BACKGROUND Human placenta-derived mesenchymal stem cells (PD-MSCs) are powerful sources for cell therapy in regenerative medicine. However, a limited lifespan by senescence through mechanisms that are well unknown is the greatest obstacle. In the present study, we first demonstrated the characterization of replicative senescent PD-MSCs and their possible mitochondrial functional alterations. METHODS Human PD-MSCs were cultured to senescent cells for a long period of time. The cells of before passage number 8 were early cells and after passage number 14 were late cells. Also, immortalized cells of PD-MSCs (overexpressed hTERT gene into PD-MSCs) after passage number 14 were positive control of non-senescent cells. The characterization and mitochondria analysis of PD-MSCs were explored with long-term cultivation. RESULTS Long-term cultivation of PD-MSCs exhibited increases of senescent markers such as SA-β-gal and p21 including apoptotic factor, and decreases of proliferation, differentiation potential, and survival factor. Mitochondrial dysfunction was also observed in membrane potential and metabolic flexibility with enlarged mitochondrial mass. Interestingly, we founded that fatty acid oxidation (FAO) is an important metabolism in PD-MSCs, and carnitine palmitoyltransferase1A (CPT1A) overexpressed in senescent PD-MSCs. The inhibition of CPT1A induced a change of energy metabolism and reversed senescence of PD-MSCs. CONCLUSIONS These findings suggest that alteration of FAO by increased CPT1A plays an important role in mitochondrial dysfunction and senescence of PD-MSCs during long-term cultivation.

中文翻译：

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通过增加胎盘来源的间充质干细胞的复制衰老对CPT1A脂肪酸氧化的改变。

背景技术人胎盘来源的间充质干细胞（PD-MSC）是再生医学中细胞疗法的有力来源。然而，通过未知的衰老来限制寿命是最大的障碍。在本研究中，我们首先证明了复制性衰老PD-MSC的特性及其可能的线粒体功能改变。方法将人类PD-MSCs长期培养至衰老细胞。第8代之前的细胞是早期细胞，而第14代之后的细胞是晚期细胞。同样，第14代后PD-MSC的永生细胞（过表达hTERT基因进入PD-MSC）是非衰老细胞的阳性对照。长期培养探索了PD-MSCs的特征和线粒体分析。结果PD-MSCs的长期培养表现出SA-β-gal和p21等衰老标记物的增加，包括凋亡因子，而增殖，分化潜能和存活因子降低。线粒体膜功能增高时，膜电位和代谢柔韧性也观察到线粒体功能障碍。有趣的是，我们发现脂肪酸氧化（FAO）是PD-MSC中的重要代谢，而肉碱棕榈酰转移酶1A（CPT1A）在衰老的PD-MSC中过表达。CPT1A的抑制诱导了PD-MSCs能量代谢的改变和衰老的逆转。结论这些发现表明，长期培养过程中CPT1A的增加对FAO的改变在PD-MSCs的线粒体功能障碍和衰老中起着重要作用。