PICH: Safety profiling of CAR T cells in healthy human tissues
Project leaders: Diane Damotte (Department of Pathology, Cochin hospital) and Alice Machado (Emmanuel Donnadieu team)
CAR-T cells can induce undesirable effects associated to the destruction of healthy cells expressing the targeted antigen (On-Target Off-Tumor). Our ambition is to design new models with strong predictive value for clinical safety, aiming to enhance the selection of genetically modified T cell products. This approach will establish a predictive range of CAR-T cell toxicity on healthy tissues.
Unravelling the impact of diet-induced obesity on sperm metabolism and epigenetic program
Project leaders: Carina Prip-Buus (Frédéric Bouillaud team) and Alberto De La Iglesia (Julie Cocquet group)
In a context of increasing infertility worldwide according to the latest WHO report in 2023, growing evidence supports the effect of lifestyle on male fertility status. This is in line with the fact that environmental cues can induce epigenetic alterations in male gametes, influencing not only male fertility potential but also embryo development and offspring health. Obesity is a striking example, as it is linked to higher risk of infertility and of transmitting late-onset diseases to the progeny (particularly metabolic).
In the present project, Alberto DE LA IGLESIA and Carina PRIP-BUUS will combine their complementary expertise to explore the link between epigenomic changes and metabolic alterations in spermatozoa from diet-induced obese mice (obtained thanks to the Catherine POSTIC team). The data will be integrated with embryonic epigenomic and transcriptomic data to identify which sperm epigenomic alterations induced by obesity could be more deleterious to the offspring development and health.
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Evaluation of the impact of plastic culture dishes used in in vitro fertilization procedures on gene expression during early embryonic devopment in mice: a single-cell sequencing approach
Project leaders: Antoine Zalc and Daniel Vaiman teams
The prevalence of children born after Assisted Reproductive Technology (ART) keeps increasing worldwide, with more than 10 million births per year over the last decade. However, higher rates of preterm births, low birth weight, and placental pathologies are observed in the short-term outcomes of ART, without any identified etiology. Currently, in in vitro fertilization (IVF) labs, embryo culture is conducted in plastic dishes heated to 37°C, with embryos exposed to the same culture medium for 5 days, under mineral oil. Accumulation of plastic derivatives in the culture media is suspected, during a critical period of embryonic genome activation. Recently, Dr. Vaiman's team demonstrated on a murine model that culture in plastic dishes leads to a significant alteration of placental genes (microarray approach) [1]. The objective of this project is to confirm and refine these results using a single-cell sequencing approach, allowing characterization of the potential impact of plastic on each cell type at an early stage of embryonic development and, consequently, on a small number of cells.
This study will be conducted in collaboration with Dr. Zalc's team, which has expertise in Smart-Seq3 sequencing on a small number of embryonic cells [2]. In this study, mouse embryos obtained through IVF will be cultured either in plastic or glass dishes for 5 days. Subsequently, they will be manually dissociated, and the cells from each embryo will be analyzed using Smart-Seq3 within the GENOM'IC platform. Bioinformatic analysis of gene expression in each embryonic cell under each condition will be performed. This study will provide a robust foundation for potential application to human embryos
1. Kouakou F, Denizot A-L, L’Hostis A, Colet J, Jacques S, Sallem A, et al. Plastic used in in vitro fertilization procedures induces massive placental gene expression alterations. EBioMedicine. 2023;91:104572.
2. Zalc A, Sinha R, Gulati GS, Wesche DJ, Daszczuk P, Swigut T, et al. Reactivation of the pluripotency program precedes formation of the cranial neural crest. Science. 2021;371:eabb4776.
Role of Serotonin in Placental Immunology: creation of an atlas of immune cells at the feto-maternal interface in Tph1 KO mice, towards a model of intervillitis? (SIMPL)
Project leaders: Guillemette Fouquet (Carole Peyssonnaux team) and Patrick Lores (Céline Méhats group)
Chronic histiocytic intervillitis is a rare placental pathology with a high risk of complicated pregnancies: miscarriage, intrauterine growth retardation, prematurity. This pathology is still poorly understood and we have no predictive biomarkers or any treatment options. This pathology is characterized by an infiltrate of maternal immune cells in the placenta. We suspect that an immune dysregulation of maternal origin would be the cause of alterations in the placental structure. However, no study model has yet been established to study such a pathology.
Our team has been interested in peripheral serotonin for several years thanks to a mouse model lacking tryptophan hydroxylase 1 (Tph1), which is the enzyme that synthesizes peripheral serotonin: Tph1 KO mice. In 2007, it was demonstrated that embryos from Tph1 KO mice exhibited developmental delay. Analysis of their placentas revealed histological abnormalities similar to those observed in chronic histiocytic intervillitis.
The objective of this study is to determine the immune characteristics of placentas from Tph1 KO mice and to identify possible causes of histiocytic intervillitis.
