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Research Paper|Volume 16, Issue 22|pp 13505—13525

When do the pathological signs become evident? Study of human mesenchymal stem cells in MDPL syndrome

Spitalieri Paola1, Guerrieri Lara1, Murdocca Michela1, Di Cesare Silvia2, Maccaroni Serena1, Pecorari Rosalba3, Nardone Anna Maria4, Candi Eleonora3, Colasuonno Fiorella3,5, Gori Giulia6, Traficante Giovanna6, Novelli Giuseppe1, Sangiuolo Federica1
  • 1Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
  • 2Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  • 3Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
  • 4Medical Genetics Unit, Fondazione Policlinico Tor Vergata, Rome, Italy
  • 5Department of Science – LIME, Roma Tre University, Rome, Italy
  • 6Meyer Children’s Hospital IRCCS, Florence, Italy
Received: July 19, 2024Accepted: November 11, 2024Published: November 26, 2024
https://doi.org/10.18632/aging.206159

Copyright: © 2024 Paola et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aging syndromes are rare genetic disorders sharing the features of accelerated senescence. Among these, Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy (MDPL; OMIM #615381) is a rare autosomal dominant disease due to a de novo in-frame deletion in POLD1 gene, encoding the catalytic subunit of DNA polymerase delta.

Here, we investigated how MSCs may contribute to the phenotypes and progression of premature aging syndromes such as MDPL.

In human induced pluripotent stem cells (hiPSCs)-derived MSCs of three MDPL patients we detected several hallmarks of senescence, including (i) abnormal nuclear morphology, (ii) micronuclei presence, (iii) slow cell proliferation and cell cycle progression, (iv) reduced telomere length, and (v) increased levels of mitochondrial reactive oxygen species (ROS). We newly demonstrated that the pathological hallmarks of senescence manifest at an early stage of human development and represent a warning sign for the progression of the disease.

Dissecting the mechanisms underlying stem cell dysfunction during aging can thereby contribute to the development of timely pharmacological therapies for ameliorating the pathological phenotype.