Aika Yamawaki-Ogata1, Hideki Oshima1, Akihiko Usui1, Yuji Narita2. 1. Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. 2. Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: ynarita@med.nagoya-u.ac.jp.
Abstract
BACKGROUND AIMS: 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. METHODS: Angiotensin II-infused apolipoprotein E-deficient mice were treated by intravenous injection of 1 × 106 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. RESULTS: 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). CONCLUSIONS: 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.
BACKGROUND AIMS: 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. METHODS: Angiotensin II-infused apolipoprotein E-deficient mice were treated by intravenous injection of 1 × 106 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. RESULTS: 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). CONCLUSIONS: 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.