Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging.
Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging.
复制标题
DOI：
10.26508/lsa.202201501
复制
发表时间：
2022-09-14
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
利用全基因组方法对有或没有早老蛋白积累的核纤层蛋白病模型（HGPS，HGPS-L，APS）进行研究，这项研究为间充质干细胞分化早期改变的途径提供了新的见解。类早衰综合征是一种罕见的遗传性疾病，其发病率低于1/10，000，000。这些由编码A型核纤层蛋白的LMNA基因突变引起的综合征属于一组称为核纤层蛋白病的疾病。核纤层蛋白参与细胞核和染色质的结构和功能。受早衰样核纤层蛋白病影响的患者显示与核形态异常相关的间充质干细胞（MSC）衍生的组织的加速老化。为了鉴定早老症患者间充质干细胞中改变的通路，我们使用了来自典型Hutchinson-Gilford早老症患者的诱导多能干细胞（hiPSC），（HGPS，c.1824C>T-p. G608 G），HGPS样综合征（HGPS-L; c.1868C>G-p. T623 S）与法尼基化前核纤层蛋白A积累或非典型早老综合征相关（APS;纯合c.1583C> T-p. T528 M;杂合c.1762T>C-p. C588 R;复合杂合c.1583C>T和c.1619T>C-p. T528 M和p.M540T），而无早老蛋白积累。通过对hiPSC衍生的MSC的转录组和甲基化组的比较分析，我们发现患者的MSC在分化的早期阶段显示特定的DNA甲基化模式和调节的转录。我们进一步探索了在LMNA变体存在下解除调节的选定生物过程，并证实了MSC分化过程中年龄相关途径的改变。特别是，我们报告了存在改变的线粒体模式;对双链DNA损伤的反应增加; HGPS，HGPS-L和APS MSC中的端粒侵蚀，表明会聚途径，独立于早老蛋白积累，但与APS细胞相比，HGPS和HGPS-L中有不同的DNA甲基化特征。
Using of genome-wide approaches on models from laminopathies with or without progerin accumulation (HGPS, HGPS-L, APS), this study provides new insights on pathways altered during early stages of mesenchymal stem cells differentiation. Progeroid syndromes are rare genetic diseases with most of autosomal dominant transmission, the prevalence of which is less than 1/10,000,000. These syndromes caused by mutations in the LMNA gene encoding A-type lamins belong to a group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated aging of mesenchymal stem cells (MSCs)–derived tissues associated with nuclear morphological abnormalities. To identify pathways altered in progeroid patients’ MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson–Gilford progeria syndrome (HGPS, c.1824C>T—p.G608G), HGPS-like syndrome (HGPS-L; c.1868C>G—p.T623S) associated with farnesylated prelamin A accumulation, or atypical progeroid syndromes (APS; homozygous c.1583C> T—p.T528M; heterozygous c.1762T>C—p.C588R; compound heterozygous c.1583C>T and c.1619T>C—p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient’s MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of LMNA variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern; an increased response to double-strand DNA damage; and telomere erosion in HGPS, HGPS-L, and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared with APS cells.
登录
查看更多内容
影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
9
作者：
Blondel S;Egesipe AL;Picardi P;Jaskowiak AL;Notarnicola M;Ragot J;Tournois J;Le Corf A;Brinon B;Poydenot P;Georges P;Navarro C;Pitrez PR;Ferreira L;Bollot G;Bauvais C;Laustriat D;Mejat A;De Sandre-Giovannoli A;Levy N;Bifulco M;Peschanski M;Nissan X
通讯作者：
Nissan X
影响因子：
11.4
作者：
Gonzalez-Suarez, Ignacio;Redwood, Abena B.;Gonzalo, Susana
通讯作者：
Gonzalo, Susana
DOI：
10.1073/pnas.1906713117
发表时间：
2020-06-02
影响因子：
11.1
作者：
Cubria, Maria B.;Suarez, Sebastian;Nazarian, Ara
通讯作者：
Nazarian, Ara
影响因子：
6
作者：
Badja, Cherif;Maleeva, Galyna;Magdinier, Frederique
通讯作者：
Magdinier, Frederique