Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging

Jean Philippe Trani (1) , Raphaël Chevalier (1) , Leslie Caron (1) , Claire El Yazidi (1) , Natacha Broucqsault (1) , Léa Toury (1) , Morgane Thomas , Karima Annab , Bernard Binetruy , Annachiara de Sandre-Giovannoli (1, 2, 3) , Nicolas Levy (1, 2) , Frédérique Magdinier (1) , Jérôme Robin (1)

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 Département de génétique médicale [Hôpital de la Timone - APHM]
3 CRB Santé - Centre de Ressources Biologiques Santé

Progeroid syndromes are rare genetic diseases with most of autosomal dominant transmission, the prevalence of which is less than 1/10,000,000. These syndromes caused by mutations in the LMNA gene encoding A-type lamins belong to a group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated aging of mesenchymal stem cells (MSCs)–derived tissues associated with nuclear morphological abnormalities. To identify pathways altered in progeroid patients’ MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson–Gilford progeria syndrome (HGPS, c.1824C>T—p.G608G), HGPS-like syndrome (HGPS-L; c.1868C>G—p.T623S) associated with farnesylated prelamin A accumulation, or atypical progeroid syndromes (APS; homozygous c.1583C> T—p.T528M; heterozygous c.1762T>C—p.C588R; compound heterozygous c.1583C>T and c.1619T>C—p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient’s MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of LMNA variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern; an increased response to double-strand DNA damage; and telomere erosion in HGPS, HGPS-L, and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared with APS cells.

Domaines: Sciences du Vivant [q-bio]

Jean Philippe Trani, Raphaël Chevalier, Leslie Caron, Claire El Yazidi, Natacha Broucqsault, et al.. Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging. Life Science Alliance, 2022, 5 (12), pp.e202201501. ⟨10.26508/lsa.202201501⟩. ⟨hal-04034056⟩