University Medical Center Hamburg-Eppendorf, Clinic for Stem Cell Transplantation and Research Dept. Cell and Gene Therapy, Martinistr. 52, 20246 Hamburg, Germany.
Exp Cell Res. 2012 Nov 1;318(18):2284-96. doi: 10.1016/j.yexcr.2012.06.004. Epub 2012 Jun 12.
Mesenchymal stromal cells (MSCs) have been shown to display a considerable therapeutic potential in cellular therapies. However, harmful adipogenic maldifferentiation of transplanted MSCs may seriously threaten the success of this therapeutic approach. We have previously demonstrated that using platelet lysate (PL) instead of widely used fetal calf serum (FCS) diminished lipid accumulation in adipogenically stimulated human MSCs and identified, among others, lipocalin-type prostaglandin D2 synthase (L-PGDS) as a gene suppressed in PL-supplemented MSCs. Here, we investigated the role of PL and putatively pro-adipogenic L-PGDS in human MSC adipogenesis. Next to strongly reduced levels of L-PGDS we show that PL-supplemented MSCs display markedly decreased expression of adipogenic master regulators and differentiation markers, both before and after induction of adipocyte differentiation. The low adipogenic differentiation capability of PL-supplemented MSCs could be partially restored by exogenous addition of L-PGDS protein. Conversely, siRNA-mediated downregulation of L-PGDS in FCS-supplemented MSCs profoundly reduced adipocyte differentiation. In contrast, inhibiting endogenous prostaglandin synthesis by aspirin did not reduce differentiation, suggesting that a mechanism such as lipid shuttling but not the prostaglandin D2 synthase activity of L-PGDS is critical for adipogenesis. Our data demonstrate that L-PGDS is a novel pro-adipogenic factor in human MSCs which might be of relevance in adipocyte metabolism and disease. L-PGDS gene expression is a potential quality marker for human MSCs, as it might predict unwanted adipogenic differentiation after MSC transplantation.
间充质基质细胞 (MSCs) 在细胞治疗中显示出相当大的治疗潜力。然而，移植的 MSCs 发生有害的脂肪生成分化不良可能严重威胁这种治疗方法的成功。我们之前已经证明，使用血小板裂解液 (PL) 代替广泛使用的胎牛血清 (FCS) 可减少脂肪生成刺激的人 MSCs 中的脂质积累，并确定脂联素型前列腺素 D2 合酶 (L-PGDS) 是在 PL 补充的 MSC 中受到抑制的基因之一。在这里，我们研究了 PL 和潜在的促脂肪生成 L-PGDS 在人 MSC 脂肪生成中的作用。除了 L-PGDS 水平明显降低外，我们还表明 PL 补充的 MSC 在诱导脂肪细胞分化之前和之后，其脂肪生成主调控因子和分化标志物的表达明显降低。PL 补充的 MSC 的低脂肪生成分化能力可以通过外源性添加 L-PGDS 蛋白部分恢复。相反，FCS 补充的 MSC 中 L-PGDS 的 siRNA 介导下调可显著降低脂肪细胞分化。相比之下，通过阿司匹林抑制内源性前列腺素合成并没有减少分化，这表明脂质转运等机制而不是 L-PGDS 的前列腺素 D2 合酶活性对于脂肪生成至关重要。我们的数据表明，L-PGDS 是人 MSCs 中的一种新的促脂肪生成因子，它可能与脂肪细胞代谢和疾病有关。L-PGDS 基因表达是人类 MSCs 的一个潜在质量标志物，因为它可能预测 MSC 移植后不希望发生的脂肪生成分化。
