Research Paper Advance Articles
When do the pathological signs become evident? Study of human mesenchymal stem cells in MDPL syndrome
- 1 Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
- 2 Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- 3 Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
- 4 Medical Genetics Unit, Fondazione Policlinico Tor Vergata, Rome, Italy
- 5 Department of Science – LIME, Roma Tre University, Rome, Italy
- 6 Meyer Children’s Hospital IRCCS, Florence, Italy
Received: July 19, 2024 Accepted: November 11, 2024 Published: November 26, 2024
https://doi.org/10.18632/aging.206159How to Cite
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.
Abbreviations
CM-H2DCFDA: chloromethyl derivate of 2′,7′-dichlorodihydrofluorescein diacetate; EBs: embryoid bodies; FBS: fetal bovine serum; hiPSCs: human induced pluripotent stem cells; HGPS: Hutchinson-Gilford progeria syndrome; MDPL: Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy; MNs: micronuclei; MSCs: mesenchymal stem cells; PBS: phosphate-buffered saline; PES: phenazine ethosulfate; PI: propidium iodide; P/S: penicillin/streptomycin; RA: all-trans retinoic acid; ROS: reactive oxygen species; TIFs: telomere dysfunction-induced foci; WAT: white adipose tissue; WT: wild-type.