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Takashima, Shinichiro ; Usui, Soichiro ; Inoue, Oto ; Goten, Chiaki ; Yamaguchi, Kosei ; Takeda, Yusuke ; Cui, Shihe ; Sakai, Yoshio ; Hayashi, Kenshi ; Sakata, Kenji ; Kawashiri, Masa-aki ; Takamura, Masayuki ; 高島, 伸一郎 ; 薄井, 荘一郎 ; 井上, 己音 ; 林, 研至 ; 川尻, 剛照 ; 高村, 雅之
概要:
Cardiomyocyte regeneration is limited in adults. The adipose tissue-derived stromal vascular fraction (Ad-SVF) contains
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pluripotent stem cells that rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the characteristics of beating CMs and the factors that regulate the differentiation of Ad-SVF toward the cardiac lineage are unknown. We developed a simple culture protocol under which the adult murine inguinal Ad-SVF reproducibly transdifferentiates into beating CMs without induction. The beating CMs showed the striated ventricular phenotype of cardiomyocytes and synchronised oscillation of the intracellular calcium concentration among cells on day 28 of Ad-SVF primary culture. We also identified beating CM-fated progenitors (CFPs) and performed single-cell transcriptome analysis of these CFPs. Among 491 transcription factors that were differentially expressed (≥ 1.75-fold) in CFPs and the beating CMs, myocyte-specific enhancer 2c (Mef2c) was key. Transduction of Ad-SVF cells with Mef2c using a lentiviral vector yielded CFPs and beating CMs with ~ tenfold higher cardiac troponin T expression, which was abolished by silencing of Mef2c. Thus, we identified the master gene required for transdifferentiation of Ad-SVF into beating CMs. These findings will facilitate the development of novel cardiac regeneration therapies based on gene-modified, cardiac lineage-directed Ad-SVF cells.
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| 2.
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Takashima, Shinichiro ; Sugimoto, Naotoshi ; Takuwa, Noriko ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Takamura, Masayuki ; Takata, Shigeo ; Kaneko, Shuichi ; Takuwa, Yoh
概要:
金沢大学医薬保健研究域医学系<br />Aims: The lysophospholipid mediator sphingosine-1-phosphate (S1P) activates G protein-coupled recept
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ors (GPCRs) to induce potent inhibition of platelet-derived growth factor (PDGF)-induced Rac activation and, thereby, chemotaxis in rat vascular smooth muscle cells (VSMCs). We explored the heterotrimeric G protein and the downstream mechanism that mediated S1P inhibition of Rac and cell migration in VSMCs. Methods and results: S1P inhibition of PDGF-induced cell migration and Rac activation in VSMCs was abolished by the selective S1P2 receptor antagonist JTE-013. The C-terminal peptides of Gα subunits (Gα-CTs) act as specific inhibitors of respective G protein-GPCR coupling. Adenovirus-mediated expression of Gα12-CT, Gα13-CT, and Gα q-CT, but not that of Gαs-CT or LacZ or pertussis toxin treatment, abrogated S1P inhibition of PDGF-induced Rac activation and migration, indicating that both G12/13 and Gq classes are necessary for the S1P inhibition. The expression of Gαq-CT as well as Gα12-CT and Gα13-CT also abolished S1P-induced Rho stimulation. C3 toxin, but not a Rho kinase inhibitor or a dominant negative form of Rho kinase, abolished S1P inhibition of PDGF-induced Rac activation and cell migration. The angiotensin II receptor AT1, which robustly couples to Gq, did not mediate either Rho activation or inhibition of PDGF-induced Rac activation or migration, suggesting that activation of Gq alone was not sufficient for Rho activation and resultant Rac inhibition. However, the AT1 receptor fused to Gα12 was able to induce not only Rho stimulation but also inhibition of PDGF-induced Rac activation and migration. Phospholipase C inhibition did not affect S1P-induced Rho activation, and protein kinase C activation by a phorbol ester did not mimic S1P action, suggesting that S1P inhibition of migration or Rac was not dependent on the phospholipase C pathway. Conclusion: These observations together suggest that S1P2 mediates inhibition of Rac and migration through the coordinated action of G 12/13 and Gq for Rho activation in VSMCs. © The Author 2008..
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| 3.
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Katsuki, Tomonori ; Furusho, Hiroshi ; Kusayama, Takashi ; Takashima, Shinichiro ; Kato, Takeshi ; Murai, Hisayoshi ; Usui, Soichiro ; Kaneko, Shuichi ; Takamura, Masayuki
概要:
Many Riata (St. Jude Medical, St. Paul, MN, USA) implantable cardioverter defibrillator (ICD) leads have reportedly deve
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loped cable externalization. The most likely cause of cable externalization is insulation abrasion, which often occurs at the can or between the right ventricular coil and superior vena cava (SVC) coil. We report a rare case of an adult male whose ICD lead cable was externalized at the proximal portion of the SVC coil. This lead became fixed to the wall at the subclavian vein and SVC and became bent between these adhesions. Furthermore, the motion of this lead was affected by pulsation of the aortic arch. The ICD lead might develop inside-out abrasion due to mechanical stress evoked by pulsation of the aortic arch at this site.<. Learning objective: Cable externalization of the implantable cardioverter defibrillator lead at the proximal portion of the superior vena cava (SVC) coil has rarely been reported. Externalization might be the result of deformation of the left brachiocephalic vein and the anatomical relationship with the aortic arch. The anatomical pathway of the lead should be carefully considered during the procedure, especially when a dual-coil lead is selected. Moreover, possible cable externalization at both the proximal and distal portions of the SVC coil should be kept in mind during follow-up>. © 2016 Japanese College of Cardiology.<br />Embargo Period 12 months
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Hamaoka, Takuto ; Omi, Wataru ; Sekiguti, Yoshiteru ; Takata, Shigeo ; Kaneko, Shuichi ; Inoue, Oto ; Takashima, Shinichiro ; Murai, Hisayoshi ; Usui, Soichiro ; Kato, Takeshi ; Furusho, Hiroshi ; Takamura, Masayuki
概要:
Background: Intestinal angina is characterized by recurrent postprandial abdominal pain and anorexia. Commonly, these sy
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mptoms are caused by severe stenosis of at least two vessels among the celiac and mesenteric arteries. However, intestinal perfusion is affected not only by the degree of arterial stenosis but also by systemic perfusion. We experienced a unique case of intestinal angina caused by relatively mild stenosis of the abdominal arteries complicated with hypertrophic obstructive cardiomyopathy. Case presentation: We report an 86-year old Japanese man with hypertrophic obstructive cardiomyopathy and advanced atrioventricular block who was diagnosed with intestinal angina. Computed tomography showed mild stenosis of the celiac artery and severe stenosis of the inferior mesenteric artery, and these lesions were relatively mild compared with other reports. A dual-chamber pacemaker with right ventricular apical pacing was implanted to improve the obstruction of the left ventricular outflow tract. After implantation, the patient's abdominal symptoms diminished markedly, and improvement of the left ventricular outflow tract obstruction was observed. Conclusions: Although intestinal angina is generally defined by severe stenosis of at least two vessels among the celiac and mesenteric arteries, the present case suggests that hemodynamic changes can greatly affect intestinal perfusion and induce intestinal angina in the presence of mild stenosis of the celiac and mesenteric arteries. © 2016 The Author(s).
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高島, 伸一郎 ; Takashima, Shinichiro
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金沢大学附属病院<br />心血管疾患に対する待機的手術を受けた患者17例を対象に、手術時に得た余剰皮下脂肪組織1-2gを酵素処理し、フローサイトメトリー法にて皮下脂肪組織由来間葉系幹細胞のプロファイリングを施行し、背景疾患との関連を検討し
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た。17例の平均年齢は72歳(男性は12例)、背景疾患の内訳は高血圧94%、脂質異常77%、糖尿病59%であった。左室駆出分画が40%未満の低心機能患者は24％であった。注目すべきことに再生治療効果が高いとされるCD271陽性細胞の含有比率は症例ごとに特に大きなばらつきを認め、個々の背景が皮下脂肪組織由来間葉系幹細胞プロファイリングに影響し、治療効果に影響を及ぼす可能性が示された。<br />The problem of autologous stem cell therapy for cardiovascular disease is that a large variability of therapeutic effects among patients. We conducted a clinical study to examine the variation in yield of therapeutic stem cells in subcutaneous adipose tissue (SAT) among patients. From 17 patients who underwent cardiac surgery, 1-2g of SAT was obtained and digested with collagenase to isolate stromal vascular fraction (SVF). Mesenchymal stem cell markers in SVF were analyzed by flow cytometry. The frequency of the patients with hypertension, dyslipidemia and diabetes was 94%, 77% and 59%, respectively. Interestingly, the content of CD271-positive cells that is reported as a specific marker of therapeutic stem cells largely varied among patients and was associated with the specific clinical feature. These indicated that the clinical background would impact on yield of therapeutic stem cells in SAT and efficacy of cardiac stem cell therapy.<br />研究課題/領域番号:26860549, 研究期間(年度):2014-04-01 - 2016-03-31
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髙島, 伸一郎 ; Takashima, Shinichiro
概要:
金沢大学附属病院救急部<br />i1. 基礎研究：頸動脈結紮にて誘導された内膜肥厚はCD271遺伝子機能欠損モデルにおいて増加した。CD271遺伝子機能欠損モデルに形成された内膜内のアポトーシスは減少した。CD271陽性細胞は骨髄由来であ
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る可能性が示唆された。2. 臨床研究：末梢血CD271陽性細胞数は、急性冠症候群（ACS）発症3日目には発症0日目に比べて1.5倍増加した。9ヶ月目のプラーク容積変化率は、ACS発症0日目のCD271陽性細胞数と逆相関した。また多変量解析の結果、ACS発症0日目のCD271陽性細胞数は9ヶ月目の非責任病変のプラーク容積変化率の負の予測因子であった。<br />1. Basic research: Carotid ligation-induced intimal thickening increased in the CD271-gene deficiency model. Apoptosis in the neointima formed in the CD271 gene deficiency model was reduced. Moreover, CD271-positive cells were suggested to be derived from bone marrow.2. Clinical study: Peripheral blood CD271-positive cell count increased 1.5-fold on day 3 of an acute coronary syndrome (ACS) compared to day 0 of onset. The rate of change in plaque volume at 9 months was inversely correlated with the number of CD271-positive cells on day 0 of ACS onset. Multivariate analysis showed that the number of CD271 positive cells on day 0 of ACS onset was a negative predictor of the plaque volume change rate of the non-targeted lesion at the 9 months.<br />研究課題/領域番号:18K08031, 研究期間(年度):2018-04-01 - 2021-03-31<br />出典：「CD271陽性細胞の血管リモデリング制御機能の解析」研究成果報告書 課題番号18K08031（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18K08031/18K08031seika/）を加工して作成
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