Atsuhiro Saito

Osaka University, Suika, Ōsaka, Japan

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Publications (54)249.69 Total impact

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    ABSTRACT: Osteopontin (OPN) is involved in various physiological processes such as inflammatory and wound healing. However, little is known about the effects of OPN on these tissues. OPN is cleaved by thrombin, and cleavage of the N-terminal fragment exposes a SVVYGLR sequence on its C-terminus. In this study, we examined the effects of the thrombin-cleaved OPN fragments on fibroblasts and myocardial fibrosis, particularly the role of the SVVYGLR sequence. The recombinant thrombin-cleaved OPN fragments (N-terminal fragment [N-OPN], C-terminal fragment [C-OPN], and the N-terminal fragment lacking the SVVYGLR sequence [ΔSV N-OPN]) were added to fibroblasts, and the cellular motility, signal activity, and production of collagen were evaluated. A sustained-release gel containing an OPN fragment or SVVYGLR peptide was transplanted into a rat model of ischemic cardiomyopathy and the quantities and ratio of collagen type I (COL I) and type III (COL III) were estimated. N-OPN significantly promoted fibroblast migration. Smad signal activity, expression of smooth muscle actin (SMA), and the production of COL III were enhanced by N-OPN and SVVYGLR peptide. Conversely, ΔSV N-OPN and C-OPN had no effect. In vivo, the expression level of N-OPN was associated with COL III distribution, and the COL III/COL I ratio was significantly increased by the sustained-release gel containing N-OPN or SVVYGLR peptide. The cardiac function was also significantly improved by the N-OPN- or SVVYGLR peptide-released gel treatment. The N-terminal fragment of thrombin-cleaved OPN-induced Smad signal activation, SMA expression, and COL III production, and its SVVYGLR sequence influences this function.
    Molecular and Cellular Biochemistry 06/2015; DOI:10.1007/s11010-015-2495-y · 2.39 Impact Factor
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    ABSTRACT: Introduction Bone marrow-derived autologous human mesenchymal stem cells (MSC) are one of the most promising cell sources for cell therapy to treat heart failure. The cell sheet technique has allowed transplantation of a large number of cells and enhanced the efficacy of cell therapy. We hypothesized that the transplantation of MSC sheets may be a feasible, safe, and effective treatment for ischemic cardiomyopathy (ICM). Methods and Results Human MSCs acquired from bone marrow were positive for CD73, CD90, and CD105, and negative for CD11b and CD45 by flow cytometry. Ten MSC sheets were created from a total cell number of 1 × 108 MSCs using temperature-responsive culture dishes. These were successfully transplanted over the infarct myocardium of porcine ICM models induced by placing an ameroid constrictor on LAD without any procedural-related complications (MSC group = 6: sheet transplantation; sham group = 6, oral intake of tacrolimus in both groups). Premature ventricular contractions were rarely detected by Holter ECG in the MSC group in the first week after transplantation. On echocardiography, the cardiac performance of the MSC group was significantly better than that of the sham group at 8 weeks after transplantation. On histological examination 8 weeks after transplantation, LV remodeling was significantly attenuated compared with the sham group (cardiomyocyte size and interstitial fibrosis were measured). Immunohistochemistry of the vWF showed that the vascular density in the infarct-border area was significantly greater in the MSC group than the sham group. Expression of angiogenesis-related factors in the infarct-border area of the MSC group was significantly greater than that of the sham group, as measured by real-time PCR. Conclusions Bone marrow derived MSC sheets improved cardiac function and attenuated LV remodeling in ischemic cardiomyopathy without major complications, indicating that this strategy would be applicable in clinical settings.
    Tissue Engineering Part A 06/2015; DOI:10.1089/ten.TEA.2014.0036 · 4.64 Impact Factor
  • Protein & Cell 06/2015; DOI:10.1007/s13238-015-0170-4 · 2.85 Impact Factor
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    ABSTRACT: In vitro expanded beating cardiac myocytes derived from induced pluripotent stem cells (iPSC-CMs) are a promising source of therapy for cardiac regeneration. Meanwhile, the cell-sheet method has been shown to potentially maximize survival, functionality and integration of the transplanted cells into the heart. It is thus hypothesized that transplanted iPSC-CMs in a cell-sheet manner may contribute to functional recovery via direct mechanical effects on the myocardial infarction (MI) heart. : F344/NJcl-rnu/rnu rat were left coronary artery-ligated (n=30), followed by transplantation of Dsred-labeled iPSC-CMs cell-sheets of murine origin over the infarct heart surface. Effects of the treatment were assessed, including in vivo molecular/cellular evaluations using a synchrotron radiation scattering technique. Ejection fraction and activation recovery interval were significantly greater from day 3 onwards after iPSC-CMs transplantation compared to those after sham operation. A number of transplanted iPSC-CMs were present on the heart surface expressing cardiac myosin or connexin43 over two weeks, assessed by immunoconfocal microscopy, while mitochondria in the transplanted iPSC-CMs gradually showed mature structure as assessed by electronmicroscopy. Of note, X-ray diffraction identified 1,0 and 1,1 equatorial reflections attributable to myosin and actin-myosin lattice planes typical of organized cardiac muscle fibers within the transplanted cell-sheets at 4 weeks, suggesting cyclic systolic myosin mass transfer to actin filaments in the transplanted iPSC-CMs. Transplantation of iPSC-CM cell-sheets into the heart yielded functional and electrical recovery with cyclic contraction of transplanted cells in the rat MI heart, indicating that this strategy may be a promising "cardiac muscle replacement" therapy.
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    ABSTRACT: Cell-sheet transplantation induces angiogenesis for chronic myocardial infarction (MI), though insuf?cient capillary maturation and paucity of arteriogenesis may limit its therapeutic effects. Omentum has been used clinically to promote revascularization and healing of ischemic tissues. We hypothesized that cell-sheet transplantation covered with an omentum-flap would effectively establish mature blood vessels and improve coronary microcirculation physiology, enhancing the therapeutic effects of cell-sheet therapy. Rats were divided into 4 groups after coronary ligation; skeletal myoblast cell-sheet plus omentum-flap (combined), cell-sheet only, omentum-flap only, and sham operation. At 4 weeks after the treatment, the combined group showed attenuated cardiac hypertrophy and fibrosis, and a greater amount of functionally (CD31(+)/lectin(+)) and structurally (CD31(+)/α-SMA(+)) mature blood vessels, along with myocardial upregulation of relevant genes. Synchrotron-based microangiography revealed that the combined procedure increased vascularization in resistance arterial vessels with better dilatory responses to endothelium-dependent agents. Serial (13)N-ammonia PET showed better global coronary flow reserve in the combined group, mainly attributed by improvement in the basal left ventricle. Consequently, the combined group had sustained improvements in cardiac function parameters and better functional capacity. Cell-sheet transplantation with an omentum-flap better promoted arteriogenesis and improved coronary microcirculation physiology in ischemic myocardium, leading to potent functional recovery in failing heart.Molecular Therapy (2014); doi:10.1038/mt.2014.225.
    Molecular Therapy 11/2014; 23(2). DOI:10.1038/mt.2014.225 · 6.43 Impact Factor
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    ABSTRACT: Background:Clinical prognosis is critically poor in fulminant myocarditis, while it's initiation or progression is fated, in part, by T cell-mediated autoimmunity. Adiponectin (APN) and associated adipokines were shown to be immune tolerance inducers, although the clinically relevant delivery method into target pathologies is under debate. Whether the cell sheet-based delivery system of adipokines might induce immune tolerance and functional recovery in experimental autoimmune myocarditis (EAM) was tested.Methods and Results:Scaffold-free-induced adipocyte cell-sheet (iACS) was generated by differentiating adipose tissue-derived syngeneic stromal vascular-fraction cells into adipocytes on temperature-responsive dishes. Rats with EAM underwent iACS implantation or sham operation. Supernatants of iACS contained a high level of APN and hepatocyte growth factor (HGF), and reduced proliferation of CD4-positive T cells in vitro. Immunohistolabelling showed that the iACS implantation elevated the levels of APN and HGF in the myocardium compared to the sham operation, which attenuated the immunological response by inhibiting CD68-positive macropharges and CD4-positive T-cells and activating Foxp3-positive regulatory T cells. Consequently, left ventricular ejection fraction was significantly greater after the iACS implantation than after the sham operation, in association with less collagen accumulation.Conclusions:The targeted delivery of adipokines using tissue-engineered iACS ameliorated cardiac performance of the EAM rat model via effector T cell suppression and induction of immune tolerance. These findings might suggest a potential of this tissue-engineered drug delivery system in treating fulminant myocarditis in the clinical setting.
    Circulation Journal 11/2014; 79(1). DOI:10.1253/circj.CJ-14-0840 · 3.69 Impact Factor
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    ABSTRACT: Cell surface glycans vary widely, depending on cell properties. We hypothesized that glycan expression on induced pluripotent stem cells (iPSCs) might change during cardiomyogenic differentiation toward the myocardial phenotype. N-glycans were isolated from iPSCs, iPSC-derived cardiomyocytes (iPSC-CM), and original C57BL/6 mouse myocardium (Heart). Their structures were analyzed by a mapping technique based on HPLC elution times and MALDI-TOF/MS spectra. Sixty-eight different N-glycans were isolated; the structures of 60 of these N-glycans were identified. The quantity of high-mannose type (immature) N-glycans on the iPSCs decreased with cardiomyogenic differentiation, but did not reach the low levels observed in the heart. We observed a similar reduction in neutral N-glycans and an increase in fucosylated or sialyl N-glycans. Some structural differences were detected between iPSC-CM and Heart. No N-glycolyl neuraminic acid (NeuGc) structures were detected in iPSC-CM, whereas the heart contained numerous NeuGc structures, corresponding to the expression of cytidine monophosphate-N-acetylneuraminic acid hydroxylase. Furthermore, several glycans containing Galα1-6 Gal, rarely identified in the other cells, were detected in the iPSC-CM. The expression of N-glycan on murine iPSCs changed toward the myocardial phenotype during cardiomyogenic differentiation, leaving the structural differences of NeuGc content or Galα1-6 Gal structures. Further studies will be warranted to reveal the meaning of the difference of N-glycans between the iPSC-CM and the myocardium.
    PLoS ONE 10/2014; 9(10):e111064. DOI:10.1371/journal.pone.0111064 · 3.53 Impact Factor
  • Transplantation 09/2014; 98(5):e38-9. DOI:10.1097/TP.0000000000000353 · 3.78 Impact Factor
  • Nature Reviews Cardiology 08/2014; 11(9). DOI:10.1038/nrcardio.2014.9-c1 · 10.15 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs) and a family of tissue inhibitors of metalloproteinases (TIMPs) may contribute to myocardial remodeling in heart failure. TIMPs are the main inhibitors of MMPs and have other MMP-independent functions. Because little is known of the role of TIMPs in the heart, we examined the effects of TIMPs on cardiac fibroblasts (CFs) and cardiomyocytes. In vitro, TIMP-1-4 enhanced smooth muscle actin (SMA) expression in CFs, and TIMP-1 and TIMP-3 enhanced the expression of phosphorylated Smad-3 and phosphorylated transforming growth factor (TGF)-β type 1 receptor in CFs; this effect was inhibited by TGF-β receptor blocker SB-505124. TIMP-1, -3, and -4 also inhibited the FAK, AKT, and ERK pathways that induce cardiac hypertrophy. TIMP-1 and TIMP-2 suppressed apoptosis in cardiomyocytes; in contrast, TIMP-4 induced apoptosis in CFs. TIMP-2 stimulated collagen synthesis. Collagen gels containing TIMP-1 or TIMP-3, which exhibit cardioprotective effects in vitro, were transplanted to the left ventricular anterior wall of a rat heart model of myocardial infarction (MI). Gel-released TIMP-1 and TIMP-3 significantly improved cardiac function and myocardial remodeling and enhanced SMA expression in the infarcted area in ischemic cardiomyopathy model rats. Furthermore, the transplantation of TIMP-1 or TIMP-3 gels inhibited apoptosis in the ischemic myocardium and reduced MMP-2 activity. TIMPs may be an ideal target of cardiac regeneration therapy.
    Tissue Engineering Part A 05/2014; DOI:10.1089/ten.TEA.2013.0763 · 4.64 Impact Factor
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    ABSTRACT: Remodeling of the left ventricle (LV) in idiopathic dilated cardiomyopathy (IDCM) is known to be associated with multiple pathologic changes that endogenous factors, such as hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), protect against. Although a clinically relevant delivery method of these factors has not been established, ONO1301, a synthetic prostacyclin agonist, has been shown to upregulate multiple cardioprotective factors, including HGF and VEGF, in vivo. We thus hypothesized that ONO1301 may reverse LV remodeling in the DCM heart. ONO1301 dose-dependently added to the normal human dermal fibroblasts and human coronary artery smooth muscle cells in vitro, to measure the expression of HGF, VEGF, stromal cell-derived factor (SDF)-1, and granulocyte-colony stimulating factor (G-CSF), assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. δ-Sarcoglycan-deficient J2N-k hamsters, which is an established DCM model, were treated by epicardial implantation of an atelocollagen sheet with or without ONO1301 immersion or sham operation. ONO1301 dose-dependently upregulated expression of these 4 factors in vitro. ONO1301 treatment, which induced dominant elevation of ONO1301 levels for 2 weeks, significantly preserved cardiac performance and prolonged survival compared with the other groups. This treatment significantly upregulated expressions of cardioprotective factors and was associated with increased capillaries, attenuated fibrosis, and upregulation of α-sarcoglycan in the DCM heart. ONO1301 atelocollagen-sheet implantation reorganized cytoskeletal proteins, such as α-sarcoglycan, increased capillaries, reduced fibrosis, and was associated with upregulated expression of multiple cardioprotective factors, leading to preservation of cardiac performance and prolongation of survival in the δ-sarcoglycan-deficient DCM hamster.
    The Journal of thoracic and cardiovascular surgery 12/2013; 146(6):1516-1525. DOI:10.1016/j.jtcvs.2013.02.045 · 3.99 Impact Factor
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    ABSTRACT: Introdunction: Functional skeletal myoblasts (SMBs) are transplanted into the heart effectively and safely as cell sheets, which induce functional recovery in myocardial infarction (MI) patients without lethal arrhythmia. However, their therapeutic effect is limited by ischemia. Mesenchymal stem cells (MSCs) have pro-survival/proliferation and anti-apoptotic effects on co-cultured cells in vitro. We hypothesized that adding MSCs to the SMB cell sheets might enhance SMB survival post-transplantation and improve their therapeutic effects. Methods and Results: Cell sheets of primary SMBs of male Lewis rats (r-SMBs), primary MSCs of human female fat tissues (h-MSCs), and their co-cultures were generated using temperature-responsive dishes. The levels of candidate paracrine factors, rat HGF and VEGF, in vitro were significantly greater in the h-MSC/rSMB co-cultures than in those containing r-SMBs only, by real-time PCR and ELISA. MI was generated by left-coronary artery occlusion in female athymic nude rats. Two weeks later, co-cultured, r-SMB, or h-MSC cell sheets were implanted or no treatment was performed (n=10 each). Eight weeks later, systolic and diastolic function parameters were improved in all three treatment groups compared to no treatment, with the greatest improvement in the co-cultured cell sheet transplantation group. Consistent results were found for capillary density, collagen accumulation, myocyte hypertrophy, Akt-signaling, STAT3 signaling, and survival of transplanted cells of rat origin, and were related to poly (ADP-ribose) polymerase-dependent signal-transduction. Conclusions: Adding MSCs to SMB cell sheets enhanced the sheets' angiogenesis-related paracrine mechanics and, consequently, functional recovery in a rat MI model, suggesting a possible strategy for clinical applications.
    Tissue Engineering Part A 10/2013; DOI:10.1089/ten.TEA.2012.0534 · 4.64 Impact Factor
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    ABSTRACT: The cardiac support device supports the heart and mechanically reduces left ventricular (LV) diastolic wall stress. Although it has been shown to halt LV remodeling in dilated cardiomyopathy, its therapeutic efficacy is limited by its lack of biological effects. In contrast, the slow-release synthetic prostacyclin agonist ONO-1301 enhances reversal of LV remodeling through biological mechanisms such as angiogenesis and attenuation of fibrosis. We therefore hypothesized that ONO-1301 plus a cardiac support device might be beneficial for the treatment of ischemic cardiomyopathy. Twenty-four dogs with induced anterior wall infarction were assigned randomly to 1 of 4 groups at 1 week postinfarction as follows: cardiac support device alone, cardiac support device plus ONO-1301 (hybrid therapy), ONO-1301 alone, or sham control. At 8 weeks post-infarction, LV wall stress was reduced significantly in the hybrid therapy group compared with the other groups. Myocardial blood flow, measured by positron emission tomography, and vascular density were significantly higher in the hybrid therapy group compared with the cardiac support device alone and sham groups. The hybrid therapy group also showed the least interstitial fibrosis, the greatest recovery of LV systolic and diastolic functions, assessed by multidetector computed tomography and cardiac catheterization, and the lowest plasma N-terminal pro-B-type natriuretic peptide levels (P < .05). The combination of a cardiac support device and the prostacyclin agonist ONO-1301 elicited a greater reversal of LV remodeling than either treatment alone, suggesting the potential of this hybrid therapy for the clinical treatment of ischemia-induced heart failure.
    The Journal of thoracic and cardiovascular surgery 10/2013; 147(3). DOI:10.1016/j.jtcvs.2013.05.035 · 3.99 Impact Factor
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    ABSTRACT: Background: Because human cardiac stem cells (CSC) have regeneration potential in damaged cardiac tissue, there is increasing interest in using them in cell-based therapies for cardiac failure. However, culture conditions, by which CSCs are expanded while maintaining their therapeutic potential, have not been optimized. We hypothesized that the plating cell-density would affect proliferation activity, differentiation and therapeutic potential of CSCs through the Notch signaling pathway. Methods and Results: Human CSCs were plated at 4 different densities. The population doubling time, C-KIT positivity, and dexamethasone-induced multidifferentiation potential were examined in vitro. The therapeutic potential of CSCs was assessed by transplanting them into a rat acute myocardial infarction (AMI) model. The low plating density (340cells/cm(2)) maintained the multidifferentiation potential with greater proliferation activity and C-KIT positivity in vitro. On the other hand, the high plating density (5,500cells/cm(2)) induced autonomous differentiation into endothelial cells by activating Notch signaling in vitro. CSCs cultured at low or high density with Notch signal inhibitor showed significantly greater therapeutic potential in vivo compared with those cultured at high density. Conclusions: CSCs cultured with reduced Notch signaling showed better cardiomyogenic differentiation and therapeutic potentials in a rat AMI model. Thus, reducing Notch signaling is important when culturing CSCs for clinical applications.
    Circulation Journal 10/2013; 78(1). DOI:10.1253/circj.CJ-13-0534 · 3.69 Impact Factor
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    ABSTRACT: Transplantation of cardiomyocytes that are derived from human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) shows promise in generating new functional myocardium in situ, whereas the survival and functionality of the transplanted cells are critical in considering this therapeutic impact. Cell-sheet method has been used to transplant many functional cells; however, potential ischemia might limit cell survival. The omentum, which is known to have rich vasculature, is expected to be a source of blood supply. We hypothesized that transplantation of hiPS-CM cell sheets combined with an omentum flap may deliver a large number of functional hiPS-CMs with enhanced blood supply. Retrovirally established human iPS cells were treated with Wnt signaling molecules to induce cardiomyogenic differentiation, followed by superparamagnetic iron oxide labeling. Cell sheets were created from the magnetically labeled hiPS-CMs using temperature-responsive dishes and transplanted to porcine hearts with or without the omentum flap (n=8 each). Two months after transplantation, the survival of superparamagnetic iron oxide-labeled hiPS-CMs, assessed by MRI, was significantly greater in mini-pigs with the omentum than in those without it; histologically, vascular density in the transplanted area was significantly greater in mini-pigs with the omentum than in those without it. The transplanted tissues contained abundant cardiac troponin T-positive cells surrounded by vascular-rich structures. The omentum flap enhanced the survival of hiPS-CMs after transplantation via increased angiogenesis, suggesting that this strategy is useful in clinical settings. The combination of hiPS-CMs and the omentum flap may be a promising technique for the development of tissue-engineered vascular-rich new myocardium in vivo.
    Circulation 09/2013; 128(26 Suppl 1):S87-94. DOI:10.1161/CIRCULATIONAHA.112.000366 · 14.95 Impact Factor
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    ABSTRACT: A prostacyclin analogue, ONO-1301, is reported to upregulate beneficial proteins, including stromal cell derived factor-1 (SDF-1). We hypothesized that the sustained-release delivery of ONO-1301 would enhance SDF-1 expression in the acute myocardial infarction (MI) heart and induce bone marrow cells (BMCs) to home to the myocardium, leading to improved cardiac function in mice. ONO-1301 significantly upregulated SDF-1 secretion by fibroblasts. BMC migration was greater to ONO-1301-stimulated than unstimulated conditioned medium. This increase was diminished by treating the BMCs with a CXCR4-neutralizing antibody or CXCR4 antagonist (AMD3100). Atelocollagen sheets containing a sustained-release form of ONO-1301 (n = 33) or ONO-1301-free vehicle (n = 48) were implanted on the left ventricular (LV) anterior wall immediately after permanent left-anterior descending artery occlusion in C57BL6/N mice (male, 8-weeks-old). The SDF-1 expression in the infarct border zone was significantly elevated for 1 month in the ONO-1301-treated group. BMC accumulation in the infarcted hearts, detected by in vivo imaging after intravenous injection of labeled BMCs, was enhanced in the ONO-1301-treated hearts. This increase was inhibited by AMD3100. The accumulated BMCs differentiated into capillary structures. The survival rates and cardiac function were significantly improved in the ONO-1301-treated group (fractional area change 23±1%; n = 22) compared to the vehicle group (19±1%; n = 20; P = 0.004). LV anterior wall thinning, expansion of infarction, and fibrosis were lower in the ONO-1301-treated group. Sustained-release delivery of ONO-1301 promoted BMC recruitment to the acute MI heart via SDF-1/CXCR4 signaling and restored cardiac performance, suggesting a novel mechanism for ONO-1301-mediated acute-MI heart repair.
    PLoS ONE 07/2013; 8(7):e69302. DOI:10.1371/journal.pone.0069302 · 3.53 Impact Factor
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    ABSTRACT: AIMS: Myoblast sheet transplantation is a promising therapy for enhancing cardiac function after heart failure. We have previously demonstrated that a 7-amino-acid sequence (Ser-Val-Val-Tyr-Gly-Leu-Arg) derived from osteopontin (SV peptide) induces angiogenesis. In this study, we evaluated the long-term therapeutic effects of myoblast sheets secreting SV-peptide in a rat infarction model.Methods and ResultsTwo weeks after ligation, the animals were divided into 3 groups: a group transplanted with wild-type myoblast sheets (WT-rSkMs); a group transplanted with SV-peptide-secreting myoblast sheets (SV-rSkMs); and a control group (ligation only). We evaluated cardiac function, histological changes, and smooth muscle actin (SMA) expression through transforming growth factor (TGF)-β signaling. Ejection fraction and fractional shortening were significantly better, and the enlargement of end-systolic volume was also significantly attenuated in the SV-rSkM group. Left ventricular remodeling, including fibrosis and hypertrophy, was significantly attenuated in the SV-rSkM group, and SV secreted by myoblast sheets promoted angiogenesis in the infarcted border area. Furthermore, many clusters of SMA-positive cells were observed in the infarcted areas in the SV-rSkM group. In vitro SMA expression was increased when SV was added to the isolated myocardial fibroblasts. Moreover, SV bound to the TGF-β receptor, and SV treatment activated TGF-β receptor-Smad signaling. CONCLUSION: SV-peptide-secreting myoblast sheets facilitate a long-term improvement in cardiac function. SV can differentiate fibroblasts to myofibroblasts via TGF-β-Smad signaling. SV could possibly be used as a bridge to heart implantation, or as an ideal peptide drug for cardiac regeneration therapy.
    Cardiovascular Research 04/2013; 99(1). DOI:10.1093/cvr/cvt088 · 5.81 Impact Factor
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    ABSTRACT: BACKGROUND: The transplantation of cardiac stem cell sheets (CSC sheets) is apromising therapeutic strategy for ischemic cardiomyopathy, although potential ischemia inthe transplanted area remains a problem. Injected endothelial progenitor cells (EPCs) canreportedly induce angiogenesis in the injected area. We hypothesized that concomitant CSCsheet transplantation and EPC injection might show better therapeutic effects for chronicischemic injury model than the transplantation of CSC sheets alone.METHODS: Scaffold-free CSC-sheets were generated from human c-kit-positive heartderivedcells. A porcine chronic ischemic injury model was generated by placing an ameroidconstrictor around the left coronary artery for 4 weeks. The animals then underwent a shamoperation, epicardial transplantation of CSC sheet over the ischemic area, intramyocardialinjection of EPCs into the ischemic and peri-ischemic area, or CSC-sheet transplantation plusEPC injection. The efficacy of each treatment was then assessed for 2 months.RESULTS: Speckle-tracking echocardiography was used to dissect the layer-specificregional systolic function by measuring the radial strain (RS). The epicardial RS in theischemic area was similarly greater after treatment with the CSC-derived cell-sheets alone(19±5%) or in combination with EPC injection (20±5%) compared with the EPC only(9±4%) or sham (7±1%) treatment. The endocardial RS in the ischemic area was greatestafter the combined treatment (14±1%), followed by EPC only (12±1%), compared to theCSC only (11±1%) and sham (9±1%) treatments. Consistently, either epicardial CSC-sheetimplantation or intramyocardial EPC injection yielded increased capillary number andreduced cardiac fibrosis in the ischemic epicardium or endocardium, respectively.Concomitant EPC injection induced the migration of transplanted CSCs into the hostCopyright © 2013 Cognizant Communication CorporationCT-0968 Cell Transplantation Epub; provisional acceptance 02/27/2013 3myocardium, leading to further neovascularization and reduced fibrosis in the ischemicendocardium, compared to the CSC-sole therapy.CONCLUSION: Transplantation of CSC-sheets induced significant functional recovery ofthe ischemic epicardium, and concomitant EPC transplantation elicited transmuralimprovement in chronic ischemic injury.
    Cell Transplantation 04/2013; 23(10). DOI:10.3727/096368913X665602 · 3.57 Impact Factor
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    ABSTRACT: OBJECTIVES: Cardiac functional deterioration in dilated cardiomyopathy (DCM) is known to be reversed by intramyocardial up-regulation of multiple cardioprotective factors, whereas a prostacyclin analog, ONO1301, has been shown to paracrinally activate interstitial cells to release a variety of protective factors. We here hypothesized that intramyocardial delivery of a slow-releasing form of ONO1301 (ONO1301SR) might activate regional myocardium to up-regulate cardiotherapeutic factors, leading to regional and global functional recovery in DCM. METHODS AND RESULTS: ONO1301 elevated messenger RNA and protein level of hepatocyte growth factor, vascular endothelial growth factor, and stromal-derived factor-1 of normal human dermal fibroblasts in a dose-dependent manner in vitro. Intramyocardial delivery of ONO1301SR, which is ONO1301 mixed with polylactic and glycolic acid polymer (PLGA), but not that of PLGA only, yielded significant global functional recovery in a canine rapid pacing-induced DCM model, assessed by echocardiography and cardiac catheterization (n = 5 each). Importantly, speckle-tracking echocardiography unveiled significant regional functional recovery in the ONO1301-delivered territory, consistent to significantly increased vascular density, reduced interstitial collagen accumulation, attenuated myocyte hypertrophy, and reversed mitochondrial structure in the corresponding area. CONCLUSIONS: Intramyocardial delivery of ONO1301SR, which is a PLGA-coated slow-releasing form of ONO1301, up-regulated multiple cardiotherapeutic factors in the injected territory, leading to region-specific reverse left ventricular remodeling and consequently a global functional recovery in a rapid-pacing-induced canine DCM model, warranting a further preclinical study to optimize this novel drug-delivery system to treat DCM.
    The Journal of thoracic and cardiovascular surgery 03/2013; 146(2). DOI:10.1016/j.jtcvs.2012.10.003 · 3.99 Impact Factor
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    ABSTRACT: PURPOSE: Myocardial infarction (MI) remains a major cause of mortality because of the limited regenerative capacity of the myocardium. Transplantation of somatic tissue-derived cells into the heart has been shown to enhance the endogenous healing process, but the magnitude of its therapeutic effects is dependent upon the cell-source or cell-delivery method. We investigated the therapeutic effects of C-Kit positive cardiac cell (CSC) cell-sheet transplantation therapy in a rat model of MI. METHODS AND RESULTS: CSCs of human origin were sorted and cultured to generate scaffold-free CSC cell-sheets. One-layered or 3-layered cell-sheets were transplanted into nude rats 1 h after left coronary artery ligation. We observed a significant increase in the left ventricular ejection fraction and a significant decrease in left ventricular systolic dimension at 2 and 4 weeks in the 3-layer group, but not in the 1-layer or sham groups. Consistently, there was less accumulation of interstitial fibrosis in the 3-layer group than in the 1-layer or sham groups. Moreover, capillary density was significantly greater in the 3-layer group than in the 1-layer or sham groups. CONCLUSIONS: The 3-layered cell-sheet improved cardiac function associated with angiogenic and anti-fibrotic effects. Thus, CSC is a promising cell-source to use with the cell-sheet method for the treatment of cardiac failure, as long as a sufficient number of cells are delivered.
    Surgery Today 03/2013; 43(9). DOI:10.1007/s00595-013-0528-2 · 1.21 Impact Factor

Publication Stats

689 Citations
249.69 Total Impact Points

Institutions

  • 2010–2014
    • Osaka University
      • • Department of Surgery
      • • Division of Cardiovascular Surgery
      Suika, Ōsaka, Japan
  • 2008–2014
    • Osaka City University
      • Department of Cardiovascular Surgery
      Ōsaka, Ōsaka, Japan