Department of Dermatology and IMETUM, Technische Universität München , Munich , Germany.
Biol Open. 2012 Jun 15;1(6):516-26. doi: 10.1242/bio.20121149. Epub 2012 Apr 16.
Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by segmental accelerated aging and early death from coronary artery disease or stroke. Nearly 90% of HGPS sufferers carry a G608G mutation within exon 11 of LMNA, producing a truncated form of prelamin A, referred to as "progerin". Here, we report the isolation of naïve multipotent skin-derived precursor (SKP) cells from dermal fibroblast cultures from HGPS donors. These cells form spheres and express the neural crest marker, nestin, in addition to the multipotent markers, OCT4, Sox2, Nanog and TG30; these cells can self-renew and differentiate into smooth muscle cells (SMCs) and fibroblasts. The SMCs derived from the HGPS-SKPs accumulate nuclear progerin with increasing passages. A subset of the HGPS-naïve SKPs express progerin in vitro and in situ in HGPS skin sections. This is the first in vivo evidence that progerin is produced in adult stem cells, and implies that this protein could induce stem cells exhaustion as a mechanism contributing to aging. Our study provides a basis on which to explore therapeutic applications for HGPS stem cells and opens avenues for investigating the pathogenesis of other genetic diseases.
亨廷顿氏舞蹈症 - 吉福德早衰综合征（HGPS，OMIM 176670）是一种罕见的疾病，其特征为节段性加速衰老以及由于冠状动脉疾病或中风过早死亡。将近 90%的 HGPS 患者在 LMNA 的外显子 11 中携带 G608G 突变，产生前层粘连蛋白的截断形式，称为“progerin”。在这里，我们报告了从 HGPS 供体的真皮成纤维细胞培养物中分离出幼稚多能皮肤衍生前体（SKP）细胞。这些细胞形成球体，并表达神经嵴标记物巢蛋白，除了多能标记物 OCT4、Sox2、Nanog 和 TG30 之外；这些细胞可以自我更新并分化为平滑肌细胞（SMCs）和成纤维细胞。源自 HGPS-SKPs 的 SMCs 在传代过程中积累核 progerin。HGPS-幼稚 SKPs 的一部分在体外和 HGPS 皮肤切片中表达 progerin。这是 progerin 在成年干细胞中产生的第一个体内证据，并暗示该蛋白可能通过诱导干细胞衰竭作为导致衰老的机制之一。我们的研究为探索 HGPS 干细胞的治疗应用提供了基础，并为研究其他遗传疾病的发病机制开辟了途径。
