Faculty Profiles - OGATA Aika

Papers - OGATA Aika

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A review of current status of cell-based therapies for aortic aneurysms. Invited Reviewed Open Access

Yamawaki-Ogata A, Mutsuga M, Narita Y

Inflammation and regeneration Vol. 43 ( 1 ) page： 40 2023.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Inflammation and Regeneration

An aortic aneurysm (AA) is defined as focal aortic dilation that occurs mainly with older age and with chronic inflammation associated with atherosclerosis. The aneurysmal wall is a complex inflammatory environment characterized by endothelial dysfunction, macrophage activation, vascular smooth muscle cell (VSMC) apoptosis, and the production of proinflammatory molecules and matrix metalloproteases (MMPs) secreted by infiltrated inflammatory cells such as macrophages, T and B cells, dendritic cells, neutrophils, mast cells, and natural killer cells. To date, a considerable number of studies have been conducted on stem cell research, and growing evidence indicates that inflammation and tissue repair can be controlled through the functions of stem/progenitor cells. This review summarizes current cell-based therapies for AA, involving mesenchymal stem cells, VSMCs, multilineage-differentiating stress-enduring cells, and anti-inflammatory M2 macrophages. These cells produce beneficial outcomes in AA treatment by modulating the inflammatory environment, including decreasing the activity of proinflammatory molecules and MMPs, increasing anti-inflammatory molecules, modulating VSMC phenotypes, and preserving elastin. This article also describes detailed studies on pathophysiological mechanisms and the current progress of clinical trials.

DOI： 10.1186/s41232-023-00280-8

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

Mesenchymal stem cells for treatment of aortic aneurysms. Reviewed Open Access

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

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

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

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

A doxycycline loaded, controlled-release, biodegradable fiber for the treatment of aortic aneurysms Reviewed

A. Yamawaki-Ogata, R. Hashizume, M. Satake, H. Kaneko, S. Mizutani, T. Moritan, Y. Ueda, V. Narita

BIOMATERIALS Vol. 31 ( 36 ) page： 9554 - 64 2010.12

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

The pathogenesis of aortic aneurysm (AA) is characterized by degradation of extracellular matrix with Increased matrix metalloproteinases (MMPs) and inflammatory reaction Doxycycline (DOXY) has been reported to control the extension of AA by regulation of MMP However systemic administration may cause adverse side effects In this study we demonstrated the possibility of local administration of DOXY controlled-release biodegradable fiber (DCRBF) for AA in mice DCRBF was fabricated by biodegradable polymer (polylactic acid PLA) mixed with DOXY using an electrospinning technique DCRBF was cocultured with SMCs macrophages and aortic tissue and placed on an abdominal aortic aneurysm which induced apolipoprotein E-deficient mice We evaluated gene and protein expression of proteases elastin and inflammatory markers In the presence of DCRBF MMP-12 was significantly decreased TGF-beta 1 and Lox were significantly increased in SMC gene expression MMP-9 and -12 significantly decreased gene expression of macrophages The DCRBF preserved elastin content and decreased MMP-2 and -9 in aortic tissue In addition IGF-1 and TIMP-1 were significantly increased and IL-6 and TNF-alpha were significantly decreased with DCRBF in vivo In conclusion our results suggested that local administration of DCRBF may become a promising alternative therapeutic strategy for AA (C) 2010 Elsevier Ltd All rights reserved

DOI： 10.1016/j.biomaterials.2010.08.069

Combination Therapy With Clarithromycin and Montelukast Suppresses the Progression of Aortic Aneurysms in Mice With Chronic Obstructive Pulmonary Disease Invited Reviewed

Yuhara Satoshi, Narita Yuji, Yamawaki-Ogata Aika, Mutsuga Masato

Circulation Reports Vol. 7 ( 10 ) page： 842 - 851 2025.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Circulation Society

<p><b><i>Background:</i></b> Chronic obstructive pulmonary disease (COPD) is a known risk factor for aortic aneurysm (AA) enlargement and rupture. This study investigated the effects of clarithromycin (CAM) and montelukast (Mont), which are medications used to treat COPD, on AA progression in a murine model of COPD.</p><p><b><i>Methods and Results:</i></b> Apolipoprotein E-deficient mice, aged 28–40 weeks, were infused with angiotensin II by osmotic pumps to induce AA formation. Some of them received COPD induction through a single dose of porcine pancreatic elastase via the trachea. Mice were divided into 3 groups: AA (n=16; AA only, treated with saline); AA-C (n=10; AA and COPD, treated with saline); and AA-Cm (n=10; AA and COPD, treated with CAM and Mont). CAM and Mont were administered orally on a daily basis. After 28 days, aortic diameter, elastin content, matrix metalloproteinase (MMP) activity, and inflammatory markers were evaluated. The AA-C group exhibited significantly larger aneurysm diameter than the AA group (2.41 vs. 1.97 mm; P<0.05). Compared with the AA-C group, the AA-Cm group had higher elastin content (46.8 vs. 32.3%; P<0.01), decreased TNF-α level (115.5 vs. 141.0 pg/mL; P<0.05), reduced MMP-9 activity (54.8 vs. 75.4 pg/mL; P<0.01), and lower M1/M2 macrophage ratio.</p><p><b><i>Conclusions:</i></b> CAM and Mont attenuate AA progression in COPD by reducing inflammation, preserving elastin, and increasing infiltrated M2 macrophages, suggesting they have a therapeutic potential.</p>

DOI： 10.1253/circrep.CR-25-0142

Administration of a recombinant secretory leukocyte protease inhibitor prevents aortic aneurysm growth in mice. Invited Reviewed

Yamawaki-Ogata A, Mutsuga M, Narita Y

Molecular and cellular biochemistry 2025.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Molecular and Cellular Biochemistry

Pharmacological interventions to inhibit the progression of aortic aneurysm (AA) have not yet been established. We previously reported that mesenchymal stem cells (MSCs) provide a potential foundation for less invasive treatment of AA. In this study, we investigated the secretory proteins from MSC supernatants to clarify the therapeutic effects of MSCs. Furthermore, we treated thoracoabdominal aortic aneurysm (TAAA) mice with two anti-inflammatory proteins from among these secretory proteins to confirm their therapeutic effects. Protein profiles of MSC-secreted factors were analyzed using protein microarrays, and two anti-inflammatory proteins, namely progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI), were identified. Apolipoprotein E-deficient mice were continuously infused with angiotensin II via an osmotic pump for 4 weeks to induce TAAA formation, and then recombinant rPGRN and/or rSLPI were administered intraperitoneally. Mice were sacrificed at 8 weeks, and aortas were analyzed for protein expression and also stained with Elastica van Gieson and immunofluorescence to detect inflammatory cells. Intraperitoneal administration of rSLPI inhibited TAAA growth more than rPGRN alone or the combination of rPGRN and rSLPI, by inducing the following effects: downregulation of inflammatory cytokines and chemokines, specifically IL-1β, IL-6, TNF-α, and MCP-1; reduced NO production; decreased phosphorylated NF-κB levels; and decreased elastin destruction and infiltration of inflammatory cells. We identified anti-inflammatory proteins, including PGRN and SLPI, in the MSC supernatants and showed that the administration of rSLPI inhibited TAAA progression in mice. These promising preliminary data present a new approach for the treatment of less invasive TAAA.

DOI： 10.1007/s11010-025-05374-0

Effect of Oral Administration of Colchicine on Progression of Aortic Aneurysm in Mice Invited

Okawa Hideyuki, Yamawaki-Ogata Aika, Narita Yuji, Mutsuga Masato

Circulation Journal Vol. advpub ( 0 ) 2025.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Circulation Society

<p><b><i>Background:</i></b> The pathogenesis of aortic aneurysm (AA) is characterized by chronic inflammation of the aortic wall, the associated accumulation of macrophages, and degradation of the extracellular matrix, including elastin. Colchicine (COL) has long been known for its anti-inflammatory effects, so in this study we investigated its effects on AA.</p><p><b><i>Methods and Results:</i></b> In vitro, tumor necrosis factor (TNF)-α-stimulated macrophages and vascular smooth muscle cells (VSMCs) were treated with and without COL for 24 h. Unstimulated cells were used as controls. COL significantly reduced interleukin (IL)-1β, TNF-α, monocyte chemotactic protein (MCP)-1, nuclear factor kappa B (NF-κB), matrix metalloproteinase (MMP)-9, and activated caspase-1 in macrophages, and increased lysyl oxdase (Lox) and tissue inhibitor of metalloproteinase (TIMP)-2 expression in VSMCs. In vivo, aged male apolipoprotein E-deficient (ApoE<sup>−</sup>/<sup>−</sup>) mice were infused with angiotensin II (Ang II) for 28 days. The mice received either normal saline (NS) or COL orally. The control group of ApoE<sup>−</sup>/<sup>−</sup>mice did not receive Ang II infusion or treatment. COL significantly suppressed aortic enlargement and reduced AA incidence by preserving elastin and decreasing IL-1β, TNF-α, MCP-1, NLRP3 inflammasome, neutrophil elastase, and myeloperoxidase expression. No significant differences were observed in the enzymatic activities of MMP-2 and MMP-9 between the 2 groups.</p><p><b><i>Conclusions:</i></b> The results suggested that COL prevents AA progression in a clinically relevant model and is expected to be a novel preventive agent for AA.</p>

DOI： 10.1253/circj.CJ-24-0854

Modification of Antibacterial Copolymers on the Surface of PVA-Based Microfibers via Thermal Cross-Linking and Their Antibacterial Properties. Invited Reviewed

Saito S, Matsuno S, Saito A, Mutsuga M, Yamawaki-Ogata A, Narita Y, Kotsuchibashi Y

ACS omega Vol. 9 ( 46 ) page： 45961 - 45969 2024.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ACS Omega

Bacterial infections on material surfaces are a serious public health concern worldwide. Although poly(vinyl alcohol) (PVA)-based materials have great potential as medical devices, they lack antibacterial properties on their surfaces and pose bacterial infection risks during implantation surgery. Copolymers containing antibacterial [2-(methacryloyloxy)ethyl]trimethylammonium chloride (METAC) units were used to modify the surfaces of chemically cross-linked water-insoluble PVA-based microfibers. The copolymers also had carboxy units that were used to react with the hydroxy group of the PVA-based microfibers via a simple thermal treatment at 135 °C. PVA-based materials containing METAC units exhibit significant swelling due to electrostatic repulsions. Because the copolymers were modified on the extreme surface of the microfibers, no difference in the diameters between unmodified microfibers (PM-fiber) and copolymers with METAC unit-modified microfibers (PM-METAC-fiber), in both the dry and swollen states, was observed. The viable bacterial cell numbers, which were evaluated by colony counting, decreased by exposure to the poly(METAC-co-methacrylic acid (MAAc)) aqueous solution or PM-METAC-fibers. The value of CFU/mL decreased to 0.1% (against B. subtilis) and 3.9% (against E. coli) after contact with the PM-METAC-fibers compared to the PM-fibers. The percentage of hemolysis against rabbit red blood cells was equivalent to that of the negative control, suggesting that PM-METAC-fibers can selectively exhibit antibacterial properties. This modification method can be applied to various PVA-based materials if hydroxy groups are present on their surface. This study provides a facile, cost-effective, and promising strategy to impart antibacterial properties to the surface of PVA-based materials without significantly affecting their physicochemical properties.

DOI： 10.1021/acsomega.4c05637

Administration of an antibody against apoptosis inhibitor of macrophage prevents aortic aneurysm progression in mice. Invited Reviewed

Fujii T, Yamawaki-Ogata A, Terazawa S, Narita Y, Mutsuga M

Scientific reports Vol. 14 ( 1 ) page： 15878 2024.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

Apoptosis inhibitor of macrophage (AIM) is known to induce apoptosis resistance in macrophages and to exacerbate chronic inflammation, leading to arteriosclerosis. The role of AIM in aortic aneurysm (AA) remains unknown. This study examined the effects of an anti-AIM antibody in preventing AA formation and progression. In apolipoprotein E-deficient mice, AA was induced by subcutaneous angiotensin II infusion. Mice were randomly divided into two groups: (i) AIM group; weekly anti-murine AIM monoclonal antibody injection (n = 10), and (ii) IgG group; anti-murine IgG antibody injection as control (n = 14). The AIM group, compared with the IgG group, exhibited reduced AA enlargement (aortic diameter at 4 weeks: 2.1 vs. 2.7 mm, respectively, p = 0.012); decreased loss of elastic lamellae construction; reduced expression levels of IL-6, TNF-α, and MCP-1; decreased numbers of AIM-positive cells and inflammatory M1 macrophages (AIM: 1.4 vs. 8.0%, respectively, p = 0.004; M1 macrophages: 24.5 vs. 55.7%, respectively, p = 0.017); and higher expression of caspase-3 in the aortic wall (22.8 vs. 10.5%, respectively, p = 0.019). Our results suggest that administration of an anti-AIM antibody mitigated AA progression by alleviating inflammation and promoting M1 macrophage apoptosis.

DOI： 10.1038/s41598-024-66791-7

Development of novel waxy bone haemostatic agents composed of biodegradable polymers with osteogenic-enhancing peptides in rabbit models Invited Reviewed Open Access

Tsukasa Ohno, Hiroto Suenaga, Aika Yamawaki-Ogata, Kei Kanie, Ryuji Kato, Koichiro Uto, Mitsuhiro Ebara, Hideki Ito, Yuji Narita, Akihiko Usui, Masato Mutsuga

Interdisciplinary CardioVascular and Thoracic Surgery Vol. 37 ( 5 ) 2023.11

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

<jats:title>Abstract</jats:title>
<jats:p />
<jats:sec>
<jats:title>OBJECTIVES</jats:title>
<jats:p>The use of bone wax (BW) is controversial for sternal haemostasis because it increases the risk of wound infection and inhibits bone healing. We developed new waxy bone haemostatic agents made from biodegradable polymers containing peptides and evaluated them using rabbit models.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>METHODS</jats:title>
<jats:p>We designed 2 types of waxy bone haemostatic agents: peptide wax (PW) and non-peptide wax (NPW), which used poly(ε-caprolactone)-based biodegradable polymers with or without an osteogenesis-enhancing peptide, respectively. Rabbits were randomly divided into 4 groups based on treatment with BW, NPW, PW or no treatment. In a tibial defect model, the bleeding amount was measured and bone healing was evaluated by micro-computed tomography over 16 weeks. Bone healing in a median sternotomy model was assessed for 2 weeks using X-ray, micro-computed tomography, histological examination and flexural strength testing.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>RESULTS</jats:title>
<jats:p>The textures of PW and NPW (n = 12 each) were similar to that of BW and achieved a comparable degree of haemostasis. The crevice area of the sternal fracture line in the BW group was significantly larger than that in other groups (n = 10 each). The PW group demonstrated the strongest sternal flexural strength (n = 10), with complete tibial healing at 16 weeks. No groups exhibited wound infection, including osteomyelitis.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>CONCLUSIONS</jats:title>
<jats:p>Waxy biodegradable haemostatic agents showed satisfactory results in haemostasis and bone healing in rabbit models and may be an effective alternative to BW.</jats:p>
</jats:sec>

DOI： 10.1093/icvts/ivad170

Fabrication of pH-responsive poly(vinyl alcohol)-based microfibers crosslinked with copolymers containing benzoxaborole and carboxy groups Invited Reviewed

Momose, T; Takeuchi, K; Uchida, H; Saito, S; Nakada, K; Mutsuga, M; Yamawaki-Ogata, A; Narita, Y; Kotsuchibashi, Y

POLYMER Vol. 283 2023.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Polymer

Water-insoluble pH-responsive poly (vinyl alcohol) (PVA)-based microfibers were prepared using terpolymer of poly ([2-(methacryloyloxy)ethyl]trimethylammonium chloride (METAC)-co-methacrylic acid (MAAc)-co-5-methacrylamido-1,2-benzoxaborole (MAAmBO)) (TP) containing a quaternary ammonium cation, as well as carboxy and benzoxaborole groups. The surface of the microfibers could be positively charged by the permanent positive charge of the METAC units owing to the presence of the quaternary ammonium cation. The MAAc units formed a covalent bond with the hydroxy group of the vinyl alcohol unit by thermal treatment at 135 °C for 24 h, and the MAAmBO units formed a dynamic covalent bond with the diol group in PVA. After thermal crosslinking for 24 h, the PVA/TP microfibers exhibited almost 100% of the residual weight after immersion in water at 80 °C for 30 min. The diameters of the dried PVA/TP_25 wt% fibers were 21.4 ± 3.9 μm, and the swelling ratio was 1.65 ± 0.16 after immersing in water for 24 h. All microfibers showed a low degree of hemolysis (<5%). The PVA/TP_25 wt% fibers were strongly dyed with anionic acid red 1 (AR1) molecules at pH 3 and with cationic methylene blue (MB) molecules at pH 12, since the balance of the surface charge depend on the solution pH. These microfibers could be bundled and twisted to improve their mechanical properties; the required fracture energy after twisting was 2.30 ± 0.91 times higher than that before twisting.

DOI： 10.1016/j.polymer.2023.126236

Development of tissue adhesion barrier sheet functionalized with cell-selective adhesion peptides Invited Reviewed

Sugiyama, A; Kanie, K; Uto, K; Ebara, M; Ogata, A; Narita, Y; Kato, R

TISSUE ENGINEERING PART A Vol. 29 ( 13-14 ) 2023.7

Combinatorial analysis of tag peptides for enhancement of cell-adhesion short peptides Invited Reviewed

Fujimoto, A; Kanie, K; Ogata, A; Narita, Y; Kato, R

TISSUE ENGINEERING PART A Vol. 29 ( 13-14 ) 2023.7

Novel Functional Peptide for Next-Generation Vital Pulp Therapy Invited Reviewed Open Access

M. Watanabe, M. Okamoto, S. Komichi, H. Huang, S. Matsumoto, K. Moriyama, J. Ohshima, S. Abe, M. Morita, M. Ali, K. Takebe, I. Kozaki, A. Fujimoto, K. Kanie, R. Kato, K. Uto, M. Ebara, A. Yamawaki-Ogata, Y. Narita, Y. Takahashi, M. Hayashi

Journal of Dental Research Vol. 102 ( 3 ) page： 322 - 330 2023.3

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

Although vital pulp therapy should be performed by promoting the wound-healing capacity of dental pulp, existing pulp-capping materials were not developed with a focus on the pulpal repair process. In previous investigations of wound healing in dental pulp, we found that organic dentin matrix components (DMCs) were degraded by matrix metalloproteinase-20, and DMC degradation products containing protein S100A7 (S100A7) and protein S100A8 (S100A8) promoted the pulpal wound-healing process. However, the direct use of recombinant proteins as pulp-capping materials may cause clinical problems or lead to high medical costs. Thus, we hypothesized that functional peptides derived from recombinant proteins could solve the problems associated with direct use of such proteins. In this study, we identified functional peptides derived from the protein S100 family and investigated their effects on dental pulp tissue. We first performed amino acid sequence alignments of protein S100 family members from several mammalian sources, then identified candidate peptides. Next, we used a peptide array method that involved human dental pulp stem cells (hDPSCs) to evaluate the mineralization-inducing ability of each peptide. Our results supported the selection of 4 candidate functional peptides derived from proteins S100A8 and S100A9. Direct pulp-capping experiments in a rat model demonstrated that 1 S100A8-derived peptide induced greater tertiary dentin formation compared with the other peptides. To investigate the mechanism underlying this induction effect, we performed liquid chromatography–tandem mass spectrometry analysis using hDPSCs and the S100A8-derived peptide; the results suggested that this peptide promotes tertiary dentin formation by inhibiting inflammatory responses. In addition, this peptide was located in a hairpin region on the surface of S100A8 and could function by direct interaction with other molecules. In summary, this study demonstrated that a S100A8-derived functional peptide promoted wound healing in dental pulp; our findings provide insights for the development of next-generation biological vital pulp therapies.

DOI： 10.1177/00220345221135766

Administration of anti-inflammatory M2 macrophages suppresses progression of angiotensin II-induced aortic aneurysm in mice. Reviewed Open Access

Ashida S, Yamawaki-Ogata A, Tokoro M, Mutsuga M, Usui A, Narita Y

Scientific reports Vol. 13 ( 1 ) page： 1380 2023.1

Bi-layered carboxymethyl cellulose-collagen vitrigel dual-surface adhesion-prevention membrane Invited Reviewed Open Access

Yue Wang, Kei Kanie, Toshiaki Takezawa, Miki Horikawa, Kyoshiro Kaneko, Ayako Sugimoto, Aika Yamawaki-Ogata, Yuji Narita, Ryuji Kato

CARBOHYDRATE POLYMERS Vol. 285 page： 119223 2022.6

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

During wound regeneration, both cell adhesion and adhesion-inhibitory functions must be controlled in parallel. We developed a membrane with dual surfaces by merging the properties of carboxymethyl cellulose (CMC) and collagen using vitrification. A rigid membrane was formed by vitrification of a bi-layered CMC and collagen hydrogel without using cross-linking reagents, thus providing dual functions, strong cell adhesion-inhibition with the CMC layer, and cell adhesion with the collagen layer. We referred to this bi-layered CMC-collagen vitrigel membrane as "Bi-C-CVM" and optimized the process and materials. The introduction of the CMC layer conferred a "tough but stably wet" property to Bi-C-CVM. This enables Bi-C-CVM to cover wet tissue and make the membrane non-detachable while preventing tissue adhesion on the other side. The bi-layered vitrification procedure can expand the customizability of collagen vitrigel devices for wider medical applications.

DOI： 10.1016/j.carbpol.2022.119223

Alternative therapeutic strategy for existing aortic aneurysms using mesenchymal stem cell-derived exosomes. Invited Reviewed

Kozakai M, Narita Y, Yamawaki-Ogata A, Fujimoto KL, Mutsuga M, Tokuda Y, Usui A

Expert opinion on biological therapy Vol. 22 ( 1 ) page： 95 - 104 2022.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Expert Opinion on Biological Therapy

Background: Several studies demonstrated the therapeutic potential of mesenchymal stem cell–derived exosomes (MSC-exs) based on their anti-inflammatory properties. The objective was to determine the therapeutic effects of MSC-exs on aortic aneurysms (AAs) caused by atherosclerosis. Research design and methods: Apolipoprotein E knockout mice with AAs induced by angiotensin II were injected with MSC-exs or saline as a control. The change in the diameter of the aorta was measured. The expression of AA-related proteins and the histology of the aortic wall were investigated at 1 week after treatment. MicroRNA and protein profiles of MSC-exs were examined. Results: MSC-exs significantly attenuated AA progression (2.04 ± 0.20 mm in the saline group and 1.34 ± 0.13 mm in the MSC-ex group, P = 0.004). In the MSC-ex group, the expression of IL-1β, TNF-α and MCP-1 decreased, and expression of IGF-1 and TIMP-2 increased. MSC-ex induced the M2 phenotype in macrophages and suppressed the destruction of the elastic lamellae in the aortic wall. MSC-exs contained high levels of 10 microRNAs that inhibit AA formation and 13 proteins that inhibit inflammation and promote extracellular matrix synthesis. Conclusions: MSC-ex might be a novel alternative therapeutic tool for treatment of existing AAs.

DOI： 10.1080/14712598.2022.2005575

Fabrication of Cationic Poly(vinyl alcohol) Films Cross-Linked Using Copolymers Containing Quaternary Ammonium Cations, Benzoxaborole, and Carboxy Groups. Invited Reviewed Open Access

Fujimoto K, Yamawaki-Ogata A, Narita Y, Kotsuchibashi Y

ACS omega Vol. 6 ( 27 ) page： 17531 - 17544 2021.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ACS Omega

Water-insoluble cationic poly(vinyl alcohol) (PVA) films were fabricated using a mixed aqueous solution of PVA and poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride (METAC)-co-methacrylic acid (MAAc)-co-5-methacrylamido-1,2-benzoxaborole (MAAmBO)) copolymer (3D). The surface of the PVA film is typically negatively charged, and simple fabrication methods for water-insoluble PVA films with cationic surface charges are required to expand their application fields. METAC, which has a permanent positive charge owing to the presence of a quaternary ammonium cation, was selected as the cationic unit. The MAAc and MAAmBO units were used as two types of cross-linking structures for the thermal cross-linking of the hydroxy and carboxy groups of the MAAc unit (covalent bonding) as well as the diol and benzoxaborole groups of the MAAmBO unit (dynamic covalent bonding). The films were thermally cross-linked at 135 °C for 4 h without the addition of materials. After immersion in surplus water at 80 °C for 3 h, the cross-linked PVA/3D films retained almost 100% of their weights. The ζ-potential of the water-insoluble PVA/3D film was 9.4 ± 0.8 mV. The PVA/3D film was strongly dyed using anionic acid red 1 (AR1) because of its positively charged surface. Interestingly, it could also be slightly dyed using cationic methylene blue (MB) and became transparent (original state) after immersion in water for 2 days. These results suggested that positive and negative charges coexisted in the PVA/3D film, and the surface properties were positively inclined. Moreover, the degree of hemolysis of the PVA/3D films was similar to that of the negative control, which showed high blood compatibility. To our knowledge, this is the first report on the fabrication of water-insoluble cationic PVA films using two types of cross-linking structures containing carboxy and benzoxaborole groups. The cross-linked PVA films were analyzed using Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and contact angle (CA) and ζ-potential measurement, as well as by determining the mechanical properties, adsorption of charged molecules, and biocompatibility. These readily fabricated water-insoluble PVA films with positive charges can show potential applications in sensors, adsorption systems, and antimicrobial materials.

DOI： 10.1021/acsomega.1c02013

Long term efficacy and fate of a right ventricular outflow tract replacement using an elastomeric cardiac patch consisting of caprolactone and D,L-lactide copolymers Invited Reviewed Open Access

Kazuro L. Fujimoto, Aika Yamawaki-Ogata, Koichiro Uto, Akihiko Usui, Yuji Narita, Mitsuhiro Ebara

Acta Biomaterialia Vol. 123 page： 222 - 229 2021.3

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

For decades, researchers have investigated the ideal material for clinical use in the cardiovascular field. Several substitute materials are used clinically, but each has drawbacks. Recently we developed biodegradable and elastic poly(ε-caprolactone-co-D,L-lactide) (P(CL-DLLA)) copolymers by adjusting the CL/DLLA composition, and evaluated the long-term efficacy and outcomes of these copolymers when used for right ventricular outflow tract (RVOT) replacement. This P(CL-DLLA) material was processed into a circular patch and used to replace a surgical defect in the RVOT of adult rats. Control rats were implanted with expanded polytetrafluoroethylene (ePTFE). Histologic evaluation was performed at 8, 24, and 48 weeks post-surgery. All animals survived the surgery with no aneurysm formation or thrombus. In all periods, ePTFE demonstrated fibrous tissue. In contrast, at 8 weeks P(CL-DLLA) showed infiltration of macrophages and fibroblast-like cells into the remaining material. At 24 weeks, P(CL-DLLA) was absorbed completely, and muscle-like tissue was present with positive staining for α-sarcomeric actinin and cardiac troponin T (cTnT). At 48 weeks, the cTnT-positive area had increased. The biodegradable and elastic P(CL-DLLA) induced cardiac regeneration throughout the 48-week study period. Future application of this material as a cardiovascular scaffold seems promising. Statement of significance: Biomaterials for reconstruction of tissue deficiencies in cardiovascular surgery require having suitable mechanical properties for cardiac tissue and biodegradation resulting in native tissue growth. Several biodegradable polymers such as poly-ε-caprolactone (PCL) and polylactic acid (PLA) have excellent biocompatibility and already been widely used clinically. In general, PCL and PLA are quite mechanically rigid. Meanwhile, significant elasticity is required in the high-pressure environment of the heart while the material is being replaced by new tissue. The present study provides a novel four-armed crosslinked poly(ε-caprolactone-co-D,L-lactide) (i.e., P(CL-DLLA)) material for cardiac patch, which was demonstrated properties including tissue-compatible, super-elastic nature, that made it suitable for long-term, in vivo RVOT repair. This super-elastic biomaterial could be useful for reconstruction of various muscular tissues deficiencies.

DOI： 10.1016/j.actbio.2021.01.022

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