Xiong Zheng-Mei, LaDana Christina, Wu Di, Cao Kan
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Aging (Albany NY). 2013 Apr;5(4):288-303. doi: 10.18632/aging.100550.
Lipodystrophies, characterized by partial or complete loss of adipose tissue, have been associated with mutations in the lamin A gene. It remains unclear how lamin A mutants interfere with adipose tissue formation. Hutchinson-Gilford progeria syndrome (HGPS) presents the most severe form of lamin A-associated diseases, whose patients show a complete loss of subcutaneous fat. Using iPSCs reprogrammed from HGPS fibroblasts, we induced adipocyte formation from iPSC derived embryoid bodies or from iPSC derived mesenchymal stem cells. Both approaches revealed a severe lipid storage defect in HGPS cells at late differentiation stage, faithfully recapitulating HGPS patient phenotype. Expression analysis further indicated that progerin inhibited the transcription activation of PPARγ2 and C/EBPα, but had little effects on the early adipogenic regulators. Our experiments demonstrate two comparable approaches of in vitro modeling lipodystrophies with patient-specific iPSCs, and support a regulatory role of lamin A in the terminal differentiation stage of adipogenesis.
脂肪营养不良症的特征是脂肪组织部分或完全丧失，它与核纤层蛋白A基因的突变有关。目前尚不清楚核纤层蛋白A突变体如何干扰脂肪组织的形成。哈钦森-吉尔福德早衰综合征（HGPS）是核纤层蛋白A相关疾病中最严重的一种形式，其患者的皮下脂肪完全丧失。利用从HGPS成纤维细胞重编程而来的诱导多能干细胞（iPSC），我们从iPSC衍生的胚状体或iPSC衍生的间充质干细胞中诱导脂肪细胞形成。这两种方法都揭示了HGPS细胞在分化后期存在严重的脂质储存缺陷，如实地再现了HGPS患者的表型。表达分析进一步表明，早老素抑制了PPARγ2和C/EBPα的转录激活，但对早期脂肪生成调节因子影响很小。我们的实验展示了两种利用患者特异性iPSC在体外模拟脂肪营养不良症的可比方法，并支持核纤层蛋白A在脂肪生成终末分化阶段的调节作用。
