Laurent DAVID

 “Understanding embryo development to improve fertility”  

Team leaders: Jerome Jullien (DR2 Inserm) and Laurent David (MCU-PH)

Research program

Our team uses a combination of models to understand early embryonic development, with the goal of improving IVF.

• Epigenetic programming of sperm for the regulation of early embryonic development. At fertilization the sperm delivers to the embryo paternal genomic information, as well as epigenetic information such as those encoded in DNA methylation, post translational modifications of histones, and small RNAs. We are interested in evaluating the contribution of these epigenetic cues in the normal development of embryos, in particular in the regulation of gene expression and the establishment of early embryonic cell fate. We also investigate how such sperm-mediated epigenetic inheritance could be hijacked to transmit paternal experience of the environment to the next generation.

• Epigenetic reprogramming of cell fate. During development, cells acquire distinct cell fate that need to be stabilized in order to ensure organismal health. We aim to identify the epigenetic mechanisms involved in the stabilization of cell identity. To that end, we use somatic cell nuclear transfer to egg or oocyte to challenge the epigenetic mechanisms that are responsible for the stabilization of cell identity and resist the reprogramming of cell fate. By identifying these epigenetic mechanisms of resistance to change, we hope to improve reprogramming processes for therapeutical purposes as well as identify disruption in epigenetic mechanisms associated with ageing or diseases such as cancer.

• Understanding human pre- and post-implantation development. Despite 40 years of in vitro fertilization (IVF) practice in medicine, human development remains a black box. We are convinced that understanding human early development is a gateway to improve IVF. We are mapping molecular events with embryo morphological parameter in order to link clinical practice to fundamental research. We are currently extending the mapping up do 14 days post fertilisation and are adding proteomics analysis as an additional modality. In order to speed up our projects, mapped molecular events are used to generate a Boolean gene regulatory network, that could predict effect of perturbation on embryonic development. We now leverage all those approaches to modulate embryo culture conditions in order to improve IVF.

• Leveraging stem cell models to study human early development

The human embryo is our reference; however, investigations are limited. To complement our analyses of human embryos, we have generated induced naïve pluripotent stem cells, induced trophoblast stem cells, and contributed to the generation of blastoids. We now use those models for mechanistic investigations of mechanism regulating cell fate, and to complement transcriptomics datasets with metabolic and proteomics analyses.

• Markers of IVF success  Nantes CHU has one of the French biggest reproductive biology department. Clinical data are routinely used to monitor and improve patient path. More specifically, we are performing proteomics analyses of culture media and deep learning analyses of morphokinetics parameters.

Selected publications:

Onfray et al, Cell Rep, 2024

Kagawa et al, Nature, 2022

Meisterman et al, Cell Stem Cell, 2021

Oikawa et al, Nature communications, 2020

Castel et al, Cell Rep, 2020

Feyeux et al, Hum Rep, 2020

Can et al, Science, 2019

Kilens et al, Nat Com, 2018

Grants:

• ANR Research Grants:

EPIPROSPECT: Epigenetic programming of the sperm chromatin.

HU_BLAST: Shaping the human embryo for uterus implantation

BOOSTIVF: Improving IVF through integration of morphological and molecular analyses CHROMNESS: Pluripotent stem cells in rabbits: manipulating epigenetic status to promote cell reprogramming and self-renewal stability.

• Regional Grant:

Connect Talent Grant, Epigenetic programming and reprogramming of cell fate.

Research scientist:

Jerome Jullien DR2 Inserm

Laurent David MCU-PH

Thomas Freour PU-PH

Clinicians:

Sophie Loubersac, MD, PH

Carole Splingart, PharmD, PH

Associate Researchers:

Djemil Bencharif PU, DVM oniris

Lamia Briand Amirat PU, DVM oniris

Pierre Calvel MCF Agroparitech

Postdoctoral Fellows:

Vanessa Quillaud-Chenouard, PhD

Nolwenn Malterre, PhD

PhD student

Florian Berger

Maissa Goumeidane

Oceane Girard

Eva Moinard

Simon Chevolleau

Emilie Rochard

Research Assistants :

Valentin Francois—campion PhD,IR

Jenna Lammers PhD, IH
 

PIs from the team are managing core facilities:

- The iPSC Induced Pluripotent Stem Cell core facility led by Laurent David (6 technical staff, the core is part of our local cluster of research (SFR)) mission is to accelerate research in the stem cell field by facilitating the derivation and distribution of induced pluripotent stem (iPS) cell lines, genome editing, training and assisting partners in the setup of differentiation protocols. The platform is opened to local (45%), national (45%) or international (10%) users. R&D: the iPSC core facility has optimized differentiation and reprogramming protocols.

-The Rat Transgenesis TRIP platform is a platform led by Jerome Jullien and Matthieu Giraud and that generates genetically-modified rats. TRIP has a working force of 7 persons (ETP 3). TRIP services also include the distribution of rat models created for our own research but that also have widespread interest. Importantly, TRIP performs research and development on genome editing and transgenesis in the rat and other organisms as well as immunophenomic techniques.

Collaborators :

Nicolas Rivron (IMBA, Vienna, AUT)

Charles Pineau (IRSET, Rennes, FR)

Hilde van de Velde (UZ Brussel, BEL)

Vincent Pasque (KU Leuven, BEL)

Peter Rugg-Gun (Babraham, Cambridge, UK)

Rita Vassena (EUGIN, Barcelona, SP)

Claire Rougeulle (Paris Cité, FR)

Claire Chazaud (GReD, Clermont-Ferrand, FR)

Anna Phillpott (CSCI, Cambridge, UK)

Estelle Marion (INCIT, Angers, FR)

Nathalie Beaujean (SBRI, Lyon, FR)

Romain Gibeaux (IGDR, Rennes,FR)