研究者詳細 - 秋山　謙太郎

論文 - 秋山　謙太郎

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Implant-supported fixed prostheses with cantilever: a systematic review and meta-analysis. 査読国際誌

Yusuke Kondo, Kiyoshi Sakai, Hajime Minakuchi, Takuya Horimai, Takuo Kuboki, JSOI Clinical Guideline Working, Group collaborators, Ikiru Atsuta, Kazuki Takaoka, Norimasa Tanabe, Akira Hasuike, Kensuke Yamauchi, Aita Hideki, Kentaro Akiyama, Yasunori Ayukaw, Masamitsu Oshima, Yoko Kurosaki, Yohei Sato, Kazuhiko Hiroyasu, Junichi Furuya, Takuya Mino, Takashi Sakamoto, Hisatomo Kondo, Takashi Miyazaki, Ryuji Hosokaw

International journal of implant dentistry 10 ( 1 ) 57 - 57 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: This systematic review (SR) aimed to investigate whether the presence of a cantilever affects the results of implant treatment for partial edentulism, including an analysis of the anterior and posterior regions of the dental arches. METHODS: An electronic search was performed, and original articles published between 1995 and November 2023 were included. The outcomes were the implant survival rate, patient satisfaction, occurrence of mechanical complications, and marginal bone loss around the implants. Two SR members independently examined the validity of the studies, extracted evidence from the included studies, and performed risk of bias assessment, comprehensive evidence evaluation, and meta-analysis. RESULTS: Nine studies met our inclusion criteria. Implant survival rate tended to be lower in the cantilever group, and marginal bone loss tended to be higher in the cantilever group; however, there was no significant difference. There was no significant difference in patient satisfaction based on the presence or absence of a cantilever. Moreover, the incidence of mechanical complications was significantly higher in the cantilever group. According to the analysis of anterior and posterior regions, implant survival rate tended to be lower in the cantilever group of the posterior region, and marginal bone loss around the implants tended to be higher in the cantilever group of the anterior region. CONCLUSION: Implant-supported fixed prostheses with cantilevers did not negatively affect implant survival rate, marginal bone loss, or patient satisfaction. However, the incidence of mechanical complications significantly increased in the cantilever group.

DOI： 10.1186/s40729-024-00573-8

Macrophages modulate mesenchymal stem cell function via tumor necrosis factor alpha in tooth extraction model. 国際誌

Aung Ye Mun, Kentaro Akiyama, Ziyi Wang, Jiewen Zhang, Wakana Kitagawa, Teisaku Kohno, Ryuji Tagashira, Kei Ishibashi, Naoya Matsunaga, Tingling Zou, Mitsuaki Ono, Takuo Kuboki

JBMR plus 8 ( 8 ) ziae085 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mesenchymal stem cells (MSCs) and macrophages collaboratively contribute to bone regeneration after injury. However, detailed mechanisms underlying the interaction between MSCs and inflammatory macrophages (M1) remain unclear. A macrophage-depleted tooth extraction model was generated in 5-wk-old female C57BL/6J mice using clodronate liposome (12.5 mg/kg/mouse, intraperitoneally) or saline injection (control) before maxillary first molar extraction. Mice were sacrificed on days 1, 3, 5, 7, and 10 after tooth extraction (n = 4). Regenerated bone volume evaluation of tooth extraction socket (TES) and histochemical analysis of CD80+M1, CD206+M2 (anti-inflammatory macrophages), PDGFRα+MSC, and TNF-α+ cells were performed. In vitro, isolated MSCs with or without TNF-α stimulation (10 ng/mL, 24 h, n = 3) were bulk RNA-sequenced (RNA-Seq) to identify TNF-α stimulation-specific MSC transcriptomes. Day 7 micro-CT and HE staining revealed significantly lower mean bone volume (clodronate vs control: 0.01 mm3 vs 0.02 mm3, p<.0001) and mean percentage of regenerated bone area per total TES in clodronate group (41.97% vs 54.03%, p<.0001). Clodronate group showed significant reduction in mean number of CD80+, TNF-α+, PDGFRα+, and CD80+TNF-α+ cells on day 5 (306.5 vs 558.8, p<.0001; 280.5 vs 543.8, p<.0001; 365.0 vs 633.0, p<.0001, 29.0 vs 42.5, p<.0001), while these cells recovered significantly on day 7 (493.3 vs 396.0, p=.0004; 479.3 vs 384.5, p=.0008; 593.0 vs 473.0, p=.0010, 41.0 vs 32.5, p=.0003). RNA-Seq analysis showed that 15 genes (|log2FC| > 5.0, log2TPM > 5) after TNF-α stimulation were candidates for regulating MSC's immunomodulatory capacity. In vivo, Clec4e and Gbp6 are involved in inflammation and bone formation. Clec4e, Gbp6, and Cxcl10 knockdown increased osteogenic differentiation of MSCs in vitro. Temporal reduction followed by apparent recovery of TNF-α-producing M1 macrophages and MSCs after temporal macrophage depletion suggests that TNF-α activated MSCs during TES healing. In vitro mimicking the effect of TNF-α on MSCs indicated that there are 15 candidate MSC genes for regulation of immunomodulatory capacity.

DOI： 10.1093/jbmrpl/ziae085

Age-Related Effects on MSC Immunomodulation, Macrophage Polarization, Apoptosis, and Bone Regeneration Correlate with IL-38 Expression. 国際誌

Jiewen Zhang, Kentaro Akiyama, Aung Ye Mun, Ryuji Tagashira, Tingling Zou, Naoya Matsunaga, Teisaku Kohno, Takuo Kuboki

International journal of molecular sciences 25 ( 6 ) 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mesenchymal stem cells (MSCs) are known to promote tissue regeneration and suppress excessive inflammation caused by infection or trauma. Reported evidence indicates that various factors influence the expression of MSCs' endogenous immunomodulatory properties. However, the detailed interactions of MSCs with macrophages, which are key cells involved in tissue repair, and their regulatory mechanisms are not completely understood. We herein investigated how age-related immunomodulatory impairment of MSCs alters the interaction of MSCs with macrophages during bone healing using young (5-week old) and aged (50-week old) mice. To clarify the relationship between inflammatory macrophages (M1) and MSCs, their spatiotemporal localization at the bone healing site was investigated by immunostaining, and possible regulatory mechanisms were analyzed in vitro co-cultures. Histomorphometric analysis revealed an accumulation of M1 and a decrease in MSC number at the healing site in aged mice, which showed a delayed bone healing. In in vitro co-cultures, MSCs induced M1 apoptosis through cell-to-cell contact but suppressed the gene expression of pro-inflammatory cytokines by soluble factors secreted in the culture supernatant. Interestingly, interleukin 38 (Il-38) expression was up-regulated in M1 after co-culture with MSCs. IL-38 suppressed the gene expression of inflammatory cytokines in M1 and promoted the expression of genes associated with M1 polarization to anti-inflammatory macrophages (M2). IL-38 also had an inhibitory effect on M1 apoptosis. These results suggest that MSCs may induce M1 apoptosis, suppress inflammatory cytokine production by M1, and induce their polarization toward M2. Nevertheless, in aged conditions, the decreased number and immunomodulatory function of MSCs could be associated with a delayed M1 clearance (i.e., apoptosis and/or polarization) and consequent delayed resolution of the inflammatory phase. Furthermore, M1-derived IL-38 may be associated with immunoregulation in the tissue regeneration site.

DOI： 10.3390/ijms25063252

卒前臨床技術教育でデジタル光学印象を経験させる相互実習の導入

下村侑司, 土山雄司, 窪木慎野介, 松永直也, 北川若奈, 黄野頂策, 石橋啓, 田仲由希恵, 大森江, 水口真実, 中川晋輔, 三木春奈, 三野卓哉, 前田あずさ, 縄稚久美子, 秋山謙太郎, 水口一, 窪木拓男

岡山歯学会雑誌 41 ( 2 ) 58 - 59 2022年12月

Therapeutic effects of peptide P140 in a mouse periodontitis model. 国際誌

Kentaro Akiyama, Kyaw Thu Aung, Laura Talamini, Olivier Huck, Takuo Kuboki, Sylviane Muller

Cellular and molecular life sciences : CMLS 79 ( 10 ) 518 - 518 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

In our search for innovative drugs that could improve periodontal treatment outcomes, autophagy and its anomalies represent a potential target for therapeutic intervention. We sought to identify autophagy defects in murine experimental periodontitis and study the effectiveness of P140, a phosphopeptide known to bind HSPA8 and inhibit its chaperone properties, and that corrects autophagy dysfunctions in several autoimmune and inflammatory diseases. Experimental periodontitis was induced by placing silk ligature around mandibular first molars. Sick mice were treated intraperitoneally with either P140 or a control, scrambled peptide. After 10 days, mandibles were harvested and bone loss was measured by micro-CT. Immune cells infiltration was studied by histological analyses. Cytokines levels and autophagy-related markers expression were evaluated by qRT-PCR and western blotting. A comparison with non-affected mice revealed significant alterations in the autophagy processes in mandibles of diseased mice, especially in the expression of sequestosome 1/p62, Maplc3b, Atg5, Ulk1, and Lamp2. In vivo, we showed that P140 normalized the dysregulated expression of several autophagy-related genes. In addition, it diminished the infiltration of activated lymphocytes and pro-inflammatory cytokines. Unexpectedly P140 decreased the extent of bone loss affecting the furcation and alveolar areas. Our results indicate that P140, which was safe in clinical trials including hundreds of autoimmune patients with systemic lupus erythematosus, not only decreases the inflammatory effects observed in mandibular tissues of ligation-induced mice but strikingly also contributes to bone preservation. Therefore, the therapeutic peptide P140 could be repositioned as a decisive breakthrough for the future therapeutic management of periodontitis.

DOI： 10.1007/s00018-022-04537-2

間葉系幹細胞とM1,M2マクロファージの間接的相互作用による骨再生

田頭龍二, 黄野頂策, 秋山謙太郎, 窪木拓男

日本口腔インプラント学会誌 35 ( 特別号 ) O - 12 2022年9月

院内で完結する補綴主導口腔インプラント手術のための汎用デジタルワークフロー

大國峻, 坂本和基, 北川若奈, 下村侑司, 松永直也, 三野卓哉, 秋山謙太郎, 清水浩明, 前川賢治, 窪木拓男

日本補綴歯科学会誌 14 ( 中国・四国支部学術大会特別号 ) 27 - 27 2022年8月

院内で完結する補綴主導口腔インプラント手術のための汎用デジタルワークフロー

大國峻, 坂本和基, 北川若奈, 下村侑司, 松永直也, 三野卓哉, 秋山謙太郎, 清水浩明, 前川賢治, 窪木拓男

日本補綴歯科学会誌 14 ( 中国・四国支部学術大会特別号 ) 27 - 27 2022年8月

創傷治癒過程における間葉系幹細胞とマクロファージの相互作用

田頭龍二, 黄野頂策, 秋山謙太郎, 窪木拓男

日本補綴歯科学会誌 14 ( 特別号 ) 179 - 179 2022年7月

加齢が骨髄ニッチ関連細胞および類洞基底膜に与える影響

石橋啓, 大野充昭, 土佐郁恵, 北川若奈, 秋山謙太郎, 窪木拓男, 大橋俊孝

日本補綴歯科学会誌 14 ( 特別号 ) 148 - 148 2022年7月

【インプラント治療の症型分類】エビデンスに基づいたインプラント治療難易度診断ツールの開発

鮎川保則, 會田英紀, 秋山謙太郎, 大島正充, 佐藤洋平, 廣安一彦, 古屋純一, 山田陽一, 澤瀬隆, 窪木拓男

日本口腔インプラント学会誌 35 ( 2 ) 83 - 91 2022年6月

記述言語：日本語出版者・発行元：(公社)日本口腔インプラント学会

本邦では口腔外科や補綴,歯周病のいずれかに軸足を置く歯科医師がインプラント治療を担当することが多いように思われる.そのため,特に自身がメインフィールドとする領域以外の治療において正確な難易度を判定する手法があれば,安心安全なインプラント治療を提供することができると考えられる.現在,いくつかのインプラント治療難易度判定ツールが提案されているが,これまでに用いられてきた種々の分類法では難易度をうまく表現できない問題も存在する.たとえば,骨の質,量ともに問題なく咬合にも問題ない下顎臼歯部1歯中間欠損などはイージーケースといっても差し支えないと思われるが,一方で未経験者にとっては,骨をドリリングすること自体が難しく感じられるだろう.このように,ある症例が簡単か難しいかは,術者の感じ方や経験で大きく異なる.また,このような術者間で感じ方に差がある技術的難易度とは別個に,全身状態や治療部位,患者の個性に基づく難易度が存在する.これらの項目に問題がある場合にインプラント治療の成功率が低下することは,多くの場合質が高いエビデンスで裏づけされている.日本口腔インプラント学会研究推進委員会では,Evidence-Based Difficulty Assessment Toolともいえる,術者の経験によらないインプラント治療の難易度分類を試みている.本稿ではその試案を提示する.(著者抄録)

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J02151&link_issn=&doc_id=20220801250004&doc_link_id=10.11237%2Fjsoi.35.83&url=https%3A%2F%2Fdoi.org%2F10.11237%2Fjsoi.35.83&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

インプラント治療は高齢者の残存歯を守りQOLを高めるか?

窪木拓男, 黒崎陽子, 大野彩, 三野卓哉, 荒川光, 小山絵理, 中川晋輔, Ha Thi Thu Nguyen, 逢坂卓, 佐伯真未子, 水口一, 大野充昭, 前川賢治, 會田英紀, 澤瀬隆, 鮎川保則, 秋山謙太郎, 大島正充, 佐藤裕二, 佐藤洋平, 廣安一彦, 山田陽一, 阪本貴司, 宮崎隆, 日本口腔インプラント学会研究推進委員会

8020: はち・まる・にい・まる 2020 ( 21 ) 153 - 155 2022年2月

記述言語：日本語出版者・発行元：(公財)8020推進財団

インプラント治療後の残存歯および口腔関連QOLを他の歯科補綴治療との比較から明らかにすることを目的に、過去にインプラント義歯(IP)、ブリッジ(BR)、床義歯(RPD)治療前後に口腔関連QOL評価を受けた患者105名(IP群58名、BR群27名、RPD群20名)を対象に、6年経過後の追跡調査時における対象補綴装置の6年累積生存率、残存歯数、および口腔関連QOLを評価した。その結果、6年累積生存率はIP群94.7%、BR群77.4%、RPD群33.3%で、IP群は他の2群に比べ有意に高かった。追跡調査時の残存歯数については、IP群がRPD群に比べ有意に多かった。また、口腔関連QOLについては、IP群では治療開始前後、および治療前・追跡調査時のいずれにおいても有意に高くなっていたのに対し、他の2群ではいずれも有意差は認めなかった。

口腔インプラントの補綴主導型デジタルシミュレーションを確実に一次手術に反映する新しいワークフロー

北川若奈, 坂本和基, 大國峻, 下村侑司, 松永直也, 三野卓哉, 秋山謙太郎, 前川賢治, 窪木拓男

日本補綴歯科学会誌 13 ( 中国・四国支部学術大会特別号 ) 12 - 12 2021年8月

Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo. 国際誌

Hai Thanh Pham, Mitsuaki Ono, Emilio Satoshi Hara, Ha Thi Thu Nguyen, Anh Tuan Dang, Hang Thuy Do, Taishi Komori, Ikue Tosa, Yuri Hazehara-Kunitomo, Yuya Yoshioka, Yasutaka Oida, Kentaro Akiyama, Takuo Kuboki

Materials (Basel, Switzerland) 14 ( 1 ) 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Aging tissues present a progressive decline in homeostasis and regenerative capacities, which has been associated with degenerative changes in tissue-specific stem cells and stem cell niches. We hypothesized that amino acids could regulate the stem cell phenotype and differentiation ability of human bone marrow-derived mesenchymal stromal cells (hBMSCs). Thus, we performed a screening of 22 standard amino acids and found that D-tryptophan (10 μM) increased the number of cells positive for the early stem cell marker SSEA-4, and the gene expression levels of OCT-4, NANOG, and SOX-2 in hBMSCs. Comparison between D- and L-tryptophan isomers showed that the latter presents a stronger effect in inducing the mRNA levels of Oct-4 and Nanog, and in increasing the osteogenic differentiation of hBMSCs. On the other hand, L-tryptophan suppressed adipogenesis. The migration and colony-forming ability of hBMSCs were also enhanced by L-tryptophan treatment. In vivo experiments delivering L-tryptophan (50 mg/kg/day) by intraperitoneal injections for three weeks confirmed that L-tryptophan significantly increased the percentage of cells positive for SSEA-4, mRNA levels of Nanog and Oct-4, and the migration and colony-forming ability of mouse BMSCs. L-kynurenine, a major metabolite of L-tryptophan, also induced similar effects of L-tryptophan in enhancing stemness and osteogenic differentiation of BMSCs in vitro and in vivo, possibly indicating the involvement of the kynurenine pathway as the downstream signaling of L-tryptophan. Finally, since BMSCs migrate to the wound healing site to promote bone healing, surgical defects of 1 mm in diameter were created in mouse femur to evaluate bone formation after two weeks of L-tryptophan or L-kynurenine injection. Both L-tryptophan and L-kynurenine accelerated bone healing compared to the PBS-injected control group. In summary, L-tryptophan enhanced the stemness and osteoblastic differentiation of BMSCs and may be used as an essential factor to maintain the stem cell properties and accelerate bone healing and/or prevent bone loss.

DOI： 10.3390/ma14010208

Aging-Affected MSC Functions and Severity of Periodontal Tissue Destruction in a Ligature-Induced Mouse Periodontitis Model. 国際誌

Kyaw Thu Aung, Kentaro Akiyama, Masayoshi Kunitomo, Aung Ye Mun, Ikue Tosa, Ha Thi Thu Nguyen, Jiewen Zhang, Teisaku Kohno, Mitsuaki Ono, Emilio Satoshi Hara, Takuo Kuboki

International journal of molecular sciences 21 ( 21 ) 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mesenchymal stem cells (MSCs) are known to play important roles in the repair of lost or damaged tissues and immunotolerance. On the other hand, aging is known to impair MSC function. However, little is currently known about how aged MSCs affect the host response to the local inflammatory condition and tissue deterioration in periodontitis, which is a progressive destructive disease of the periodontal tissue potentially leading to multiple tooth loss. In this study, we examined the relationship between aging-induced impairment of MSC function and the severity of periodontal tissue destruction associated with the decrease in host immunomodulatory response using a ligature-induced periodontitis model in young and aged mice. The results of micro computerized tomography (micro-CT) and histological analysis revealed a more severe bone loss associated with increased osteoclast activity in aged (50-week-old) mice compared to young (5-week-old) mice. Immunostaining analysis revealed that, in aged mice, the accumulation of inflammatory T and B cells was higher, whereas the percentage of platelet-derived growth factor receptor α (PDGFRα)+ MSCs, which are known to modulate the apoptosis of T cells, was significantly lower than in young mice. In vitro analysis of MSC function showed that the expression of surface antigen markers for MSCs (Sca-1, CD90, CD146), colony formation, migration, and osteogenic differentiation of aged MSCs were significantly declined compared to those of young MSCs. Moreover, a significantly higher proportion of aged MSCs were positive for the senescence-associated β galactosidase activity. Importantly, aged MSCs presented a decreased expression of FAS-L, which was associated with a lower immunomodulatory property of aged MSCs to induce T cell apoptosis in co-cultures compared with young MSCs. In summary, this is the first study showing that aging-induced impairment of MSC function, including immunomodulatory response, is potentially correlated with progressive periodontal tissue deterioration.

DOI： 10.3390/ijms21218103

口腔インプラント治療に対するカダバー外科トレーニングの取り組み

大野充昭, 秋山謙太郎, 三野卓哉, 大野彩, 水口一, 黒崎陽子, 園山亘, 窪木拓男

日本口腔インプラント学会誌 33 ( 特別号 ) 423 - 423 2020年9月

Ammonium tetrathiomolybdate enhances the antitumor effect of cisplatin via the suppression of ATPase copper transporting beta in head and neck squamous cell carcinoma. 査読国際誌

Shoji Ryumon, Tatsuo Okui, Yuki Kunisada, Koji Kishimoto, Tsuyoshi Shimo, Kazuaki Hasegawa, Soichiro Ibaragi, Kentaro Akiyama, Nguyen Thi Thu Ha, Nur Mohammad Monsur Hassan, Akira Sasaki

Oncology reports 42 ( 6 ) 2611 - 2621 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Platinum‑based antitumor agents have been widely used to treat head and neck squamous cell carcinoma (HNSCC) and numerous other malignancies. Cisplatin is the most frequently used platinum‑based antitumor agent, however drug resistance and numerous undesirable side effects limit its clinical efficacy for cancer patients. Cancer cells discharge cisplatin into the extracellular space via copper transporters such as ATPase copper transporting beta (ATP7B) in order to escape from cisplatin‑induced cell death. In the present study, it was demonstrated for the first time that the copper chelator ammonium tetrathiomolybdate (TM) has several promising effects on cisplatin and HNSCC. First, TM suppressed the ATP7B expression in HNSCC cell lines in vitro, thereby enhancing the accumulation and apoptotic effect of cisplatin in the cancer cells. Next, it was revealed that TM enhanced the antitumor effect of cisplatin in HNSCC cell tumor progression in a mouse model of bone invasion, which is important since HNSCC cells frequently invade to facial bone. Finally, it was demonstrated that TM was able to overcome the cisplatin resistance of a human cancer cell line, A431, via ATP7B depression in vitro.

DOI： 10.3892/or.2019.7367

骨髄環境におけるBMP-2誘導性骨形成・骨芽細胞分化抑制メカニズムの解明

納所秋二, 大野充昭, Nguyen Ha, 笈田育尚, 小盛大志, 秋山謙太郎, 大橋俊孝, 窪木拓男

日本補綴歯科学会誌 11 ( 特別号 ) 130 - 130 2019年5月

抗Dickkopf1(DKK-1)抗体による骨分化能メカニズムの解明

井上美穂, ラジュ・レスミ, 岩浅匠真, 秋山謙太郎, 大島正充, 窪木拓男, 松香芳三

日本補綴歯科学会誌 11 ( 特別号 ) 301 - 301 2019年5月

Acidic Pre-Conditioning Enhances the Stem Cell Phenotype of Human Bone Marrow Stem/Progenitor Cells 査読

Yuri Hazehara-Kunitomo, Emilio Hara, Mitsuaki Ono, Kyaw Thu Aung, Keiko Komi, Hai Thanh Pham, Kentaro Akiyama, Masahiro Okada, Toshitaka Oohashi, Takuya Matsumoto, Takuo Kuboki

International Journal of Molecular Sciences 20 ( 5 ) 2019年3月

Impact of commensal flora on periodontal immune response to lipopolysaccharide. 査読国際誌

Fukuhara D, Irie K, Uchida Y, Kataoka K, Akiyama K, Ekuni D, Tomofuji T, Morita M

Journal of periodontology 89 ( 10 ) 1213 - 1220 2018年10月

補綴医に贈る再生医療の話(第3回) 再生医療と免疫組織再生と間葉系幹細胞

秋山謙太郎, 窪木拓男

日本補綴歯科学会誌 10 ( 4 ) 296 - 301 2018年10月

記述言語：日本語出版者・発行元：(公社)日本補綴歯科学会

組織再生は、外的要因や疾患により破壊または喪失した組織構造がもとの通りに復元されることであり、その詳細なメカニズムの全貌は未だ解明されていないのが現状である。その理由として、組織再生には、未分化間葉系幹細胞の組織特異細胞への分化だけでなく、さまざまなサイトカインや免疫細胞などから構成される組織再生ニッチの形成が複雑に関与しているからと考えられている。本稿では、組織再生における間葉系幹細胞と免疫細胞の関わりについて、特に歯や補綴物の安定した予後に必要不可欠である骨の吸収、再生について、著者らのデータの一部と共に概要を紹介する。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J05334&link_issn=&doc_id=20181031230003&doc_link_id=%2Fdv5proso%2F2018%2F001004%2F005%2F0296-0301%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdv5proso%2F2018%2F001004%2F005%2F0296-0301%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

骨髄細胞は骨髄環境下においてBMP-2誘導性骨形成を抑制する(Marrow cells inhibits BMP-2-induced bone formation in the marrow)

Nguyen Ha, Nguyen H, 大野充昭, 笈田育尚, 小盛大志, 秋山謙太郎, 大橋俊孝, 窪木拓男

日本口腔インプラント学会学術大会抄録集 48回 302 - 302 2018年9月

骨増生法施術後のインプラント体周囲頬側骨厚径に関する多施設観察研究

小田師巳, 中田光太郎, 高山賢一, 三野卓哉, 大野彩, 秋山謙太郎, 園山亘, 荒川光, 窪木拓男

日本口腔インプラント学会学術大会抄録集 48回 66 - 66 2018年9月

審美領域における結合組織移植術を用いたインプラント体周囲の垂直的組織増生埋入時の水平的な硬組織増生と同時に行った結合組織移植術の形態学的臨床評価

小田師巳, 中田光太郎, 園山亘, 黒崎陽子, 三野卓哉, 秋山謙太郎, 荒川光, 窪木拓男

日本口腔インプラント学会誌 31 ( 3 ) E162 - E163 2018年9月

遺伝子検査に関する講義・実習の補綴学教育への導入

大野充昭, 秋山謙太郎, 大野彩, 納所秋二, 三海晃弘, 樋口隆晴, 前川賢治, 大橋俊孝, 窪木拓男

日本補綴歯科学会誌 10 ( 特別号 ) 288 - 288 2018年6月

Bone Marrow Cells Inhibit BMP-2-Induced Osteoblast Activity in the Marrow Environment 査読

Nguyen, H.T., Ono, M., Oida, Y., Hara, E.S., Komori, T., Akiyama, K., Nguyen, H.T.T., Aung, K.T., Pham, H.T., Tosa, I., Takarada, T., Matsuo, K., Mizoguchi, T., Oohashi, T., Kuboki, T.

Journal of Bone and Mineral Research 34 ( 2 ) 327 - 332 2018年

必須アミノ酸Tryptophanは骨髄由来間葉系幹細胞の幹細胞性を制御し骨形成を促進する

大野充昭, Hai Pham, 笈田育尚, 小盛大志, 土佐郁恵, 大橋俊孝, 秋山謙太郎, 窪木拓男

日本口腔インプラント学会学術大会抄録集 47回 O - 7 2017年9月

本大学病院における口腔インプラント外科手術のための臨床応用解剖実習の取り組み

丸濱功太郎, 大野充昭, 秋山謙太郎, 大野彩, 笈田育尚, 三野卓哉, 前川賢治, 窪木拓男

日本口腔インプラント学会学術大会抄録集 47回 P - 20 2017年9月

創傷治癒過程における宿主骨髄由来間葉系幹細胞と炎症性サイトカイン

古味佳子, 秋山謙太郎, 吉岡裕也, 國友雅義, 國友由理, 大野充昭, 前川賢治, 窪木拓男

日本口腔インプラント学会学術大会抄録集 47回 P - 8 2017年9月

宿主年齢と骨髄由来間葉系幹細胞の機能

國友雅義, 秋山謙太郎, 古味佳子, 大野充昭, 前川賢治, 窪木拓男

日本補綴歯科学会誌 9 ( 特別号 ) 128 - 128 2017年6月

ヒト結合組織移植術後軟組織の組織学的評価

秋山謙太郎, 小田師巳, 中田光太郎, 三野卓哉, 園山亘, 荒川光, 窪木拓男

日本口腔インプラント学会誌 30 ( 2 ) E78 - E79 2017年6月

ヒト骨髄由来間葉系幹細胞および軟骨細胞の核内の染色体配置の解析の試み

大野充昭, 小盛大志, 土佐郁恵, 秋山謙太郎, 大野彩, 窪木拓男, 大橋俊孝

日本補綴歯科学会誌 9 ( 特別号 ) 271 - 271 2017年6月

高齢者の変化に応じた対応を考えた1症例

細川美鶴, 園山亘, 原博章, 秋山謙太郎, 窪木拓男

日本口腔インプラント学会学術大会抄録集 46回 O - 18 2016年9月

創傷治癒過程における宿主骨髄由来間葉系幹細胞がもたらす免疫寛容性とそのメカニズム

古味佳子, 秋山謙太郎, 吉岡裕也, 國友雅義, 小盛大志, 國友由理, 大野充昭, 前川賢治, 窪木拓男

日本補綴歯科学会誌 8 ( 特別号 ) 150 - 150 2016年7月

Ccn4欠損マウスを用いた関節軟骨創傷治癒におけるCCN4の役割の解明

吉岡裕也, 大野充昭, 前田あずさ, 秋山謙太郎, 園山亘, Young Marian F., 窪木拓男

日本補綴歯科学会誌 7 ( 特別号 ) 258 - 258 2015年5月

mTOR inhibition rescues osteopenia in mice with systemic sclerosis 査読

Chider Chen, Kentaro Akiyama, Dandan Wang, Xingtian Xu, Bei Li, Alireza Moshaverinia, Frank Brombacher, Lingyun Sun, Songtao Shi

JOURNAL OF EXPERIMENTAL MEDICINE 212 ( 1 ) 73 - 91 2015年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ROCKEFELLER UNIV PRESS

Fibrillin-1 (FBN1) deficiency-induced systemic sclerosis is attributed to elevation of interleukin-4 (IL4) and TGF-beta, but the mechanism underlying FBN1 deficiency-associated osteopenia is not fully understood. We show that bone marrow mesenchymal stem cells (BMMSCs) from FBN1-deficient (Fbn1(+/-)) mice exhibit decreased osteogenic differentiation and increased adipogenic differentiation. Mechanistically, this lineage alteration is regulated by IL4/IL4R alpha-mediated activation of mTOR signaling to down-regulate RUNX2 and up-regulate PPAR gamma 2, respectively, via P70 ribosomal S6 protein kinase (P70S6K). Additionally, we reveal that activation of TGF-beta/SMAD3/SP1 signaling results in enhancement of SP1 binding to the IL4R alpha promoter to synergistically activate mTOR pathway in Fbn1(+/-) BMMSCs. Blockage of mTOR signaling by osteoblastic-specific knockout or rapamycin treatment rescues osteopenia phenotype in Fbn1(+/-) mice by improving osteogenic differentiation of BMMSCs. Collectively, this study identifies a previously unrecognized role of the FBN1/TGF-beta/IL4R alpha/mTOR cascade in BMMSC lineage selection and provides experimental evidence that rapamycin treatment may provide an anabolic therapy for osteopenia in Fbn1(+/-) mice.

DOI： 10.1084/jem.20140643

Cell-based bone regeneration for alveolar ridge augmentation - Cell source, endogenous cell recruitment and immunomodulatory function 査読

Kaku, M., Akiba, Y., Akiyama, K., Akita, D., Nishimura, M.

Journal of Prosthodontic Research 59 ( 2 ) 96 - 112 2015年

Gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection: a case report. 査読国際誌

Omori K, Hanayama Y, Naruishi K, Akiyama K, Maeda H, Otsuka F, Takashiba S

Clinical case reports 2 ( 6 ) 286 - 295 2014年12月

血清中ビタミンCの欠乏が原因の一つと考える歯肉増殖症患者の歯周治療経過

河村麻理, 大森一弘, 秋山謙太郎, 下江正幸, 山本直史, 高柴正悟

岡山歯学会雑誌 33 ( 2 ) 41 - 42 2014年12月

軟骨分化におけるCCN4/WISP-1の機能解析

吉岡裕也, 大野充昭, 前田あずさ, 秋山謙太郎, 園山亘, 窪木拓男

日本補綴歯科学会誌 6 ( 特別号 ) 136 - 136 2014年5月

Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression 査読

Chider Chen, Kentaro Akiyama, Takayoshi Yamaza, Yong-Ouk You, Xingtian Xu, Bei Li, Yimin Zhao, Songtao Shi

EMBO MOLECULAR MEDICINE 6 ( 3 ) 322 - 334 2014年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Bone marrow mesenchymal stem cells (BMMSCs) are capable of differentiating into multiple cell types and regulating immune cell response. However, the mechanisms that govern the immunomodulatory properties of BMMSCs are still not fully elucidated. Here we show that telomerase-deficient BMMSCs lose their capacity to inhibit T cells and ameliorate the disease phenotype in systemic sclerosis mice. Restoration of telomerase activity by telomerase reverse transcriptase (TERT) transfection in TERT-/- BMMSCs rescues their immunomodulatory functions. Mechanistically, we reveal that TERT, combined with beta-catenin and BRG1, serves as a transcriptional complex, which binds the FAS ligand (FASL) promoter to upregulate FASL expression, leading to an elevated immunomodulatory function. To test the translational value of these findings in the context of potential clinical therapy, we used aspirin treatment to upregulate telomerase activity in BMMSCs, and found a significant improvement in the immunomodulatory capacity of BMMSCs. Taken together, these findings identify a previously unrecognized role of TERT in improving the immunomodulatory capacity of BMMSCs, suggesting that aspirin treatment is a practical approach to significantly reduce cell dosage in BMMSC-based immunotherapies.

DOI： 10.1002/emmm.201303000

Bone Regeneration Potential of Stem Cells Derived from Periodontal Ligament or Gingival Tissue Sources Encapsulated in RGD-Modified Alginate Scaffold 査読

Alireza Moshaverinia, Chider Chen, Xingtian Xu, Kentaro Akiyama, Sahar Ansari, Homayoun H. Zadeh, Songtao Shi

TISSUE ENGINEERING PART A 20 ( 3-4 ) 611 - 621 2014年2月

上顎洞底挙上術における大腸菌由来BMP-2/β-TCP複合体の有効性の検討

笈田育尚, 園山亘, 大野充昭, 新川重彦, 秋山謙太郎, 中島隆, 前川賢治, 窪木拓男

日本補綴歯科学会誌 6 ( 1 ) E5 - E5 2014年1月

Efficient bone formation in a swine socket lift model using Escherichia coli-derived recombinant human bone morphogenetic protein-2 adsorbed in β-tricalcium phosphate. 査読

Ono M, Sonoyama W, Yamamoto K, Oida Y, Akiyama K, Shinkawa S, Nakajima R, Pham HT, Hara ES, Kuboki T

Cells, tissues, organs 199 ( 4 ) 249 - 255 2014年

抜歯窩から採取した未分化間葉系幹細胞

Journal of Dental Research 93 ( 11 ) 1133 - 1140 2014年

Immunotherapy in Transplantation 査読

Kentaro Akiyama, Emilio Hara Satoshi, Takuo Kuboki

Stem Cell Biology and Tissue Engineering in Dental Sciences 831 2014年

Dental mesenchymal stem cells encapsulated in an alginate hydrogel co-delivery microencapsulation system for cartilage regeneration 査読

Alireza Moshaverinia, Xingtian Xu, Chider Chen, Kentaro Akiyama, Malcolm L. Snead, Songtao Shi

ACTA BIOMATERIALIA 9 ( 12 ) 9343 - 9350 2013年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI LTD

Dental-derived mesenchymal stem cells (MSCs) are promising candidates for cartilage regeneration, with a high capacity for chondrogenic differentiation. This property helps make dental MSCs an advantageous therapeutic option compared to current treatment modalities. The MSC delivery vehicle is the principal determinant for the success of MSC-mediated cartilage regeneration therapies. The objectives of this study were to: (1) develop a novel co-delivery system based on TGF-beta 1 loaded RGD-coupled alginate microspheres encapsulating periodontal ligament stem cells (PDLSCs) or gingival mesenchymal stem cells (GMSCs); and (2) investigate dental MSC viability and chondrogenic differentiation in alginate microspheres. The results revealed the sustained release of TGF-beta 1 from the alginate microspheres. After 4 weeks of chondrogenic differentiation in vitro, PDLSCs and GMSCs as well as human bone marrow mesenchymal stem cells (hBMMSCs) (as positive control) revealed chondrogenic gene expression markers (Col II and Sox-9) via qPCR, as well as matrix positively stained by Toluidine Blue and Safranin-O. In animal studies, ectopic cartilage tissue regeneration was observed inside and around the transplanted microspheres, confirmed by histochemical and immunofluorescent staining. Interestingly, PDLSCs showed more chondrogenesis than GMSCs and hBMMSCs (p < 0.05). Taken together, these results suggest that RGD-modified alginate microencapsulating dental MSCs make a promising candidate for cartilage regeneration. Our results highlight the vital role played by the microenvironment, as well as value of presenting inductive signals for viability and differentiation of MSCs. (C) 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.actbio.2013.07.023

Ossifying fibroma tumor stem cells are maintained by epigenetic regulation of a TSP1/TGF-β/SMAD3 autocrine loop. 査読国際誌

Qin H, Qu C, Yamaza T, Yang R, Lin X, Duan XY, Akiyama K, Liu Y, Zhang Q, Chen C, Chen Y, Qi HH, Feng XH, Le AD, Shi S

Cell stem cell 13 ( 5 ) 577 - 589 2013年11月

Encapsulated dental-derived mesenchymal stem cells in an injectable and biodegradable scaffold for applications in bone tissue engineering 査読

Alireza Moshaverinia, Chider Chen, Kentaro Akiyama, Xingtian Xu, Winston W. L. Chee, Scott R. Schricker, Songtao Shi

JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A 101 ( 11 ) 3285 - 3294 2013年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Bone grafts are currently the major family of treatment options in modern reconstructive dentistry. As an alternative, stem cell-scaffold constructs seem to hold promise for bone tissue engineering. However, the feasibility of encapsulating dental-derived mesenchymal stem cells in scaffold biomaterials such as alginate hydrogel remains to be tested. The objectives of this study were, therefore, to: (1) develop an injectable scaffold based on oxidized alginate microbeads encapsulating periodontal ligament stem cells (PDLSCs) and gingival mesenchymal stem cells (GMSCs); and (2) investigate the cell viability and osteogenic differentiation of the stem cells in the microbeads both in vitro and in vivo. Microbeads with diameters of 1 +/- 0.1 mm were fabricated with 2 x 10(6) stem cells/mL of alginate. Microbeads containing PDLSCs, GMSCs, and human bone marrow mesenchymal stem cells as a positive control were implanted subcutaneously and ectopic bone formation was analyzed by micro CT and histological analysis at 8-weeks postimplantation. The encapsulated stem cells remained viable after 4 weeks of culturing in osteo-differentiating induction medium. Scanning electron microscopy and X-ray diffraction results confirmed that apatitic mineral was deposited by the stem cells. In vivo, ectopic mineralization was observed inside and around the implanted microbeads containing the immobilized stem cells. These findings demonstrate for the first time that immobilization of PDLSCs and GMSCs in alginate microbeads provides a promising strategy for bone tissue engineering. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 3285-3294, 2013.

DOI： 10.1002/jbm.a.34546

Mesenchymal stem cells inhibit multiple myeloma cells via the Fas/Fas ligand pathway 査読

Ikiru Atsuta, Shiyu Liu, Yasuo Miura, Kentaro Akiyama, Chider Chen, Ying An, Songtao Shi, Fa-Ming Chen

STEM CELL RESEARCH & THERAPY 4 ( 5 ) 111 2013年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

Introduction: Cell-based therapy represents a new frontier in the treatment of a wide variety of human diseases traditionally associated with morbidity outcomes, including those involving inflammation, autoimmunity, tissue damage, and cancer. However, the use of mesenchymal stem cells (MSCs) to treat multiple myeloma (MM) bone disease has raised concerns. Specifically, evidence has shown that infused MSCs might support tumor growth and metastasis.
Methods: In this study, we used a standard disseminated MM model in mice to identify the in vivo effects of intravenous MSC infusion. In addition, a series of in vitro co-culture assays were preformed to explore whether Fas/Fas ligand (Fas-L) is involved in the inhibitory effects of MSCs on MM cells.
Results: In the MM mouse model, treatment of MSCs with highly expressed Fas ligand (Fas-Lhigh MSCs) showed remarkable inhibitory effects on MM indenization in terms of extending the mouse survival rate and inhibiting tumor growth, bone resorption in the lumbus and collum femoris, and MM cell metastasis in the lungs and kidneys. In addition, reduced proliferation and increased apoptosis of MM cells was observed when co-cultured with Fas-Lhigh MSCs in vitro. Furthermore, mechanistically, the binding between Fas and Fas-L significantly induced apoptosis in MM cells, as evidenced through an increase in the expression of apoptosis marker and Fas in MM cells. In contrast, Fas-Lnull MSCs promote MM growth.
Conclusions: These data suggest that Fas/Fas-L-induced MM apoptosis plays a crucial role in the MSC-based inhibition of MM growth. Although whether MSCs inhibit or promote cancer growth remains controversial, the levels of Fas-L expression in MSCs determine, at least partially, the effects of MSCs on MM cell growth.

DOI： 10.1186/scrt322

Co-encapsulation of anti-BMP2 monoclonal antibody and mesenchymal stem cells in alginate microspheres for bone tissue engineering 査読

Alireza Moshaverinia, Sahar Ansari, Chider Chen, Xingtian Xu, Kentaro Akiyama, Malcolm L. Snead, Homayoun H. Zadeh, Songtao Shi

BIOMATERIALS 34 ( 28 ) 6572 - 6579 2013年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI LTD

Recently, it has been shown that tethered anti-BMP2 monoclonal antibodies (mAbs) can trap BMP ligands and thus provide BMP inductive signals for osteo-differentiation of progenitor cells. The objectives of this study were to: (1) develop a co-delivery system based on murine anti-BMP2 mAb-loaded alginate microspheres encapsulating human bone marrow mesenchymal stem cells (hBMMSCs); and (2) investigate osteogenic differentiation of encapsulated stem cells in alginate microspheres in vitro and in vivo. Alginate microspheres of 1 +/- 0.1 mm diameter were fabricated with 2 x 10(6) hBMMSCs per mL of alginate. Critical-size calvarial defects (5 mm diameter) were created in immune-compromised mice and alginate microspheres preloaded with anti-BMP mAb encapsulating hBMMSCs were transplanted into defect sites. Alginate microspheres pre-loaded with isotype-matched non-specific antibody were used as the negative control. After 8 weeks, micro CT and histologic analyses were used to analyze bone formation. In vitro analysis demonstrated that anti-BMP2 mAbs tethered BMP2 ligands that can activate the BMP receptors on hBMMSCs. The co-delivery system described herein, significantly enhanced hBMMSC-mediated osteogenesis, as confirmed by the presence of BMP signal pathway-activated osteoblast determinants Runx2 and ALP. Our results highlight the importance of engineering the microenvironment for stem cells, and particularly the value of presenting inductive signals for osteo-differentiation of hBMMSCs by tethering BMP ligands using mAbs. This strategy of engineering the microenvironment with captured BMP signals is a promising modality for repair and regeneration of craniofacial, axial and appendicular bone defects. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.biomaterials.2013.05.048

IFN-γ and TNF-α synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFκB signaling. 査読

Wang L, Zhao Y, Liu Y, Akiyama K, Chen C, Qu C, Jin Y, Shi S

Stem cells (Dayton, Ohio) 31 ( 7 ) 1383 - 1395 2013年7月

Immune therapeutic potential of stem cells from human supernumerary teeth. 査読

Makino Y, Yamaza H, Akiyama K, Ma L, Hoshino Y, Nonaka K, Terada Y, Kukita T, Shi S, Yamaza T

Journal of dental research 92 ( 7 ) 609 - 615 2013年7月

Mesenchymal progenitors residing close to the bone surface are functionally distinct from those in the central bone marrow 査読

Valerie A. Siclari, Ji Zhu, Kentaro Akiyama, Fei Liu, Xianrong Zhang, Abhishek Chandra, Hyun-Duck Nah, Songtao Shi, Ling Qin

BONE 53 ( 2 ) 575 - 586 2013年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Long bone is an anatomically complicated tissue with trabecular-rich metaphyses at two ends and cortical-rich diaphysis at the center. The traditional flushing method isolates only mesenchymal progenitor cells from the central region of long bones and these cells are distant from the bone surface. We propose that mesenchymal progenitors residing in endosteal bone marrow that is close to the sites of bone formation, such as trabecular bone and endosteum, behave differently from those in the central bone marrow. In this report, we separately isolated endosteal bone marrow using a unique enzymatic digestion approach and demonstrated that it contained a much higher frequency of mesenchymal progenitors than the central bone marrow. Endosteal mesenchymal progenitors express common mesenchymal stem cell markers and are capable of multi-lineage differentiation. However, we found that mesenchymal progenitors isolated from different anatomical regions of the marrow did exhibit important functional differences. Compared with their central marrow counterparts, endosteal mesenchymal progenitors have superior proliferative ability with reduced expression of cell cycle inhibitors. They showed greater immunosuppressive activity in culture and in a mouse model of inflammatory bowel disease. Aging is a major contributing factor for trabecular bone loss. We found that old mice have a dramatically decreased number of endosteal mesenchymal progenitors compared with young mice. Parathyroid hormone (PTH) treatment potently stimulates bone formation. A single PTH injection greatly increased the number of endosteal mesenchymal progenitors, particularly those located at the metaphyseal bone, but had no effect on their central counterparts. In summary, endosteal mesenchymal progenitors are more metabolically active and relevant to physiological bone formation than central mesenchymal progenitors. Hence, they represent a biologically important target for future mesenchymal stem cell studies. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2012.12.013

A subset of IL-17(+) mesenchymal stem cells possesses anti-Candida albicans effect 査読

Ruili Yang, Yi Liu, Peyman Kelk, Cunye Qu, Kentaro Akiyama, Chider Chen, Ikiru Atsuta, WanJun Chen, Yanheng Zhou, Songtao Shi

CELL RESEARCH 23 ( 1 ) 107 - 121 2013年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：INST BIOCHEMISTRY & CELL BIOLOGY

Bone marrow mesenchymal stem cells (MSCs) comprise a heterogeneous population of postnatal progenitor cells with profound immunomodulatory properties, such as upregulation of Foxp3(+) regulatory T cells (Tregs) and downregulation of Th17 cells. However, it is unknown whether different MSC subpopulations possess the same range of immunomodulatory function. Here, we show that a subset of single colony-derived MSCs producing IL-17 is different from bulk MSC population in that it cannot upregulate Tregs, downregulate Th17 cells, or ameliorate disease phenotypes in a colitis mouse model. Mechanistically, we reveal that IL-17, produced by these MSCs, activates the NF kappa B pathway to downregulate TGF-beta production in MSCs, resulting in abolishment of MSC-based immunomodulation. Furthermore, we show that NF kappa B is able to directly bind to TGF-beta promoter region to regulate TGF-beta expression in MSCs. Moreover, these IL-17(+) MSCs possess anti-Candida albicans growth effects in vitro and therapeutic effect in C. albicans-infected mice. In summary, this study shows that MSCs contain an IL-17(+) subset capable of inhibiting C. albicans growth, but attenuating MSC-based immunosuppression via NF kappa B-mediated downregulation of TGF-beta.

DOI： 10.1038/cr.2012.179

Alginate hydrogel as a promising scaffold for dental-derived stem cells: an in vitro study 査読

Alireza Moshaverinia, Chider Chen, Kentaro Akiyama, Sahar Ansari, Xingtian Xu, Winston W. Chee, Scott R. Schricker, Songtao Shi

JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE 23 ( 12 ) 3041 - 3051 2012年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

The objectives of this study were to: (1) develop an injectable and biodegradable scaffold based on oxidized alginate microbeads encapsulating periodontal ligament (PDLSCs) and gingival mesenchymal stem cells (GMSCs); and (2) investigate the stem cell viability, and osteogenic differentiation of the stem cells in vitro. Stem cells were encapsulated using alginate hydrogel. The stem cell viability, proliferation and differentiation to adipogenic and osteogenic tissues were studied. To investigate the expression of both adipogenesis and ontogenesis related genes, the RNA was extracted and RT-PCR was performed. The degradation behavior of hydrogel based on oxidized sodium alginate with different degrees of oxidation was studied in PBS at 37 A degrees C as a function of time by monitoring the changes in weight loss. The swelling kinetics of alginate hydrogel was also investigated. The results showed that alginate is a promising candidate as a non-toxic scaffold for PDLSCs and GMSCs. It also has the ability to direct the differentiation of these stem cells to osteogenic and adipogenic tissues as compared to the control group in vitro. The encapsulated stem cells remained viable in vitro and both osteo-differentiated and adipo-differentiated after 4 weeks of culturing in the induction media. It was found that the degradation profile and swelling kinetics of alginate hydrogel strongly depends on the degree of oxidation showing its tunable chemistry and degradation rate. These findings demonstrate for the first time that immobilization of PDLSCs and GMSCs in the alginate microspheres provides a promising strategy for bone tissue engineering.

DOI： 10.1007/s10856-012-4759-3

Cryopreserved Dental Pulp Tissues of Exfoliated Deciduous Teeth Is a Feasible Stem Cell Resource for Regenerative Medicine 査読

Lan Ma, Yusuke Makino, Haruyoshi Yamaza, Kentaro Akiyama, Yoshihiro Hoshino, Guangtai Song, Toshio Kukita, Kazuaki Nonaka, Songtao Shi, Takayoshi Yamaza

PLOS ONE 7 ( 12 ) e51777 2012年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Human exfoliated deciduous teeth have been considered to be a promising source for regenerative therapy because they contain unique postnatal stem cells from human exfoliated deciduous teeth (SHED) with self-renewal capacity, multipotency and immunomodulatory function. However preservation technique of deciduous teeth has not been developed. This study aimed to evaluate that cryopreserved dental pulp tissues of human exfoliated deciduous teeth is a retrievable and practical SHED source for cell-based therapy. SHED isolated from the cryopreserved deciduous pulp tissues for over 2 years (25-30 months) (SHED-Cryo) owned similar stem cell properties including clonogenicity, self-renew, stem cell marker expression, multipotency, in vivo tissue regenerative capacity and in vitro immunomodulatory function to SHED isolated from the fresh tissues (SHED-Fresh). To examine the therapeutic efficacy of SHED-Cryo on immune diseases, SHED-Cryo were intravenously transplanted into systemic lupus erythematosus (SLE) model MRL/lpr mice. Systemic SHED-Cryo-transplantation improved SLE-like disorders including short lifespan, elevated autoantibody levels and nephritis-like renal dysfunction. SHED-Cryo amended increased interleukin 17-secreting helper T cells in MRL/lpr mice systemically and locally. SHED-Cryo-transplantation was also able to recover osteoporosis bone reduction in long bones of MRL/lpr mice. Furthermore, SHED-Cryo-mediated tissue engineering induced bone regeneration in critical calvarial bone-defect sites of immunocompromised mice. The therapeutic efficacy of SHED-Cryo transplantation on immune and skeletal disorders was similar to that of SHED-Fresh. These data suggest that cryopreservation of dental pulp tissues of deciduous teeth provide a suitable and desirable approach for stem cell-based immune therapy and tissue engineering in regenerative medicine. Citation: Ma L, Makino Y, Yamaza H, Akiyama K, Hoshino Y, et al. (2012) Cryopreserved Dental Pulp Tissues of Exfoliated Deciduous Teeth Is a Feasible Stem Cell Resource for Regenerative Medicine. PLoS ONE 7(12): e51777. doi:10.1371/journal.pone.0051777

DOI： 10.1371/journal.pone.0051777

Technetium-99 Conjugated with Methylene Diphosphonate Ameliorates Ovariectomy-Induced Osteoporotic Phenotype without Causing Osteonecrosis in the Jaw 査読

Yinghua Zhao, Lei Wang, Yi Liu, Kentaro Akiyama, Chider Chen, Ikiru Atsuta, Tao Zhou, Xiaohong Duan, Yan Jin, Songtao Shi

CALCIFIED TISSUE INTERNATIONAL 91 ( 6 ) 400 - 408 2012年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Technetium-99 conjugated with methylene diphosphonate (Tc-99-MDP) is a novel bisphosphonate derivative without radioactivity and has been successfully used to treat arthritis in China for years. Since bisphosphonate therapy has the potential to induce bisphosphonate-related osteonecrosis of the jaw (BRONJ), we examined whether Tc-99-MDP represents a new class of bisphosphonate for antiresorptive therapy to ameliorate estrogen deficiency-induced bone resorption with less risk of causing BRONJ. We showed that Tc-99-MDP-treated, ovariectomized (OVX) mice had significantly improved bone mineral density and trabecular bone volume in comparison to the untreated OVX group by inhibiting osteoclasts and enhancing osteogenic differentiation of bone marrow mesenchymal stem cells. To determine the potential of inducing BRONJ, Tc-99-MDP/dexamethasone (Dex) or zoledronate/Dex was administered into C57BL/6J mice via the tail vein, followed by extraction of maxillary first molars. Interestingly, Tc-99-MDP treatment showed less risk to induce osteonecrosis in the maxillary bones compared to zoledronate treatment group, partially because Tc-99-MDP neither suppressed adaptive regulatory T cells nor activated the inflammatory T-helper-producing interleukin-17 cells. Taken together, our findings demonstrate that Tc-99-MDP therapy may be a promising approach in the treatment of osteoporosis with less risk of causing BRONJ.

DOI： 10.1007/s00223-012-9649-7

大腸菌由来BMP-2を応用した骨形成能を有する骨補填材の開発

笈田育尚, 大野充昭, 新川重彦, 秋山謙太郎, 中島隆, 園山亘, 前川賢治, 窪木拓男

岡山歯学会雑誌 31 ( 2 ) 94 - 94 2012年12月

間葉系幹細胞経静脈移植におけるFas/Fas Ligandを介した宿主T細胞アポトーシス誘導

秋山謙太郎, シー・ソンタオ, 窪木拓男

日本再生歯科医学会誌 10 ( 1 ) 39 - 39 2012年12月

Characterization of bone marrow derived mesenchymal stem cells in suspension 査読

Kentaro Akiyama, Yong-Ouk You, Takayoshi Yamaza, Chider Chen, Liang Tang, Yan Jin, Xiao-Dong Chen, Stan Gronthos, Songtao Shi

STEM CELL RESEARCH & THERAPY 3 ( 5 ) 40 2012年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

Introduction: Bone marrow mesenchymal stem cells (BMMSCs) are a heterogeneous population of postnatal precursor cells with the capacity of adhering to culture dishes generating colony-forming unit-fibroblasts (CFU-F). Here we identify a new subset of BMMSCs that fail to adhere to plastic culture dishes and remain in culture suspension (S-BMMSCs).
Methods: To catch S-BMMSCs, we used BMMSCs-produced extracellular cell matrix (ECM)-coated dishes. Isolated S-BMMSCs were analyzed by in vitro stem cell analysis approaches, including flow cytometry, inductive multiple differentiation, western blot and in vivo implantation to assess the bone regeneration ability of S-BMMSCs. Furthermore, we performed systemic S-BMMSCs transplantation to treat systemic lupus erythematosus (SLE)-like MRL/lpr mice.
Results: S-BMMSCs are capable of adhering to ECM-coated dishes and showing mesenchymal stem cell characteristics with distinction from hematopoietic cells as evidenced by co-expression of CD73 or Oct-4 with CD34, forming a single colony cluster on ECM, and failure to differentiate into hematopoietic cell lineage. Moreover, we found that culture-expanded S-BMMSCs exhibited significantly increased immunomodulatory capacities in vitro and an efficacious treatment for SLE-like MRL/lpr mice by rebalancing regulatory T cells (Tregs) and T helper 17 cells (Th17) through high NO production.
Conclusions: These data suggest that it is feasible to improve immunotherapy by identifying a new subset BMMSCs.

DOI： 10.1186/scrt131

Stem cells in dentistry - Part II: Clinical applications 査読

Hiroshi Egusa, Wataru Sonoyama, Masahiro Nishimura, Ikiru Atsuta, Kentaro Akiyama

JOURNAL OF PROSTHODONTIC RESEARCH 56 ( 4 ) 229 - 248 2012年10月

記述言語：英語出版者・発行元：ELSEVIER IRELAND LTD

New technologies that facilitate solid alveolar ridge augmentation are receiving considerable attention in the field of prosthodontics because of the growing requirement for esthetic and functional reconstruction by dental implant treatments. Recently, several studies have demonstrated potential advantages for stem-cell-based therapies in regenerative treatments. Mesenchymal stem/stromal cells (MSCs) are now an excellent candidate for tissue replacement therapies, and tissue engineering approaches and chair-side cellular grafting approaches using autologous MSCs represent the clinical state of the art for stem-cell-based alveolar bone regeneration. Basic studies have revealed that crosstalk between implanted donor cells and recipient immune cells plays a key role in determining clinical success that may involve the recently observed immunomodulatory properties of MSCs. Part II of this review first overviews progress in regenerative dentistry to consider the implications of the stem cell technology in dentistry and then highlights cutting-edge stem-cell-based alveolar bone regenerative therapies. Factors that affect stem-cell-based bone regeneration as related to the local immune response are then discussed. Additionally, pre-clinical stem cell studies for the regeneration of teeth and other oral organs as well as possible applications of MSC-based immunotherapy in dentistry are outlined. Finally, the marketing of stem cell technology in dental stem cell banks with a view toward future regenerative therapies is introduced. (C) 2012 Japan Prosthodontic Society. Published by Elsevier Ireland. All rights reserved.

DOI： 10.1016/j.jpor.2012.10.001

Stem cells in dentistry - Part I: Stem cell sources 査読

Hiroshi Egusa, Wataru Sonoyama, Masahiro Nishimura, Ikiru Atsuta, Kentaro Akiyama

JOURNAL OF PROSTHODONTIC RESEARCH 56 ( 3 ) 151 - 165 2012年7月

記述言語：英語出版者・発行元：ELSEVIER IRELAND LTD

Stem cells can self-renew and produce different cell types, thus providing new strategies to regenerate missing tissues and treat diseases. In the field of dentistry, adult mesenchymal stem/stromal cells (MSCs) have been identified in several oral and maxillofacial tissues, which suggests that the oral tissues are a rich source of stem cells, and oral stem and mucosal cells are expected to provide an ideal source for genetically reprogrammed cells such as induced pluripotent stem (iPS) cells. Furthermore, oral tissues are expected to be not only a source but also a therapeutic target for stem cells, as stem cell and tissue engineering therapies in dentistry continue to attract increasing clinical interest. Part I of this review outlines various types of intra-and extra-oral tissue-derived stem cells with regard to clinical availability and applications in dentistry. Additionally, appropriate sources of stem cells for regenerative dentistry are discussed with regard to differentiation capacity, accessibility and possible immunomodulatory properties. (C) 2012 Japan Prosthodontic Society. Published by Elsevier Ireland. All rights reserved.

DOI： 10.1016/j.jpor.2012.06.001

間葉系幹細胞治療におけるFas/Fas Ligandを介したT細胞アポトーシス誘導

秋山謙太郎, 窪木拓男, シー・ソンタオ

日本骨代謝学会学術集会プログラム抄録集 30回 246 - 246 2012年7月

Mesenchymal-Stem-Cell-Induced Immunoregulation Involves FAS-Ligand-/FAS-Mediated T Cell Apoptosis 査読

Kentaro Akiyama, Chider Chen, DanDan Wang, Xingtian Xu, Cunye Qu, Takayoshi Yamaza, Tao Cai, WanJun Chen, Lingyun Sun, Songtao Shi

CELL STEM CELL 10 ( 5 ) 544 - 555 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：CELL PRESS

Systemic infusion of bone marrow mesenchymal stem cells (BMMSCs) yields therapeutic benefit for a variety of autoimmune diseases, but the underlying mechanisms are poorly understood. Here we show that in mice systemic infusion of BMMSCs induced transient T cell apoptosis via the FAS ligand (FASL)dependent FAS pathway and could ameliorate disease phenotypes in fibrillin-1 mutated systemic sclerosis (SS) and dextran-sulfate-sodium-induced experimental colitis. FASL(-/-) BMMSCs did not induce T cell apoptosis in recipients, and could not ameliorate SS and colitis. Mechanistic analysis revealed that FAS-regulated monocyte chemotactic protein 1 (MCP-1) secretion by BMMSCs recruited T cells for FASL-mediated apoptosis. The apoptotic T cells subsequently triggered macrophages to produce high levels of TGF beta, which in turn led to the upregulation of Ca4(+)CD25(+)Foxp3(+) regulatory T cells and, ultimately, immune tolerance. These data therefore demonstrate a previously unrecognized mechanism underlying BMMSC-based immunotherapy involving coupling via FAS/FASL to induce T cell apoptosis.

DOI： 10.1016/j.stem.2012.03.007

Double Allogenic Mesenchymal Stem Cells Transplantations Could Not Enhance Therapeutic Effect Compared with Single Transplantation in Systemic Lupus Erythematosus 査読

Dandan Wang, Kentaro Akiyama, Huayong Zhang, Takayoshi Yamaza, Xia Li, Xuebing Feng, Hong Wang, Bingzhu Hua, Bujun Liu, Huji Xu, Wanjun Chen, Songtao Shi, Lingyun Sun

CLINICAL & DEVELOPMENTAL IMMUNOLOGY 2012 273291 2012年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：HINDAWI PUBLISHING CORPORATION

The clinical trial of allogenic mesenchymal stem cells (MSCs) transplantation for refractory SLE patients has shown significant safety and efficacy profiles. However, the optimum frequency of the MSCs transplantation (MSCT) is unknown. This study was undertaken to observe whether double transplantations of MSCs is superior to single transplantation. Fifty-eight refractory SLE patients were enrolled in this study, in which 30 were randomly given single MSCT, and the other 28 were given double MSCT. Patients were followed up for rates of survival, disease remission, and relapse, as well as transplantation-related adverse events. SLE disease activity index (SLEDAI) and serologic features were evaluated. Our results showed that no remarkable differences between single and double allogenic MSCT were found in terms of disease remission and relapse, amelioration of disease activity, and serum indexes in an SLE clinical trial with more than one year followup. This study demonstrated that single MSCs transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE patients.

DOI： 10.1155/2012/273291

Lineage differentiation of mesenchymal stem cells from dental pulp, apical papilla, and periodontal ligament. 査読

Akiyama K, Chen C, Gronthos S, Shi S

Methods in molecular biology (Clifton, N.J.) 887 111 - 121 2012年

Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α. 査読

Liu Y, Wang L, Kikuiri T, Akiyama K, Chen C, Xu X, Yang R, Chen W, Wang S, Shi S

Nature medicine 17 ( 12 ) 1594 - U106 2011年12月

Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors 査読

Sara Parsa, Koh-ichi Kuremoto, Kerstin Seidel, Reza Tabatabai, BreAnne MacKenzie, Takayoshi Yamaza, Kentaro Akiyama, Jonathan Branch, Chester J. Koh, Denise Al Alam, Ophir D. Klein, Saverio Bellusci

DEVELOPMENT 137 ( 22 ) 3743 - 3752 2010年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：COMPANY OF BIOLOGISTS LTD

Rodent incisors regenerate throughout the lifetime of the animal owing to the presence of epithelial and mesenchymal stem cells in the proximal region of the tooth. Enamel, the hardest component of the tooth, is continuously deposited by stem cell-derived ameloblasts exclusively on the labial, or outer, surface of the tooth. The epithelial stem cells that are the ameloblast progenitors reside in structures called cervical loops at the base of the incisors. Previous studies have suggested that FGF10, acting mainly through fibroblast growth factor receptor 2b (FGFR2b), is crucial for development of the epithelial stem cell population in mouse incisors. To explore the role of FGFR2b signaling during development and adult life, we used an rtTA transactivator/tetracycline promoter approach that allows inducible and reversible attenuation of FGFR2b signaling. Downregulation of FGFR2b signaling during embryonic stages led to abnormal development of the labial cervical loop and of the inner enamel epithelial layer. In addition, postnatal attenuation of signaling resulted in impaired incisor growth, characterized by failure of enamel formation and degradation of the incisors. At a cellular level, these changes were accompanied by decreased proliferation of the transit-amplifying cells that are progenitors of the ameloblasts. Upon release of the signaling blockade, the incisors resumed growth and reformed an enamel layer, demonstrating that survival of the stem cells was not compromised by transient postnatal attenuation of FGFR2b signaling. Taken together, our results demonstrate that FGFR2b signaling regulates both the establishment of the incisor stem cell niches in the embryo and the regenerative capacity of incisors in the adult.

DOI： 10.1242/dev.051672

Cell-Based Immunotherapy With Mesenchymal Stem Cells Cures Bisphosphonate-Related Osteonecrosis of the Jaw-like Disease in Mice 査読

Takashi Kikuiri, Insoo Kim, Takyoshi Yamaza, Kentaro Akiyama, Qunzhou Zhang, Yunsheng Li, Chider Chen, WanJun Chen, Songlin Wang, Anh D. Le, Songtao Shi

JOURNAL OF BONE AND MINERAL RESEARCH 25 ( 7 ) 1668 - 1679 2010年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY

Patients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ-like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ-like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T-helper-producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ-like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate- and dexamethasone-treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity-based mechanism of BRONJ-like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. (C) 2010 American Society for Bone and Mineral Research.

DOI： 10.1002/jbmr.37

Immunomodulatory properties of stem cells from human exfoliated deciduous teeth 査読

Takayoshi Yamaza, Akiyama Kentaro, Chider Chen, Yi Liu, Yufang Shi, Stan Gronthos, Songlin Wang, Songtao Shi

STEM CELL RESEARCH & THERAPY 1 ( 1 ) 5 2010年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

Introduction: Stem cells from human exfoliated deciduous teeth (SHED) have been identified as a population of postnatal stem cells capable of differentiating into osteogenic and odontogenic cells, adipogenic cells, and neural cells. Herein we have characterized mesenchymal stem cell properties of SHED in comparison to human bone marrow mesenchymal stem cells (BMMSCs).
Methods: We used in vitro stem cell analysis approaches, including flow cytometry, inductive differentiation, telomerase activity, and Western blot analysis to assess multipotent differentiation of SHED and in vivo implantation to assess tissue regeneration of SHED. In addition, we utilized systemic SHED transplantation to treat systemic lupus erythematosus (SLE)-like MRL/lpr mice.
Results: We found that SHED are capable of differentiating into osteogenic and adipogenic cells, expressing mesenchymal surface molecules (STRO-1, CD146, SSEA4, CD73, CD105, and CD166), and activating multiple signaling pathways, including TGF beta, ERK, Akt, Wnt, and PDGF. Recently, BMMSCs were shown to possess an immunomodulatory function that leads to successful therapies for immune diseases. We examined the immunomodulatory properties of SHED in comparison to BMMSCs and found that SHED had significant effects on inhibiting T helper 17 (Th17) cells in vitro. Moreover, we found that SHED transplantation is capable of effectively reversing SLE-associated disorders in MRL/lpr mice. At the cellular level, SHED transplantation elevated the ratio of regulatory T cells (Tregs) via Th17 cells.
Conclusions: These data suggest that SHED are an accessible and feasible mesenchymal stem cell source for treating immune disorders like SLE.

DOI： 10.1186/scrt5

Simvastatin Induces the Odontogenic Differentiation of Human Dental Pulp Stem Cells In Vitro and In Vivo 査読

Yosuke Okamoto, Wataru Sonoyama, Mitsuaki Ono, Kentaro Akiyama, Takuo Fujisawa, Masamitstu Oshima, Yohei Tsuchimoto, Yoshizo Matsuka, Tatsuji Yasuda, Songtao Shi, Takuo Kuboki

JOURNAL OF ENDODONTICS 35 ( 3 ) 367 - 372 2009年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Statin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is known to promote bone formation. However, it is not clear whether statin affects the differentiation of pulp cells. This study used a cell proliferation assay, cell cycle analysis, quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and in vivo transplantation to examine the effects of simvastatin on human dental pulp stem cells (DPSCs) in vitro and in vivo. Simvastatin at 1 mu mol/L was able to significantly suppress the proliferation of DPSCs without inducing apoptosis. Quantitative RT-PCR revealed both osteocalcin and dentin sialophosphoprotein to be significantly up-regulated when DPSCs were cultured with simvastatin in comparison to bone morphogenetic protein-2 treatment. The in vivo transplantation data showed that simvastatin treatment promoted mineralized tissue formation. Taken together, these results suggest that statin might be an ideal active ingredient to accelerate the differentiation of DPSCs. (J Endod 2009;35:367-372)

DOI： 10.1016/j.joen.2008.11.024

Mesenchymal stem cell-mediated ectopic hematopoiesis alleviates aging-related phenotype in immunocompromised mice 査読

Takayoshi Yamaza, Yasuo Miura, Kentaro Akiyama, Yanming Bi, Wataru Sonoyama, Stan Gronthos, WanJun Chen, Anh Le, Songtao Shi

BLOOD 113 ( 11 ) 2595 - 2604 2009年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC HEMATOLOGY

Subcutaneous transplants of bone marrow mesenchymal stem cells (BMMSCs) are capable of generating ectopic bone and organizing functional hematopoietic marrow elements in animal models. Here we report that immunocompromised mice received subcutaneous BMMSC transplants using hydroxyapatite tricalcium phosphate as a carrier suppressed age-related degeneration in multiple organs and benefited an increase in life span extension compared with control littermates. The newly organized ectopic bone/marrow system restores active hematopoiesis via the erythropoietin receptor/signal transducer and activator of transcription 5 (Stat5) pathway. Furthermore, the BMMSC recipient mice showed elevated level of Klotho and suppression of insulin-like growth factor I signaling, which may be the mechanism contributing to the alleviation of aging-like phenotypes and prolongation of life in the treated mice. This work reveals that erythropoietin receptor/Stat5 pathway contributes to BMMSC-organized ectopic hematopoiesis, which may offer a treatment paradigm of reversing age-related degeneration of multiple organs in adult immunocompromised mice. (Blood.2009;113:2595-2604)

DOI： 10.1182/blood-2008-10-182246

Simvastatin induces the odontogenic differentiation of human dental pulp stem cells in vitro and in vivo. 査読

Yosuke Okamoto, Wataru Sonoyama, Mitsuaki Ono, Kentaro Akiyama, Takuo Fujisawa, Masamitsu Oshima, Yohei Tsuchimoto, Yoshizo Matsuka, Tatsuji Yasuda, Songtao Shi, Takuo Kuboki

Journal of Endodontics Vol.35 ( No.3 ) 367 - 372 2009年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Statin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is known to promote bone formation. However, it is not clear whether statin affects the differentiation of pulp cells. This study used a cell proliferation assay, cell cycle analysis, quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and in vivo transplantation to examine the effects of simvastatin on human dental pulp stem cells (DPSCs) in vitro and in vivo. Simvastatin at 1 mumol/L was able to significantly suppress the proliferation of DPSCs without inducing apoptosis. Quantitative RT-PCR revealed both osteocalcin and dentin sialophosphoprotein to be significantly up-regulated when DPSCs were cultured with simvastatin in comparison to bone morphogenetic protein-2 treatment. The in vivo transplantation data showed that simvastatin treatment promoted mineralized tissue formation. Taken together, these results suggest that statin might be an ideal active ingredient to accelerate the differentiation of DPSCs.

DOI： 10.1016/j.joen.2008.11.024

Mesenchymal Stem Cell Transplantation Reverses Multiorgan Dysfunction in Systemic Lupus Erythematosus Mice and Humans 査読

Lingyun Sun, Kentaro Akiyama, Huayong Zhang, Takayoshi Yamaza, Yayi Hou, Shengnan Zhao, Ting Xu, Anh Le, Songtao Shi

STEM CELLS 27 ( 6 ) 1421 - 1432 2009年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ALPHAMED PRESS

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that, despite the advances in immunosuppressive medical therapies, remains potentially fatal in some patients, especially in treatment-refractory patients. Here, we reported that impairment of bone marrow mesenchymal stem cells (BMMSCs) and their associated osteoblastic niche deficiency contribute in part to the pathogenesis of SLE-like disease in MRL/lpr mice. Interestingly, allogenic BMMSC transplantation (MSCT) is capable of reconstructing the bone marrow osteoblastic niche and more effectively reverses multiorgan dysfunction when compared with medical immunosuppression with cyclophosphamide (CTX). At the cellular level, MSCT, not CTX treatment, was capable to induce osteoblastic niche reconstruction, possibly contributing to the recovery of regulatory T-cells and reestablishment of the immune homeostasis. On the basis of the promising clinical outcomes in SLE mice, we treated four CTX/glucocorticoid treatment-refractory SLE patients using allogenic MSCT and showed a stable 12-18 months disease remission in all treated patients. The patients benefited an amelioration of disease activity, improvement in serologic markers and renal function. These early evidences suggest that allogenic MSCT may be a feasible and safe salvage therapy in refractory SLE patients. STEM CELLS 2009;27:1421-1432

DOI： 10.1002/stem.68

Is aspirin treatment an appropriate intervention to osteoporosis? 査読国際誌

Shi S, Yamaza T, Akiyama K

Future rheumatology 3 ( 6 ) 499 - 502 2008年12月

Pharmacologic Stem Cell Based Intervention as a New Approach to Osteoporosis Treatment in Rodents 査読

Takayoshi Yamaza, Yasuo Miura, Yanming Bi, Yongzhong Liu, Kentaro Akiyama, Wataru Sonoyama, Voymesh Patel, Silvio Gutkind, Marian Young, Stan Gronthos, Anh Le, Cun-Yu Wang, WanJun Chen, Songtao Shi

PLOS ONE 3 ( 7 ) e2615 2008年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Background: Osteoporosis is the most prevalent skeletal disorder, characterized by a low bone mineral density (BMD) and bone structural deterioration, leading to bone fragility fractures. Accelerated bone resorption by osteoclasts has been established as a principal mechanism in osteoporosis. However, recent experimental evidences suggest that inappropriate apoptosis of osteoblasts/osteocytes accounts for, at least in part, the imbalance in bone remodeling as occurs in osteoporosis. The aim of this study is to examine whether aspirin, which has been reported as an effective drug improving bone mineral density in human epidemiology studies, regulates the balance between bone resorption and bone formation at stem cell levels.
Methods and Findings: We found that T cell-mediated bone marrow mesenchymal stem cell (BMMSC) impairment plays a crucial role in ovariectomized-induced osteoporosis. Ex vivo mechanistic studies revealed that T cell-mediated BMMSC impairment was mainly attributed to the apoptosis of BMMSCs via the Fas/Fas ligand pathway. To explore potential of using pharmacologic stem cell based intervention as an approach for osteoporosis treatment, we selected ovariectomy (OVX)-induced ostoeporosis mouse model to examine feasibility and mechanism of aspirin-mediated therapy for osteoporosis. We found that aspirin can inhibit T cell activation and Fas ligand induced BMMSC apoptosis in vitro. Further, we revealed that aspirin increases osteogenesis of BMMSCs by aiming at telomerase activity and inhibits osteoclast activity in OVX mice, leading to ameliorating bone density.
Conclusion: Our findings have revealed a novel osteoporosis mechanism in which activated T cells induce BMMSC apoptosis via Fas/Fas ligand pathway and suggested that pharmacologic stem cell based intervention by aspirin may be a new alternative in osteoporosis treatment including activated osteoblasts and inhibited osteoclasts.

DOI： 10.1371/journal.pone.0002615

SHED repair critical-size calvarial defects in mice 査読

B. M. Seo, W. Sonoyama, T. Yamaza, C. Coppe, T. Kikuiri, K. Akiyama, J. S. Lee, S. Shi

ORAL DISEASES 14 ( 5 ) 428 - 434 2008年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

OBJECTIVE: Stem cells from human exfoliated deciduous teeth (SHED) are a population of highly proliferative postnatal stem cells capable of differentiating into odontoblasts, adipocytes, neural cells, and osteo-inductive cells. To examine whether SHED-mediated bone regeneration can be utilized for therapeutic purposes, we used SHED to repair critical-size calvarial defects in immunocompromised mice.
MATERIALS AND METHODS: We generated calvarial defects and transplanted SHED with hydroxyapatite/tricalcium phosphate as a carrier into the defect areas.
RESULTS: SHED were able to repair the defects with substantial bone formation. Interestingly, SHED-mediated osteogenesis failed to recruit hematopoietic marrow elements that are commonly seen in bone marrow mesenchymal stem cell-generated bone. Furthermore, SHED were found to co-express mesenchymal stem cell marker, CC9/MUC18/CD146, with an array of growth factor receptors such as transforming growth factor beta receptor I and II, fibroblast growth factor receptor I and III, and vascular endothelial growth factor receptor I, implying their comprehensive differentiation potential.
CONCLUSIONS: Our data indicate that SHED, derived from neural crest cells, may select unique mechanisms to exert osteogenesis. SHED might be a suitable resource for orofacial bone regeneration.

DOI： 10.1111/j.1601-0825.2007.01396.x

骨再生における結合組織成長因子CCN2/CTGFの効果多機能成長因子を用いた新たな骨再生療法確立に向けて

大野充昭, 園山亘, 秋山謙太郎, 大島正充, 窪木拓男

日本口腔インプラント学会誌 21 ( 1 ) 78 - 78 2008年3月

Promotion of hydroxyapatite-associated, stem cell-based bone regeneration by CCN2 査読

Mitsuaki Ono, Satoshi Kubota, Takuo Fujisawa, Wataru Sonoyama, Harumi Kawakij, Kentaro Akiyama, Kengo Shimono, Masarnitsu Oshima, Takashi Nishida, Yasuhiro Yoshida, Kazuomi Suzuki, Masaharu Takigawa, Takuo Kuboki

CELL TRANSPLANTATION 17 ( 1-2 ) 231 - 240 2008年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：COGNIZANT COMMUNICATION CORP

Multiple roles have been already recognized for CCN2 in cartilage development and regeneration. However, the effects of CCN2 on bone regeneration remain to be elucidated. In this study, the utility of CCN2 on bone regeneration was examined in vitro and in vivo in combination with hydroxyapatite (HAp) as a scaffold. Human bone marrow stromal cells (hBMSCs) were isolated from human iliac bone marrow aspirates of healthy donors and expanded, and the effects of CCN2 on their proliferation and migration were examined in vitro. The proliferation of hBMSCs on a plastic or HAp plate was significantly enhanced by CCN2. Moreover, the migration of hBMSCs also dramatically increased by CCN2. Interestingly, a C-terminal signal modular fragment of CCN2 (CT-module) also enhanced the cell proliferation and migration as efficiently as the full-length CCN2. Next, in order to estimate the effect of CCN2 on the migration and survival of hBMSCs and bone formation inside the HAp scaffold in vivo, two experiments were performed. First, the porous HAp carrier was cultured with hBMSCs for a week, and the cell-scaffold hybrid was transplanted with or without CCN2 subcutaneously into immunocompromised mice. CCN2 accelerated the hBMSC-like cell migration and survival inside the porous HAp within 4 weeks after transplantation. Second, the porous HAp carrier with or without CCN2 was directly implanted into bone defects within a rabbit mandible, and bone regeneration inside was evaluated. As a result, CCN2 efficiently induced the cell invasion and bone formation inside the porous HAp scaffold. These findings suggest that CCN2 and its CT-module fragment could be useful for regeneration and reconstruction of large-scale bone defects.

DOI： 10.3727/000000008783907143

ハイドロキシアパタイトを援用した骨再生におけるCCN2/CTGFの効果

大島正充, 大野充昭, 久保田聡, 藤澤拓生, 園山亘, 秋山謙太郎, 川木晴美, 西田崇, 滝川正春, 窪木拓男

日本骨代謝学会学術集会プログラム抄録集 25回 254 - 254 2007年6月

Promotion of attachment of human bone marrow stromal cells by CCN2 査読

Mitsuaki Ono, Satoshi Kubota, Takuo Fujisawa, Wataru Sonoyama, Harumi Kawaki, Kentaro Akiyama, Masamitsu Oshima, Takashi Nishida, Yasuhlro Yoshida, Kazuomi Suzuki, Masaharu Takigawa, Takuo Kuboki

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 357 ( 1 ) 20 - 25 2007年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Cell attachment is a crucial step in tissue regeneration. In this study, human bone marrow stromal cells (hBMSCs) were isolated, and the effects of CCN2 on their attachment were examined. CCN2 significantly enhanced the hBMSC attachment, and this enhanced cell attachment was mainly regulated by the C-terminal module of CCN2. This enhancement was negated by the anti-integrin alpha(v)beta(3) antibody and p38 MAPK inhibitor, and phosphorylation of p38 MAPK was detected upon the enhanced cell attachment mediated by CCN2. We thus conclude that CCN2 enhances hBMSC attachment via integrin-p38 MAPK signal pathway. Enhanced hBMSC attachment on hydroxyapatite plates by CCN2 further indicated the utility of CCN2 in bone regeneration. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.03.052

骨芽細胞様細胞(MC3T3E1)分化に対するチタンの影響

秋山謙太郎, 藤澤拓生, 明貝文夫, 大野充明, 吉田靖弘, 高柴正悟, 鈴木一臣, 窪木拓男

日本骨代謝学会学術集会プログラム抄録集 24回 229 - 229 2006年7月

結合組織成長因子CCN2/CTGFによる骨髄由来間質細胞の細胞接着、遊走の亢進とシグナル伝達経路の活性化

大野充昭, 藤澤拓生, 久保田聡, 園山亘, 秋山謙太郎, 西田崇, 滝川正春, 窪木拓男

日本骨代謝学会学術集会プログラム抄録集 24回 248 - 248 2006年7月

骨芽細胞様細胞株(MC3T3E1細胞)の細胞接着,増殖,分化および遺伝子発現に対するチタンの影響

秋山謙太郎, 藤澤拓生, 明貝文夫, 完山学, 吉田靖弘, 高柴正悟, 鈴木一臣, 窪木拓男

日本口腔インプラント学会誌 19 ( 1 ) 32 - 32 2006年3月

結合組織成長因子CCN2/CTGF/Hcs24はヒト骨髄由来間質細胞の細胞接着を促進させる

大野充昭, 園山亘, 藤澤拓生, 秋山謙太郎, 前川賢治, 完山学, 西田崇, 久保田聡, 滝川正春, 窪木拓男

日本骨代謝学会学術集会プログラム抄録集 23回 225 - 225 2005年6月

ヒト歯髄細胞の細胞接着,増殖,分化に与える各種成長因子ならびにアパタイトの影響

園山亘, 大野充昭, 秋山謙太郎, 藤沢拓生, 窪木拓男

日本補綴歯科学会雑誌 48 ( 111回特別 ) 211 - 211 2004年5月

Connective tissue growth factor expressed in rat alveolar bone regeneration sites after tooth extraction 査読

M Kanyama, T Kuboki, K Akiyama, K Nawachi, FM Miyauchi, H Yatani, S Kubota, T Nakanishi, M Takigawa

ARCHIVES OF ORAL BIOLOGY 48 ( 10 ) 723 - 730 2003年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Objective: To understand bone regeneration process after tooth extraction could be a clue to develop a new strategy for alveolar bone reconstruction. Recently, accumulated evidences support that connective tissue growth factor (CTGF) is implicated in tissue repair of many tissues. In this study, we investigated the spatial and temporal expression of CTGF in the rat tooth extraction sockets. Design: Five weeks old wild type mate rats (weighing 120 g) were used for this experiment. Expression of CTGF was determined by immunohistochemistry and in situ hybridization in the rat upper molar tooth extraction sockets at 2, 4, 7, 10 and 14 days after tooth extraction. Results: CTGF was expressed strongly in the endothelial. cells migrating into the granulation tissue at the bottom of the sockets during 4 days after tooth extraction. During the reparative process, no apparent chondrocyte-like cell appeared in the sockets, while osteoblast-like cells proliferated in the sockets with low CTGF expression at 7, 10, 14 days after extraction. As expected, no staining was observed with the preimmune rabbit IgG and CTGF sense probe. CTGF may play an important rote in angiogenesis and granulation tissue formation specifically at early heating stage after tooth extraction to initiate alveolar bone repair. Conclusion: CTGF was expressed at early heating stage of the rat tooth extraction wound. (C) 2003 Elsevier Ltd. All. rights reserved.

DOI： 10.1016/S0003-9969(03)00153-5

Cbfa1/Runx2 gene expression in articular chondrocytes of the mice temporomandibular and knee joints in vivo 査読

T Kuboki, M Kanyama, T Nakanishi, K Akiyama, K Nawachi, H Yatani, K Yamashita, T Takano-Yamamoto, M Takigawa

ARCHIVES OF ORAL BIOLOGY 48 ( 7 ) 519 - 525 2003年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Healthy articular cartilage is thought to be maintained by the modulation of Cbfa1 expression, although little is currently known about Cbfa1 expression in such tissues. Therefore, we examined in vivo Cbfa1 transcript levels in the temporomandibular (TM) and knee joints of 3- and 10-week-old mate ICR mice (weighing 50-70 g). A digoxigenin-11-UTP-labeled single-stranded RNA probe (0.6 kbp PstI-HindIII fragment of the 3' of untranslated region in exon 8 of mouse Cbfa1 cDNA) was prepared and in situ hybridization was performed on paraffin-embedded TM and knee joint sections. The antisense probe detected Cbfa1 transcripts in prehypertrophic chondrocytes, but not in the articular surface layer chondrocytes, of 3- and 10-week-old mice TMJs. Despite the intense Cbfa1 expression in prehypertrophic chondrocytes, articular surface layer chondrocytes of the knee joints expressed tow and undetectable level of Cbfa1 in the 3- and 10-week-old mice, respectively. These results indicate that Cbfa1 are highly expressed in the prehypertrophic chondrocytes presumably for articular tissue remodeling during the entire lifespan of the mouse, whereas Cbfa1 expression is suppressed in the articular surface chondrocytes in the adult mouse TM and knee joints to obtain the permanent cartilage phenotype. (C) 2003 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0003-9969(03)00088-8

顎関節ならびに膝関節の関節軟骨におけるCbfα1/Runx2遺伝子の発現

窪木拓男, 完山学, 中西徹, 秋山謙太郎, 縄稚久美子, 矢谷博文, 山下和夫, 山本照子, 滝川正春

日本顎関節学会雑誌 15 ( 1 ) 112 - 112 2003年4月

日本人を対象にした口腔インプラント生存に関するメタアナリシス

吹田猛, 荒川光, 窪木拓男, 秋山謙太郎, 縄稚梢, 小島俊司, 園山亘, 完山学, 矢谷博文

日本口腔インプラント学会誌 16 ( 1 ) 164 - 165 2003年3月

オッセオインテグレーションの獲得と維持からみたオッセオインテグレーテッドインプラントの予後

完山学, 荒川光, 園山亘, 小島俊司, 秋山謙太郎, 窪木拓男, 矢谷博文

日本口腔インプラント学会誌 15 ( 1 ) 153 - 153 2002年3月

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