Paola Spitalieri, Lara Guerrieri, Michela Murdocca, Silvia Di Cesare, Serena Maccaroni, Rosalba Pecorari, Maria Nardone Anna, Eleonora Candi, Fiorella Colasuonno, Giulia Gori, Giovanna Traficante, Giuseppe Novelli, Federica Sangiuolo
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Aging (Albany NY). 2024 Nov 26;16(22):13505-13525. doi: 10.18632/aging.206159.
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 in-frame deletion in 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.
衰老综合征是一类罕见的遗传性疾病，具有加速衰老的特征。其中，下颌骨发育不全、耳聋和早衰样特征伴脂肪营养不良（MDPL；OMIM #615381）是一种罕见的常染色体显性疾病，由编码DNA聚合酶δ催化亚基的基因发生框内缺失所致。在此，我们研究了间充质干细胞（MSC）如何导致MDPL等早衰综合征的表型和病情进展。在三名MDPL患者的人诱导多能干细胞（hiPSC）来源的MSC中，我们检测到了几种衰老的标志，包括：（i）异常的核形态；（ii）微核的存在；（iii）细胞增殖缓慢和细胞周期进展；（iv）端粒长度缩短；以及（v）线粒体活性氧（ROS）水平升高。我们首次证明，衰老的病理标志在人类发育的早期阶段就已显现，并且是疾病进展的一个警示信号。剖析衰老过程中干细胞功能障碍的潜在机制，有助于开发及时的药物疗法来改善病理表型。
