Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany.
Unit of Bologna, CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", 40136 Bologna, Italy.
Cells. 2023 May 9;12(10):1350. doi: 10.3390/cells12101350.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that causes premature aging symptoms, such as vascular diseases, lipodystrophy, loss of bone mineral density, and alopecia. HGPS is mostly linked to a heterozygous and de novo mutation in the LMNA gene (c.1824 C > T; p.G608G), resulting in the production of a truncated prelamin A protein called "progerin". Progerin accumulation causes nuclear dysfunction, premature senescence, and apoptosis. Here, we examined the effects of baricitinib (Bar), an FDA-approved JAK/STAT inhibitor, and a combination of Bar and lonafarnib (FTI) treatment on adipogenesis using skin-derived precursors (SKPs). We analyzed the effect of these treatments on the differentiation potential of SKPs isolated from pre-established human primary fibroblast cultures. Compared to mock-treated HGPS SKPs, Bar and Bar + FTI treatments improved the differentiation of HGPS SKPs into adipocytes and lipid droplet formation. Similarly, Bar and Bar + FTI treatments improved the differentiation of SKPs derived from patients with two other lipodystrophic diseases: familial partial lipodystrophy type 2 (FPLD2) and mandibuloacral dysplasia type B (MADB). Overall, the results show that Bar treatment improves adipogenesis and lipid droplet formation in HGPS, FPLD2, and MADB, indicating that Bar + FTI treatment might further ameliorate HGPS pathologies compared to lonafarnib treatment alone.
亨廷顿氏舞蹈症（Huntington disease）是一种罕见的遗传疾病，会导致过早衰老的症状，如血管疾病、脂肪营养不良、骨密度丧失和脱发。HGPS 主要与 LMNA 基因（c.1824 C > T；p.G608G）的杂合和新生突变有关，导致产生一种称为“progerin”的截断前层粘连蛋白 A 蛋白。Progerin 的积累会导致核功能障碍、过早衰老和细胞凋亡。在这里，我们研究了巴瑞替尼（Bar）和 lonafarnib（FTI）联合治疗对皮肤衍生前体细胞（SKPs）脂肪生成的影响。我们分析了这些治疗方法对从已建立的人类原代成纤维细胞培养物中分离出的 SKPs 分化潜力的影响。与模拟处理的 HGPS SKPs 相比，Bar 和 Bar + FTI 治疗改善了 HGPS SKPs 向脂肪细胞的分化和脂滴形成。同样，Bar 和 Bar + FTI 治疗改善了源自两种其他脂肪营养不良疾病的 SKPs 的分化：家族性部分脂肪营养不良 2 型（FPLD2）和下颌骨面骨发育不良 2 型（MADB）。总的来说，结果表明 Bar 治疗可改善 HGPS、FPLD2 和 MADB 的脂肪生成和脂滴形成，表明与 lonafarnib 单独治疗相比，Bar + FTI 治疗可能进一步改善 HGPS 病理。
