Institute for Cell Biology, Anatomy, and Center for Integrated Protein Science, Munich (CIPSM), Ludwig Maximilian University, Biedersteinerstrasse 29, D-80802 Munich, Germany.
Endocrinology. 2010 Mar;151(3):1257-68. doi: 10.1210/en.2009-1325. Epub 2010 Feb 4.
The wall of the seminiferous tubules contains contractile smooth-muscle-like peritubular cells, thought to be important for sperm transport. Impaired spermatogenesis in men typically involves remodeling of this wall, and we now found that smooth muscle cell (SMC) markers, namely myosin heavy chain (MYH11) and smooth muscle actin (SMA) are often lost or diminished in peritubular cells of testes of men with impaired spermatogenesis. This suggests reduced contractility of the peritubular wall, which may contribute to sub- or infertility. In these cases, testicular expression of cyclooxygenase-2 (COX-2) implies formation of prostaglandins (PGs). When screening different PGs for their ability to target human testicular peritubular cells (HTPCs), only a PG metabolite, 15-deoxy-Delta(12-14)-prostaglandin-J2 (15dPGJ2), was effective. In primary cultures of HTPCs, 15dPGJ2 increased cell size in a reversible manner. Importantly, 15dPGJ2 treatment resulted in a loss of typical differentiation markers for SMCs, namely MYH11, calponin, and SMA, whereas fibroblast markers were unchanged. Collagen gel contraction assays revealed that this loss correlates with a reduced ability to contract. Experiments with an antagonist (bisphenol A diglycidyl ether) and agonist (troglitazone) for a cognate 15dPGJ2 receptor (i.e. peroxisome proliferator-activated receptor-gamma) indicated that peroxisome proliferator-activated receptor-gamma is not directly involved. Rather, the mode of action of 15dPGJ2 involves reactive oxygen species. The antioxidant N-acetylcysteine not only blocked ROS formation but also prevented the increase in cell size and the loss of contractility in HTPCs challenged with 15dPGJ2. We conclude that 15dPGJ2, via reactive oxygen species, influences SMC phenotype and contractility of human peritubular cells and possibly is involved in the development of human male sub-/infertility.
生精小管壁包含收缩性平滑肌样的小管周细胞，这些细胞被认为对精子运输很重要。男性精子发生受损通常涉及到这个壁的重塑，我们现在发现，在精子发生受损的男性睾丸的小管周细胞中，平滑肌细胞 (SMC) 标志物，即肌球蛋白重链 (MYH11) 和平滑肌肌动蛋白 (SMA) 经常丢失或减少。这表明小管周壁的收缩性降低，这可能导致生育力低下或不育。在这些情况下，睾丸中环氧化酶-2 (COX-2) 的表达意味着前列腺素 (PGs) 的形成。在筛选不同的 PGs 以确定它们对人睾丸小管周细胞 (HTPCs) 的靶向能力时，只有一种 PG 代谢物，15-脱氧-Delta(12-14)-前列腺素-J2 (15dPGJ2) 是有效的。在 HTPCs 的原代培养中，15dPGJ2 以可逆的方式增加细胞大小。重要的是，15dPGJ2 处理导致 SMC 的典型分化标志物丢失，即 MYH11、钙调蛋白和 SMA，而成纤维细胞标志物不变。胶原凝胶收缩试验表明，这种丢失与收缩能力降低相关。用 15dPGJ2 的拮抗剂（双酚 A 二缩水甘油醚）和激动剂（曲格列酮）进行实验，以确定其同源 15dPGJ2 受体（即过氧化物酶体增殖物激活受体-γ）表明过氧化物酶体增殖物激活受体-γ没有直接参与。相反，15dPGJ2 的作用模式涉及活性氧。抗氧化剂 N-乙酰半胱氨酸不仅阻断 ROS 的形成，还可以防止 HTPCs 在受到 15dPGJ2 挑战时细胞大小的增加和收缩性的丧失。我们得出结论，15dPGJ2 通过活性氧影响人小管周细胞的 SMC 表型和收缩性，并可能参与人类男性生育力低下/不育的发生。
