Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
Indiana University School of Medicine, Indianapolis, Indiana.
Am J Physiol Gastrointest Liver Physiol. 2019 Oct 1;317(4):G441-G446. doi: 10.1152/ajpgi.00132.2019. Epub 2019 Jul 25.
Mesenteric ischemia is a devastating process that can result in intestinal necrosis. Mesenchymal stem cells (MSCs) are becoming a promising treatment modality. We hypothesized that ) MSCs would promote vasodilation of mesenteric arterioles, ) hydrogen sulfide (HS) would be a critical paracrine factor of stem cell-mediated vasodilation, ) mesenteric vasodilation would be impaired in the absence of endothelial nitric oxide synthase (eNOS) within the host tissue, and ) MSCs would improve the resistin-to-adiponectin ratio in mesenteric vessels. HS was measured with a specific fluorophore (7-azido-3-methylcoumarin) in intact MSCs and in cells with the HS-producing enzyme cystathionine β synthase (CBS) knocked down with siRNA. Mechanical responses of isolated second- and third-order mesenteric arteries (MAs) from wild-type and eNOS knockout (eNOSKO) mice were monitored with pressure myography, after which the vessels were snap frozen and later analyzed for resistin and adiponectin via multiplex beaded assay. Addition of MSCs to the myograph bath significantly increased vasodilation of norepinephrine-precontracted MAs. Knockdown of CBS in MSCs decreased HS production by MSCs and also decreased MSC-initiated MA dilation. MSC-initiated vasodilation was further reduced in eNOSKO vessels. The MA resistin-to-adiponectin ratio was higher in eNOSKO vessels compared with wild-type. These results show that MSC treatment promotes dilation of MAs by an HS-dependent mechanism. Furthermore, functional eNOS within the host mesenteric bed appears to be essential for maximum stem cell therapeutic benefit, which may be attributable, in part, to modifications in the resistin-to-adiponectin ratio. Stem cells have been shown to improve survival, mesenteric perfusion, and histological injury scores following intestinal ischemia. These benefits may be due to the paracrine release of hydrogen sulfide. In an ex vivo pressure myography model, we observed that mesenteric arterial dilation improved with stem cell treatment. Hydrogen sulfide release from stem cells and endothelial nitric oxide synthase within the vessels were critical components of optimizing stem cell-mediated mesenteric artery dilation.
肠系膜缺血是一种破坏性的过程，可导致肠坏死。间充质干细胞（MSCs）正成为一种有前途的治疗方式。我们假设：) MSCs 将促进肠系膜小动脉的血管扩张，) 硫化氢（HS）将是干细胞介导的血管扩张的关键旁分泌因子，) 在宿主组织中缺乏内皮型一氧化氮合酶（eNOS）的情况下，肠系膜血管扩张会受损，) MSCs 将改善肠系膜血管中的抵抗素与脂联素比值。通过使用特定荧光探针（7-叠氮基-3-甲基香豆素）在完整的 MSCs 中和通过 siRNA 敲低 HS 产生酶胱硫醚-β 合酶（CBS）的细胞中测量 HS。使用压力肌动描记术监测来自野生型和 eNOS 敲除（eNOSKO）小鼠的第二和第三级肠系膜动脉（MAs）的分离机械反应，然后将血管迅速冷冻，并通过多重珠联免疫测定法分析抵抗素和脂联素。将 MSCs 添加到肌动描记浴中可显著增加去甲肾上腺素预收缩 MAs 的血管舒张。MSCs 中 CBS 的敲低降低了 MSCs 中 HS 的产生，并且还降低了 MSC 起始的 MA 扩张。在 eNOSKO 血管中，MSC 起始的血管舒张进一步降低。与野生型相比，eNOSKO 血管中的 MA 抵抗素与脂联素比值更高。这些结果表明，MSC 治疗通过 HS 依赖性机制促进 MAs 的扩张。此外，宿主肠系膜床内的功能性 eNOS 似乎是最大限度地发挥干细胞治疗益处的必要条件，这部分归因于抵抗素与脂联素比值的改变。已经表明干细胞可改善肠缺血后的存活、肠系膜灌注和组织学损伤评分。这些益处可能归因于硫化氢的旁分泌释放。在离体压力肌动描记模型中，我们观察到干细胞治疗可改善肠系膜动脉扩张。来自干细胞和血管内内皮型一氧化氮合酶的 HS 释放是优化干细胞介导的肠系膜动脉扩张的关键组成部分。
