Department of Neuroscience, Unit of Neuromuscular and Neurodegenerative Diseases, Children's Research Hospital Bambino Gesù, IRCCS, 00146 Rome, Italy.
Int J Mol Sci. 2017 Nov 7;18(11):2350. doi: 10.3390/ijms18112350.
Premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, are a group of rare monogenic diseases leading to reduced lifespan of the patients. Importantly, these disorders mimic several features of physiological aging. Despite the interest on the study of these diseases, the underlying biological mechanisms remain unknown and no treatment is available. Recent studies on HGPS (due to mutations of the gene encoding for the nucleoskeletal proteins lamin A/C) have reported disruptions in cellular and molecular mechanisms modulating genomic stability and stem cell populations, thus giving the nuclear lamina a relevant function in nuclear organization, epigenetic regulation and in the maintenance of the stem cell pool. In this context, modeling premature aging with induced pluripotent stem cells (iPSCs) offers the possibility to study these disorders during self-renewal and differentiation into relevant cell types. iPSCs generated by cellular reprogramming from adult somatic cells allows researchers to understand pathophysiological mechanisms and enables the performance of drug screenings. Moreover, the recent development of precision genome editing offers the possibility to study the complex mechanisms underlying senescence and the possibility to correct disease phenotypes, paving the way for future therapeutic interventions.
早衰疾病包括哈钦森-吉尔福德早衰综合征（HGPS）和沃纳综合征，是一组罕见的单基因疾病，导致患者寿命缩短。重要的是，这些疾病模拟了生理衰老的几个特征。尽管人们对这些疾病的研究很感兴趣，但潜在的生物学机制仍不清楚，也没有有效的治疗方法。最近对 HGPS（由于编码核骨架蛋白 lamin A/C 的基因突变）的研究报告称，调节基因组稳定性和干细胞群体的细胞和分子机制受到破坏，从而使核层在核组织、表观遗传调控和维持干细胞库中发挥相关功能。在这种情况下，使用诱导多能干细胞（iPSCs）对早衰进行建模为研究这些疾病在自我更新和分化为相关细胞类型期间的功能提供了可能。通过对成年体细胞进行细胞重编程生成的 iPSCs 使研究人员能够了解病理生理机制，并能够进行药物筛选。此外，最近精确基因组编辑的发展为研究衰老的复杂机制以及纠正疾病表型提供了可能，为未来的治疗干预铺平了道路。
