State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Protein Cell. 2018 Apr;9(4):333-350. doi: 10.1007/s13238-018-0517-8. Epub 2018 Feb 23.
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
亨廷顿氏舞蹈症-吉福德早衰综合征（Hutchinson-Gilford progeria syndrome，HGPS）和沃纳综合征（Werner syndrome，WS）是两种特征最明显的人类早衰综合征。HGPS 是由 lamin A（LMNA）基因突变引起的，导致截短蛋白产物-progerin 的产生。WS 是由 WRN 基因突变引起的，该基因编码一种丧失功能的 RecQ DNA 解旋酶。在这里，我们通过基因编辑技术创建了具有杂合子（G608G/+）或纯合子（G608G/G608G）LMNA 突变和双等位基因 WRN 敲除的同源人胚胎干细胞（ESC），分别用于模拟 HGPS 和 WS 的发病机制。虽然 ESC 和内皮细胞（EC）没有表现出任何过早衰老的特征，但 HGPS 和 WS 间充质干细胞（MSC）表现出不同动力学的与衰老相关的表型。WS-MSC 具有早发性轻度过早衰老表型，而 HGPS-MSC 则表现出晚发性急性过早衰老特征。总之，我们的研究比较和对比了两种早衰疾病的不同病理，提供了可靠的基于干细胞的模型，以确定病理性和生理性衰老的新治疗策略。
