Yamawaki-Ogata Aika, Oshima Hideki, Usui Akihiko, Narita Yuji
Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Cytotherapy. 2017 Oct;19(10):1167-1175. doi: 10.1016/j.jcyt.2017.07.010. Epub 2017 Aug 31.
We have confirmed that aortic aneurysm (AA) can be regressed by the administration of bone marrow-derived mesenchymal stromal cells (BM-MSCs). We investigated the kinetics of signaling pathways in AA following treatment with BM-MSCs.
Angiotensin II-infused apolipoprotein E-deficient mice were treated by intravenous injection of 1 × 10 BM-MSCs in 0.2 mL saline (BM-MSCs group, n = 5) or 0.2 mL saline (saline group, n = 5). Mice were sacrificed 2 weeks after injection and subjected to measurements of the incidence of AA and levels of phosphorylated proteins. Levels of proteins in conditioned media of BM-MSCs were also measured.
The incidence of AA in the BM-MSCs group was reduced (BM-MSC 40% versus saline 100%, P <0.05). Levels of pNF-kB and pSTAT1 were reduced (pNF-kB: 0.28 versus 0.45 unit/mL, P <0.05, pSTAT1: 0.16 versus 0.34, P <0.05), whereas levels of pAkt and pSmad3 were elevated (pAkt: 0.13 versus 0.07, P <0.01, pSmad3: 1.07 versus 0.47, P <0.05) in the BM-MSCs group. The levels of pNF-kB, pAkt, and pSmad3 were correlated with aortic diameters. Trophic factors including IGFPB-3, NRF, Activin A and PDGF-AA were secreted from BM-MSCs (IGFBP-3: 35.2 pg/mL, NRF: 3.1 pg/mL, Activin A: 3.1 pg/mL, PDGF-AA: 0.45 pg/mL).
Our findings suggested that the therapeutic mechanism of BM-MSC-mediated AA regression could contribute to regulation of the NF-kB, Smad3 and Akt signaling pathways. In addition, paracrine actions by factors including NRF, IGFBP-3, Activin A and PDGF-AA might have affected these signaling pathways.
我们已证实，给予骨髓间充质基质细胞（BM-MSCs）可使主动脉瘤（AA）消退。我们研究了用BM-MSCs治疗后AA中信号通路的动力学。
通过静脉注射0.2 mL盐水中的1×10 BM-MSCs（BM-MSCs组，n = 5）或0.2 mL盐水（盐水组，n = 5）来治疗血管紧张素II注入的载脂蛋白E缺陷小鼠。注射后2周处死小鼠，测量AA的发生率和磷酸化蛋白水平。还测量了BM-MSCs条件培养基中的蛋白水平。
BM-MSCs组中AA的发生率降低（BM-MSCs组为40%，盐水组为100%，P <0.05）。BM-MSCs组中pNF-kB和pSTAT1水平降低（pNF-kB：0.28对0.45单位/毫升，P <0.05，pSTAT1：0.16对0.34，P <0.05），而pAkt和pSmad3水平升高（pAkt：0.13对0.07，P <0.01，pSmad3：1.07对0.47，P <0.05）。pNF-kB、pAkt和pSmad3水平与主动脉直径相关。BM-MSCs分泌包括IGFPB-3、NRF、激活素A和血小板衍生生长因子AA（PDGF-AA）在内的营养因子（IGFBP-3：35.2 pg/mL，NRF：3.1 pg/mL，激活素A：3.1 pg/mL，PDGF-AA：0.45 pg/mL）。
我们的研究结果表明，BM-MSC介导的AA消退的治疗机制可能有助于调节NF-kB、Smad3和Akt信号通路。此外，包括NRF、IGFBP-3、激活素A和PDGF-AA在内的因子的旁分泌作用可能影响了这些信号通路。
