Hikaru Kobayashi García

Scopus Publications

Mitochondrial DNA insertions into nuclear DNA affecting chromosome segregation: Insights for a novel mechanism of immunosenescence in mice
Mónica González-Sánchez, Víctor García-Martínez, Sara Bravo, Hikaru Kobayashi, Irene Martínez de Toda, Blanca González-Bermúdez, Gustavo R. Plaza, and Mónica De la Fuente
Elsevier BV

Aging is accompanied by T-cell stiffening and reduced interstitial migration through dysfunctional nuclear organization
Blanca González‐Bermúdez, Hikaru Kobayashi, Aldo Abarca‐Ortega, Miguel Córcoles‐Lucas, Mónica González‐Sánchez, Mónica De la Fuente, Gustavo V. Guinea, Manuel Elices, and Gustavo R. Plaza
Wiley
Age-associated changes in T-cell function play a central role in immunosenescence. The role of aging in the decreased T-cell repertoire, primarily because of thymic involution, has been extensively studied. However, increasing evidence indicates that aging also modulates the mechanical properties of cells and the internal ordering of diverse cell components. Cellular functions are generally dictated by the biophysical phenotype of cells, which itself is also tightly regulated at the molecular level. Based on previous evidence suggesting that the relative nuclear size contributes to variations of T-cell stiffness, here we examined whether age-associated changes in T-cell migration are dictated by biophysical parameters, in part through nuclear cytoskeleton organization and cell deformability. In this study, we first performed longitudinal analyses of a repertoire of 111 functional, biophysical and biomolecular features of the nucleus and cytoskeleton of mice CD4+ and CD8+ T cells, in both naive and memory state. Focusing on the pairwise correlations, we found that age-related changes in nuclear architecture and internal ordering were correlated with T-cell stiffening and declined interstitial migration. A similarity analysis confirmed that cell-to-cell variation was a direct result of the aging process and we applied regression models to identify biomarkers that can accurately estimate individuals' age. Finally, we propose a biophysical model for a comprehensive understanding of the results: aging involves an evolution of the relative nuclear size, in part through DNA-hypomethylation and nuclear lamin B1, which implies an increased cell stiffness, thus inducing a decline in cell migration.

Sex-related differences in behavioural markers in adult mice for the prediction of lifespan
Hikaru Kobayashi, Irene Martínez de Toda, Luis Sanz-San Miguel, and Mónica De la Fuente
Springer Science and Business Media LLC

Single-cell biophysical study reveals deformability and internal ordering relationship in T cells
Blanca González-Bermúdez, Hikaru Kobayashi, Álvaro Navarrete, César Nyblad, Mónica González-Sánchez, Mónica de la Fuente, Gonzalo Fuentes, Gustavo V. Guinea, Claudio García, and Gustavo R. Plaza
Royal Society of Chemistry (RSC)
This single-cell technology allows understanding the relationships between internal ordering and mechanical properties of cells.

Lymphoproliferation impairment and oxidative stress in blood cells from early parkinson’s disease patients
Carmen Vida, Hikaru Kobayashi, Antonio Garrido, Irene Martínez de Toda, Eva Carro, José Molina, and Mónica De la Fuente
MDPI AG
In Parkinson’s Disease (PD), the peripheral changes in the functional capacity and redox state of immune cells has been scarcely investigated, especially in the early PD stages. Aging is a risk factor for PD, and the age-related impairment of the immune system, based on a chronic-oxidative stress situation, is involved in the rate of aging. We analyzed several functions in isolated peripheral blood neutrophils and mononuclear cells from PD stage 2 patients, and compared the results to those in healthy elderly and adult controls. Several oxidative stress and damage parameters were studied in whole blood cells. The results showed an impairment of the lymphoproliferative response in stimulated conditions in the PD patients compared with age-matched controls, who also showed typical immunosenescence in comparison with adult individuals. Higher oxidative stress and damage were observed in whole blood cells from PD patients (lower glutathione peroxidase activity, and higher oxidized glutathione and malondialdehyde contents). Our results suggest an accelerated immunosenescence in PD stage 2, and that several of the parameters studied could be appropriate peripheral biomarkers in the early stages of PD.

DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts
Daniel Gómez-Cabello, Isabel Adrados, David Gamarra, Hikaru Kobayashi, Yoshihiro Takatsu, Kyoko Takatsu, Jesús Gil, and Ignacio Palmero
Wiley
The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell‐cycle inhibitor p21CIP1. We further show that a subset of senescence‐associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8‐mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell‐cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger.