Dupéré-Richer, D. (Daphné)
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- The transcriptional regulator Sin3A balances IL-17A and Foxp3 expression in primary CD4 T cells(2023) Lozano-Moreda, T. (Teresa); Icardi, L. (Laura); Mondino, A. (Anna); Agresti, A. (Alessandra); Dupéré-Richer, D. (Daphné); Simone, E. (Elisabetta) di; Basso, V. (Veronica); Perucho, L. (Laura); Prosper-Cardoso, F. (Felipe); Lasarte, J.J. (Juan José)The Sin3 transcriptional regulator homolog A (Sin3A) is the core member of a multiprotein chromatin-modifying complex. Its inactivation at the CD4/CD8 double-negative stage halts further thymocyte development. Among various functions, Sin3A regulates STAT3 transcriptional activity, central to the differentiation of Th17 cells active in inflammatory disorders and opportunistic infections. To further investigate the consequences of conditional Sin3A inactivation in more mature precursors and post-thymic T cell, we have generated CD4-Cre and CD4-CreERT2 Sin3AF/F mice. Sin3A inactivation in vivo hinders both thymocyte development and peripheral T-cell survival. In vitro, in Th17 skewing conditions, Sin3A-deficient cells proliferate and acquire memory markers and yet fail to properly upregulate Il17a, Il23r, and Il22. Instead, IL-2+ and FOXP3+ are mostly enriched for, and their inhibition partially rescues IL-17A+ T cells. Notably, Sin3A deletion also causes an enrichment of genes implicated in the mTORC1 signaling pathway, overt STAT3 activation, and aberrant cytoplasmic ROR¿t accumulation. Thus, together our data unveil a previously unappreciated role for Sin3A in shaping critical signaling events central to the acquisition of immunoregulatory T-cell phenotypes.
- Functional and transcriptomic analysis of extracellular vesicles identifies calprotectin as a new prognostic marker in peripheral arterial disease (PAD)(2020) Gomez-Cabrero, D. (David); Paramo, J.A. (José Antonio); Saenz-Pipaón, G. (Goren); Ravassa, S. (Susana); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Lara-Astiaso, D. (David); Planell, N. (Núria); Dupéré-Richer, D. (Daphné); Maillo, A. (Alberto); Alameda, D. (Daniel); Martínez-Aguilar, E. (Esther); Roncal, C. (Carmen); Prosper-Cardoso, F. (Felipe); San Martín, P. (Patxi)Peripheral arterial disease (PAD) is associated with a high risk of cardiovascular events and death and is postulated to be a critical socioeconomic cost in the future. Extracellular vesicles (EVs) have emerged as potential candidates for new biomarker discovery related to their protein and nucleic acid cargo. In search of new prognostic and therapeutic targets in PAD, we determined the prothrombotic activity, the cellular origin and the transcriptomic profile of circulating EVs. This prospective study included control and PAD patients. Coagulation time (Procoag-PPL kit), EVs cellular origin and phosphatidylserine exposure were determined by flow cytometry in plateletfree plasma (n = 45 PAD). Transcriptomic profiles of medium/large EVs were generated using the MARS-Seq RNA-Seq protocol (n = 12/group). The serum concentration of the differentially expressed gene S100A9, in serum calprotectin (S100A8/A9), was validated by ELISA in control (n = 100) and PAD patients (n = 317). S100A9 was also determined in EVs and tissues of human atherosclerotic plaques (n = 3). Circulating EVs of PAD patients were mainly of platelet origin, predominantly Annexin V positive and were associated with the procoagulant activity of plateletfree plasma. Transcriptomic analysis of EVs identified 15 differentially expressed genes. Among them, serum calprotectin was elevated in PAD patients (p < 0.05) and associated with increased amputation risk before and after covariate adjustment (mean follow-up 3.6 years, p < 0.01). The combination of calprotectin with hs-CRP in the multivariate analysis further improved risk stratification (p < 0.01). Furthermore, S100A9 was also expressed in femoral plaque derived EVs and tissues. In summary, we found that PAD patients release EVs, mainly of platelet origin, highly positive for AnnexinV and rich in transcripts related to platelet biology and immune responses. Amputation risk prediction improved with calprotectin and was significantly higher when combined with hs-CRP. Our results suggest that EVs can be a promising component of liquid biopsy to identify the molecular signature of PAD patients.
- Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution(2023) Gomez-Cabrero, D. (David); Lasaga, M. (Miren); Diez-Campelo, M. (M.); Molero, A. (Antonieta); San-Martín-Uriz, P. (Patxi); Romero-Riojas, J.P. (Juan Pablo); Alfonso-Piérola, A. (Ana); San-Julian, M. (Mikel); Jimenez-Solas, T. (Tamara); Ezponda, T. (Teresa); Valcarcel, D. (David); Lopez, F. (Félix); Dupéré-Richer, D. (Daphné); NO USAR Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Alignani, D. (Diego); Montoro, J. (Julia); Mution, S. (Sandra); Hernaez, M. (Mikel); Serrano-Sanz, G. (Guillermo); Ainciburu-Fernández, M. (Marina); Prosper-Cardoso, F. (Felipe); Berastegui-Zufiaurre, N. (Nerea); Diaz-Mazquiaran, A. (Aintzane); Sanchez-Guijo, F.M. (Fermín M.)Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize an enriched population of human HSPCs obtained from young and elderly healthy individuals. Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain aging-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks (GRNs) and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRNs regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2, and RUNX1 suggesting a role of these transcription factors (TFs) in the pathogenesis of the disease. In summary, we demonstrate that the combination of single-cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients
- Revealing Cell Populations Catching The Early Stages Of Human Embryo Development In Naive Pluripotent Stem Cell Cultures(2023) Ullate-Agote, A. (Asier); Rodriguez-Madoz, J.R. (Juan Roberto); Garate-Iturriagagoitia, L. (Leire); Aranguren-López, X. (Xabier); Barreda, C. (Carolina); Coppiello, G. (Giulia); Romero-Riojas, J.P. (Juan Pablo); Carvajal-Vergara, X. (Xonia); Aguirre-Ena, X. (Xabier); Dupéré-Richer, D. (Daphné); Moya-Jódar, M. (Marta); Barlabé-Ginesta, P. (Paula); Abizanda-Sarasa, G. (Gloria); Prosper-Cardoso, F. (Felipe)Naive human pluripotent stem cells (hPSCs) are defined as the in vitro counterpart of the human preimplantation embryo's epiblast and are used as a model system to study developmental processes. In this study, we report the discovery and characterization of distinct cell populations coexisting with epiblast-like cells in 5iLAF naive human induced PSC (hiPSC) cultures. It is noteworthy that these populations closely resemble different cell types of the human embryo at early developmental stages. While epiblast-like cells represent the main cell population, interestingly we detect a cell population with gene and transposable element expression profile closely resembling the totipotent eight-cell (8C)-stage human embryo, and three cell populations analogous to trophectoderm cells at different stages of their maturation process: transition, early, and mature stages. Moreover, we reveal the presence of cells resembling primitive endoderm. Thus, 5iLAF naive hiPSC cultures provide an excellent opportunity to model the earliest events of human embryogenesis, from the 8C stage to the peri-implantation period.