Faculty Profiles - OGATA Aika

Bone marrow-derived mesenchymal stromal cells regress aortic aneurysm via the NF-kB, Smad3 and Akt signaling pathways Reviewed

Aika Yamawaki-Ogata, Hideki Oshima, Akihiko Usui, Yuji Narita

CYTOTHERAPY Vol. 19 ( 10 ) page： 1167 - 1175 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

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 x 10(6) 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.

DOI： 10.1016/j.jcyt.2017.07.010

Isolation and characterisation of peripheral blood-derived feline mesenchymal stem cells Reviewed

Clarithromycinの大動脈瘤発生抑制効果の作用機序の解明 Invited Reviewed

内田亘, 成田裕司, 緒方藍歌, 伊藤英樹, 山名孝治, 寺澤幸枝, 徳田順之, 六鹿雅登, 藤本和朗, 阿部知伸, 大島英揮, 碓氷章彦

日本心臓血管外科学会学術総会抄録集 Vol. 47回 page： 850 - 850 2017.2

Keiichi Sato, Aika Yamawaki-Ogata, Isamu Kanemoto, Akihiko Usui, Yuji Narita

VETERINARY JOURNAL Vol. 216 page： 183 - 8 2016.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

The aim of this study was to isolate mesenchymal stem cells (MSCs) from feline peripheral blood (fPB-MSCs) and to characterise the cells' in vitro properties. The mononuclear cell fractions were isolated from venous blood of cats by density gradient centrifugation and cultured on plastic dishes under various culture conditions to isolate MSCs. When these cells were cultured with 5% autologous plasma (AP) and 10% foetal bovine serum (FBS), adherent spindle shaped fibroblast-like cells (fPB-MSCs) were obtained from 15/22 (68%) cats. These cells were isolated only from medium containing both AP and FBS. The morphology of these MSCs was similar to those isolated from other species and from other feline tissues. fPB-MSCs expanded steadily up to 5-6 passages, but had increased population doubling time during passaging and almost all cells stopped proliferation at passages 7-9. These cells expressed CD44 and CD90, and were mostly negative for major histocompatibility class II and CD4. The cells could be induced to differentiate into adipogenic, osteogenic and chondrogenic cell lineages. These findings indicate that fPB-MSCs can be generated but appear to require specific culture conditions. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tvjl.2016.08.009

大動脈瘤に対する幹細胞療法効果のメカニズムに関して Invited Reviewed

成田裕司, 緒方藍歌, 小坂井基史, 藤本和朗, 六鹿雅登, 阿部知伸, 大島英揮, 碓氷章彦

日本心臓血管外科学会学術総会抄録集 Vol. 46回 page： OP10 - 2 2016.2

Exosomes Obtained from Mesenchymal Stem Cells as a Novel Therapeutic Tool for Aortic Aneurysm Invited Reviewed

A. Yamawaki-ogata, M. Kosakai, A. Usui, Y. Narita

TISSUE ENGINEERING PART A Vol. 21 page： S211 - S212 2015.9

Skin-Derived Precursor Cells Promote Wound Healing in Diabetic Mice Reviewed

Hideyoshi Sato, Katsumi Ebisawa, Keisuke Takanari, Shunjiro Yagi, Kazuhiro Toriyama, Aika Yamawaki-Ogata, Yuzuru Kamei

ANNALS OF PLASTIC SURGERY Vol. 74 ( 1 ) page： 114 - 20 2015.1

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background: Impaired wound healing as one of the complications arising from diabetes mellitus is a serious clinical issue. Recently, various cell therapies have been reported for promotion of wound healing. Skin-derived precursor cells (SKPs) are multipotent adult stem cells with the tendency to differentiate into neurons. We investigated the potency of promoting diabetic wound healing by the application of SKPs.
Methods: Skin-derived precursor cells isolated from diabetic murine skin were cultured in sphere formation medium. At passage 2, they were suspended in phosphate-buffered saline (PBS), and applied topically to full-thickness excisional cutaneous wounds in diabetic mice. Application of PBS served as controls (n = 21 for each group; n = 42 total).
Time to closure and percentage closure were calculated by morphometry. Wounds were harvested at 10 and 28 days and then processed, sectioned, and stained (CD31, alpha-smooth muscle actin, and neurofilament heavy chain) to quantify vascularity and neurofilaments.
Results: Wounds treated with SKPs demonstrated a significantly decreased time to closure (18.63 days) compared with PBS-control wounds (21.72 days, P > 0.01), and a significant improvement in percentage closure at 7, 10, 14, and 18 days compared with PBS-control wounds (P > 0.01). Histological analysis showed that the Capillary Score (the number of vessels/mm(2)) was significantly higher in SKP-treated wounds at day 10 but not at day 28. Nerve Density (the number of neurofilaments/mm(2)) had increased significantly in SKP-treated wounds at day 28 compared with control group. Some applied SKPs were stained by neurofilament heavy chain, which demonstrates that SKPs directly differentiated into neurons.
Conclusions: Skin-derived precursor cells promoted diabetic wound healings through vasculogenesis at the early stage of wound healing. Skin-derived precursor cells are a possible therapeutic tool for diabetic impaired wound healing.

DOI： 10.1097/SAP.0000000000000342

Therapeutic potential of bone marrow-derived mesenchymal stem cells in formed aortic aneurysms of a mouse model Reviewed

Mesenchymal stem cells for treatment of aortic aneurysms. Reviewed

Yamawaki-Ogata A, Hashizume R, Fu XM, Usui A, Narita Y

World journal of stem cells Vol. 6 ( 3 ) page： 278 - 87 2014.7

Aika Yamawaki-Ogata, Xianming Fu, Ryotaro Hashizume, Kazuro L. Fujimoto, Yoshimori Araki, Hideki Oshima, Yuji Narita, Akihiko Usui

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Vol. 45 ( 5 ) page： e156 - 65 2014.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

An aortic aneurysm (AA) is caused by atherosclerosis with chronic inflammation. Mesenchymal stem cells (MSCs) have potential anti-inflammatory properties. In this study, we examined whether an already-formed AA can be treated by intravenous injection of bone marrow-derived (BM)-MSCs in a mouse model.
AA was induced in apolipoprotein E-deficient mice by angiotensin II-infusion for 28 days through sub-cutaneous osmotic mini-pumps. After that, 1 x 10(6) BM-MSCs (in 0.2 ml saline) or 0.2 ml saline as a control was injected via the tail vein. Mice were sacrificed at 2 (saline group n = 10, BM-MSC group n = 10), 4 (saline group n = 6, BM-MSC group n = 7) or 8 weeks (saline group n = 5, BM-MSC group n = 6) after injection. The aortic tissues of each group were dissected. Aortic diameter, elastin content, matrix metalloproteinase (MMP)-2 and -9 enzymatic activity and cytokine concentrations were measured, as was macrophage infiltration, which was also evaluated histologically.
The incidence of AA in the BM-MSC group was reduced at 2 weeks (BM-MSC 40% vs saline 100%, P < 0.05), and aortic diameter was reduced at 2 and 4 weeks (2 weeks: 1.40 vs 2.29 mm, P < 0.001; 4 weeks: 1.73 vs 2.32 mm, P < 0.05). The enzymatic activities of MMP-2 and -9 were reduced in the BM-MSC group at 2 weeks (active-MMP-2: 0.28 vs 0.45 unit/ml, P < 0.05; active-MMP-9: 0.16 vs 0.34 unit/ml, P < 0.05). Inflammatory cytokines were down-regulated in the BM-MSC group (interleukin-6: 2 weeks: 1475.6 vs 3399.5 pg/ml, P < 0.05; 4 weeks: 2184.7 vs 3712.8 pg/ml, P < 0.05 and monocyte chemotactic protein-1: 2 weeks: 208.0 vs 352.7 pg/ml, P < 0.05) and insulin-like growth factor (IGF)-1 and tissue inhibitor of metalloproteinase (TIMP)-2 were up-regulated in the BM-MSC group at 2 weeks (IGF-1: 4.7 vs 2.0 ng/ml, P < 0.05; TIMP-2: 9.5 vs 4.0 ng/ml, P < 0.001). BM-MSC injection inhibited infiltration of M1 macrophages and preserved the construction of elastin.
Our results suggest that BM-MSCs might be an effective treatment for AA. Further investigation is necessary to optimize the injected dosage and the frequency of BM-MSCs to prevent a transient effect.

DOI： 10.1093/ejcts/ezu018

Intravenous administration of mesenchymal stem cells prevents angiotensin II-induced aortic aneurysm formation in apolipoprotein E-deficient mouse Reviewed

大動脈瘤に対する幹細胞療法投与法による大動脈瘤進展抑制効果の違い Invited Reviewed

成田裕司, 緒方藍歌, 符顕明, 荒木善盛, 阿部知伸, 大島英揮, 碓氷章彦

日本心臓血管外科学会雑誌 Vol. 43 ( Suppl. ) page： 263 - 263 2014.1

Xian-ming Fu, Aika Yamawaki-Ogata, Hideki Oshima, Yuichi Ueda, Akihiko Usui, Yuji Narita

JOURNAL OF TRANSLATIONAL MEDICINE Vol. 11 ( 1 ) page： 175 2013.7

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Mesenchymal stem cells (MSCs) are known to be capable of suppressing inflammatory responses. We previously reported that intra-abdominal implantation of bone marrow-derived MSCs (BM-MSCs) sheet by laparotomy attenuated angiotensin II (AngII)-induced aortic aneurysm (AA) growth in apolipoprotein E-deficient (apoE(-/-)) mice through anti-inflammation effects. However, cell delivery by laparotomy is invasive; we here demonstrated the effects of multiple intravenous administrations of BM-MSCs on AngII-induced AA formation.
Methods: BM-MSCs were isolated from femurs and tibiae of male apoE(-/-) mice. Experimental AA was induced by AngII infusion for 28 days in apoE(-/-) mice. Mice received weekly intravenous administration of BM-MSCs (n=12) or saline (n=10). After 4 weeks, AA formation incidence, aortic diameter, macrophage accumulation, matrix metalloproteinase (MMP)' activity, elastin content, and cytokines were evaluated.
Results: AngII induced AA formation in 100% of the mice in the saline group and 50% in the BM-MSCs treatment group (P < 0.05). A significant decrease of aortic diameter was observed in the BM-MSCs treatment group at ascending and infrarenal levels, which was associated with decreased macrophage infiltration and suppressed activities of MMP-2 and MMP-9 in aortic tissues, as well as a preservation of elastin content of aortic tissues. In addition, interleukin (IL)-1 beta, IL-6, and monocyte chemotactic protein-1 significantly decreased while insulin-like growth factor-1 and tissue inhibitor of metalloproteinases-2 increased in the aortic tissues of BM-MSCs treatment group.
Conclusions: Multiple intravenous administrations of BM-MSCs attenuated the development of AngII-induced AA in apoE(-/-) mice and may become a promising alternative therapeutic strategy for AA progression.

DOI： 10.1186/1479-5876-11-175

Prevention of arterial graft spasm in rats using a vasodilator-eluting biodegradable nano-scaled fibre Reviewed

Kei Yagami, Aika Yamawaki-Ogata, Makoto Satake, Hiroaki Kaneko, Hideki Oshima, Akihiko Usui, Yuichi Ueda, Yuji Narita

Interactive Cardiovascular and Thoracic Surgery Vol. 17 ( 1 ) page： 16 - 22 2013.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVESArterial graft spasm occasionally causes circulatory collapse immediately following coronary artery bypass graft. The aim of this study is to evaluate the efficacy of our developed materials, which were composed of milrinone (phosphodiesterase III inhibitor) or diltiazem (calcium-channel blocker), with nano-scaled fibre made of biodegradable polymer to prevent arterial spasm.METHODSMilrinone- or diltiazem-releasing biodegradable nano-scaled fibres were fabricated by an electrospinning procedure. In vivo milrinone- or diltiazem-releasing tests were performed to confirm the sustained release of the drugs. An in vivo arterial spasm model was established by subcutaneous injection of noradrenalin around the rat femoral artery. Rats were randomly divided into four groups as follows: those that received 5 mg of milrinone-releasing biodegradable nano-scaled fibre (group M, n = 14)
5 mg of diltiazem-releasing biodegradable nano-scaled fibre (group D, n = 12)
or those that received fibre without drugs (as a control
group C, n = 14) implanted into the rat femoral artery. In the fourth group, sham operation was performed (group S, n = 10). One day after the implantation, noradrenalin was injected in all groups. The femoral arterial blood flow was measured continuously before and after noradrenalin injection. The maximum blood flow before noradrenalin injection and minimum blood flow after noradrenalin injection were measured.RESULTSIn vivo drug-releasing test revealed that milrinone-releasing biodegradable nano-scaled fibre released 78% of milrinone and diltiazem-releasing biodegradable nano-scaled fibre released 50% diltiazem on the first day. The ratios of rat femoral artery blood flow after/before noradrenalin injection in groups M (0.74 ± 0.16) and D (0.72 ± 0.05) were significantly higher than those of groups C (0.54 ± 0.09) and S (0.55 ± 0.16) (P &lt
0.05).CONCLUSIONNoradrenalin-induced rat femoral artery spasm was inhibited by the implantation of milrinone-releasing biodegradable nano-scaled fibre or diltiazem-releasing biodegradable nano-scaled fibre. These results suggested that our materials might be effective for the prevention of arterial graft spasm after coronary artery bypass graft. © 2013 The Author. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

DOI： 10.1093/icvts/ivt092

Long-term results of tissue-engineered small-caliber vascular grafts in a rat carotid arterial replacement model Reviewed

KUWABARA Fumiaki, NARITA Yuji, YAMAWAKI OGATA Aika, SATAKE Makoto, KANEKO Hiroaki, OSHIMA Hideki, USUI Akihiko, UEDA Yuichi

Vol. 15 ( 4 ) page： 399 - 405 2012.12

Long-term results of tissue-engineered small-caliber vascular grafts in a rat carotid arterial replacement model Reviewed

Fumiaki Kuwabara, Yuji Narita, Aika Yamawaki-Ogata, Makoto Satake, Hiroaki Kaneko, Hideki Oshima, Akihiko Usui, Yuichi Ueda

JOURNAL OF ARTIFICIAL ORGANS Vol. 15 ( 4 ) page： 399 - 405 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

The concept of tissue engineered small-caliber vascular grafts (TE-SCVGs) is theoretically ideal. In this study, we evaluated the long-term (more than 1 year) course of TE-SCVGs using a rat carotid arterial replacement model. We fabricated a TE-SCVG scaffold (0.7 mm in diameter) with electrospun nano-scale fibers. Poly-epsilon-caprolactone was used as a biodegradable polymer. These artificial vessels were then used in carotid arterial replacement performed on Sprague-Dawley rats. The implanted grafts were removed at an early phase (1, 2, 6 weeks), middle phase (12, 24 weeks), and late phase (48, 72 weeks) after implantation. Twenty-nine patent grafts from among the 40 implanted grafts (patency 72.5 %) could be evaluated. No aneurysm formation was observed during the follow-up period. Endothelial cells positive for immunostaining with von Willebrand factor were found to be already attached to the inner surface of the TE-SCVGs in the early phase. The percentage of smooth muscle cell specific marker (a-smooth muscle actin and calponin with fluorescent immunostaining) positive cells, which seemed to be mesenchymal cells in the graft wall, increased with time, while, in contrast, the scaffold material decreased. Even after 72 weeks, however, although the scaffold material had degraded, it had not disappeared completely. These results show that the novel TE-SCVGs we developed were still functioning in the rat carotid arterial circulation after more than 1 year. However, further investigations will be required with regard to regeneration of the SMC layer and the complete degradation of graft materials.

DOI： 10.1007/s10047-012-0652-6

PS-106-2 動脈グラフと攣縮予防のための血管拡張薬徐放生体吸収性ナノファイバーの開発(PS-106 心血管基礎,ポスターセッション,第112回日本外科学会定期学術集会) Reviewed

Development of novel statin releasing biodegradable nano-scaled fiber for bone tissue engineering Invited Reviewed

Wadagaki R., Mizuno D., Yamawaki-Ogata A., Fu X., Satake M., Kaneko H., Ueda M., Narita Y.

JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE Vol. 6 page： 329 - 329 2012.9

Possibility of cell therapy for aortic aneurysm Invited Reviewed

A. Yamawaki-Ogata, X. Fu, R. Hashizume, H. Oshima, A. Usui, Y. Narita

JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE Vol. 6 page： 149 - 149 2012.9

八神啓, 成田裕司, 緒方藍歌, 佐竹真, 兼子博章, 大島英揮, 碓氷章彦, 上田裕一

日本外科学会雑誌 Vol. 113 ( 2 ) page： 703 2012.3

Effect of GDF-5 and BMP-2 on the expression of tendo/ligamentogenesis-related markers in human PDL-derived cells. Invited Reviewed

Inoue M, Ebisawa K, Itaya T, Sugito T, Yamawaki-Ogata A, Sumita Y, Wadagaki R, Narita Y, Agata H, Kagami H, Ueda M

Oral diseases Vol. 18 ( 2 ) page： 206 - 12 2012.3

Novel Small-Caliber Vascular Grafts With Trimeric Peptide for Acceleration of Endothelialization Reviewed

Fumiaki Kuwabara, Yuji Narita, Aika Yamawaki-Ogata, Kei Kanie, Ryuji Kato, Makoto Satake, Hiroaki Kaneko, Hideki Oshima, Akihiko Usui, Yuichi Ueda

ANNALS OF THORACIC SURGERY Vol. 93 ( 1 ) page： 156 - 63; discussion 163 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background. Both rapid endothelialization and the prevention of intimal hyperplasia are essential to improve the patency of small-caliber vascular grafts (SCVGs). Using the peptide array based screening system, we identified the peptide CAG (cysteine-alanine-glycine), which has a high affinity for endothelial cells and a low adhesive property for smooth muscle cells (SMCs). In this article, we report an in vivo analysis of novel vascular grafts that were constructed with a biodegradable polymer (poly-epsilon-caprolactone [PCL]) containing CAG peptide.
Methods. The novel SCVG, which measured 0.7 mm in diameter and 7 mm in length, was fabricated using the electrospinning technique. Carotid arterial replacement was performed on Sprague-Dawley rats using SCVGs with (group CAG) or without CAG (group C). Histologic and biochemical assessments were performed at 1, 2, and 6 weeks after implantation.
Results. The ratio of endothelialization was significantly higher in group CAG compared with group C (CAG versus C, 64.4 +/- 20.0% versus 42.1 +/- 8.9% at 1 week; p = 0.017; 98.2 +/- 2.3% versus 72.7 +/- 12.9% at 2 weeks; p = 0.001; and 97.4 +/- 4.6% versus 76.7 +/- 5.4% at 6 weeks; p < 0.001). Additionally, Western blot analysis showed that the level of endothelial nitric oxide synthase (eNOS) at 1 week in group CAG was significantly higher than that in group C (CAG versus C, 1.20 +/- 0.37 versus 0.34 +/- 0.16; p = 0.013), and that alpha-smooth muscle actin (ASMA) at 6 weeks in group CAG was significantly lower than that in group C (CAG versus C, 0.89 +/- 0.06 versus 1.25 +/- 0.22; p = 0.04).
Conclusions. The graft with CAG promoted rapid endothelialization and the potential for inhibition of intimal hyperplasia. (Ann Thorac Surg 2012;93:156-63) (C) 2012 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2011.07.055