alberquilla Isabel Sánchez-Pérez Maria Molina-Molina Juan A. Bueren Guillermo Guenechea Rosario Perona Leandro Sastre Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengths Scientific Reports Terc Telomere biology disorders Telomeres Pulmonary fibrosis Aplastic anemia CAST/EiJ |
| title | Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengths |
| title_full | Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengths |
| title_fullStr | Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengths |
| title_full_unstemmed | Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengths |
| title_short | Premature ageing of lung alveoli and bone marrow cells from Terc deficient mice with different telomere lengths |
| title_sort | premature ageing of lung alveoli and bone marrow cells from terc deficient mice with different telomere lengths |
| topic | Terc Telomere biology disorders Telomeres Pulmonary fibrosis Aplastic anemia CAST/EiJ |
| url | https://doi.org/10.1038/s41598-025-90246-2 |
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