Cellular Senescence in Cornelia de Lange Syndrome :
A Pharmacological Target?

Speaker

Dr. Michel Pucéat

• Research director at Inserm.

• Team leader and senior researcher.

In this Webinar, You Will Learn:

• Programmed embryonic cell senescence in cardiac developmental biology.
• The role of TGF-β pathway in regulation of embryonic senescence.
• A novel pharmacological strategy for postnatal Cornelia de Lange Syndrome (CdLS) patients.

About this Webinar:

Cornelia de Lange Syndrome (CdLS), largely caused by mutations in the cohesin DNA loader NIPBL, is a rare multi-organ developmental disorder for which there is currently no therapeutic strategy.

To faithfully mimic the disease and identify potential therapies, we generated a novel C57Bl/6J Nipbl-haploinsufficient mouse model. Under this genetic background, the mice recapitulate many of the defects observed in CdLS patients. These mice featured a severe growth delay. Both the proliferative and hypertrophic zones of the bones were reduced. Nipbl+/- embryonic and neonatal hearts developed ventricular hypertrophy, aortic and valve defects associated with a persistent truncus arteriosus and a ventricular septal defect. Neck, face and esophageal muscles derived from the embryonic second heart field were less developed in Nipbl+/- than in wt embryos. Adult hearts featured aortic senescence, stenosis, as well as left ventricular hypertrophy. We also used human iPS (induced pluripotent stem cells) derived from CdlS patients, those cells were differentiated into smooth muscle cells, Both CdLS iPS cells and smooth muscle derivative featured a cell senescence phenotype.

Using proteomics and RNA-sequencing, we identified a dysregulated TGF-β pathway in the outflow tract of embryonic hearts. We found senescent cells in Nipbl+/- embryonic hearts, limb primordium cartilage, and in postnatal tissues, including muscle and brain cortex. Treatment of pregnant Nipbl+/- mice with a TGF-βR inhibitor (galunisertib) prevented cell senescence and rescued both the cardiac phenotype and the size of mice at birth. This drug, used in oncology, also blocked the senescence of iPSC-derived smooth muscle cells from CdLS patients.

Altogether, we report that an exacerbated TGF-β pathway, associated with embryonic programmed cell senescence, is responsible for many defects in a CdLS mouse model. This druggable cell senescence pathway paves the way for a preventive and/or therapeutic strategy for postnatal CdLS patients.

Learn more about Dr. Michel Pucéat and his lab:

https://c2vn.univ-amu.fr/equipes/equipe-7-exposome-epi-genetics-of-cardiac-development-and-bioinformatics/

About Dr. Michel Pucéat

Dr. Michel Pucéat's groundbreaking research delves into the intricate world of congenital heart disease, a prevalent condition affecting approximately 9 per 1000 live births globally. While some anomalies may seem minor at birth, they can lead to significant cardiovascular complications in adulthood, necessitating surgical interventions that often result in functional sequelae for young adults. Approximately 20% of congenital heart disease cases are attributed to known genetic factors or exposure to teratogens, leaving the remaining 80% with uncertain environmental causes, known as the exposome.

Dr. Pucéat's team is dedicated to unraveling the mysteries surrounding embryonic heart formation and understanding the influence of parental nutritional factors on fetal heart development. Their work also extends to exploring innovative strategies for cardiac regeneration in young patients with congenital heart defects. Utilizing mouse models, cardiac organoids derived from pluripotent stem cells (including patient-derived cells), and employing multi-omics and bioinformatics techniques, Dr. Pucéat's research is multifaceted.

Specifically, Dr. Pucéat's research focuses on three main areas:

1. Investigating the role of embryonic cellular senescence in embryonic ventricle formation.

2. Exploring the developmental origins of myocardial and valvular malformations, while also assessing the impact of the exposome, particularly parental nutrition, on both congenital and adult heart pathologies.

3. Advancing preclinical approaches to cardiac regeneration through the modulation of myocyte reprogramming. Dr. Pucéat's work stands at the forefront of cardiac research, offering promising insights into the etiology of congenital heart disease and paving the way for innovative therapeutic interventions that hold the potential to transform the lives of affected individuals.

Dr. Michel Pucéat’s recent publications

Stem Cells and Regenerative Medicine in Valvulopathies

Understanding the cell fate and behavior of progenitors at the origin of the mouse cardiac mitral valve

OCT4-mediated inflammation induces cell reprogramming at the origin of cardiac valve development and calcification

Reactivation of the Epicardium at the Origin of Myocardial Fibro-Fatty Infiltration During the Atrial Cardiomyopathy

Loss of ADAMTS19 causes progressive non-syndromic heart valve disease