Atsuhiro Saito

Osaka City University, Ōsaka, Ōsaka, Japan

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Publications (49)191.82 Total impact

  • Transplantation 09/2014; 98(5):e38-9. · 3.78 Impact Factor
  • Nature Reviews Cardiology 08/2014; · 10.40 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; · 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. · 3.41 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; · 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; · 3.41 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; · 3.58 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. · 15.20 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. · 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; · 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; · 4.42 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; · 3.41 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; · 0.96 Impact Factor
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    ABSTRACT: Background: Induced pluripotent stem cells (iPSCs) hold promise for a new era in treating heart failure. However, the functional microstructure of iPSC-derived cardiomyocytes (iPSC-CMs) and their ability to attach to the extracellular matrix of the recipient myocardium require further elucidation. Thus, we analyzed the functional microstructure and adhesion molecules of iPSC-CM. Methods and Results: Immunostaining analysis showed that iPSC-CMs were similar to neonatal cardiomyocytes (CMs) in expressing the cytoskeletal proteins myosin heavy chain (MHC), myosin light chain (MLC) 2a, MLC2v, and especially β-MHC (a neonatal CM marker), as well as the adhesion molecules N-cadherin, α7-integrin, dystrophin, α-dystroglycan, α-sarcoglycan, and laminin-α2. Electron microscopy showed abundant myofibrillar bundles with transverse Z-bands and a developed mitochondrial structure in both iPSC-CMs and neonatal CMs, although the iPSC-CMs contained fewer mitochondria with lower-density cristae. When transplanted from in vitro conditions to nude rat hearts, iPSC-CMs acquired the ability to express α-MHC, a molecule specific to adult CMs. Mechanical stretch or stimulation by insulin-like growth factor-1 enhanced the α-MHC expression in iPSC-CMs in vitro. Conclusions: Our findings in vitro and in vivo indicate that CMs derived from iPSCs contain cardiac-specific organelles and adhesion systems. These results indicate that iPSC-derived CMs may be useful in new cell therapies for heart failure.
    Circulation Journal 02/2013; · 3.58 Impact Factor
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    ABSTRACT: Background: The implantation of skeletal myoblast (SMB) cell-sheets over the damaged area of a myocardial infarction (MI) has been shown to improve global left ventricular (LV) function through a paracrine effect. However, the regeneration process has not been fully evaluated. We hypothesized that the use of tissue Doppler strain M-mode imaging to assess myocardial layer-specific strain might enable detailed visual evaluation of the regenerative ability of SMBs. Methods and Results: SMBs were cultured on temperature-responsive culture dishes to generate cell-sheets. At 4 weeks after inducing anterior MI, the animals were divided into 2 groups: SMB cell-sheet implantation and sham operation (n=6 in each). A total of 30 cell-sheets (1.5×10(7) cells/sheet) were placed on the epicardium, covering the infarct and border regions. Subendocardial and subepicardial strain values were measured in the infarct, border, and remote regions by tissue Doppler strain analysis. SMB cell-sheet implantation produced the following major effects: progression of LV remodeling was prevented and global LV ejection fraction increased; the subendocardial strain was significantly greater than the subepicardial strain in the treated border region; vascular density in the subendocardium was significantly higher than in the subepicardium in the treated region; the expression of vascular endothelial growth factor was significantly increased. Conclusions: Tissue Doppler strain analysis allows precise evaluation of the effect of cell-sheet implantation on layer-specific myocardial function.
    Circulation Journal 12/2012; · 3.58 Impact Factor
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    ABSTRACT: Autologous transplantation of myoblast sheet has attracted attention as a new technique for curing myocardial infarction. Myoblast sheet has the ability to secret cytokines that improve heart function via the facilitation of angiogenesis on affected part. To mimic the in vivo angiogenesis in the myoblast sheet after transplantation, a five-layered cell sheet of human skeletal muscle myoblasts (HSMMs) was overlaid on human umbilical vein endothelial cells (HUVECs) which enables evaluation of dynamic HUVEC behavior. HUVECs existing initially at the bottom of the sheet changed to be a stretched shape and migrated upward compared with the surrounding HSMMs in the sheet. Prolonged incubation resulted in network formation of HUVECs in the middle of the sheet, although non-networked HUVECs continued to migrate to the top of the sheet, which meant the spatial habitation of HUVECs in the cell sheet. Image processing was performed to determine the variation in the extent of network formation at different HUVEC densities. It was found that the extent of formed network depended on the frequency of encounters among HUVECs in the middle of the sheet. The present system, which can evaluate network formation, is considered to be a promising in vitro angiogenesis model.
    Biomaterials 10/2012; · 8.31 Impact Factor
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    ABSTRACT: Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are a promising source of cells for regenerating myocardium. However, several issues, especially the large-scale preparation of hiPS-CMs and elimination of undifferentiated iPS cells, must be resolved before hiPS cells can be used clinically. The cell-sheet technique is one of the useful methods for transplanting large numbers of cells. We hypothesized that hiPS-CM-sheet transplantation would be feasible, safe, and therapeutically effective for the treatment of ischemic cardiomyopathy. Human iPS cells were established by infecting human dermal fibroblasts with a retrovirus carrying Oct3/4, Sox2, Klf4, and c-Myc. Cardiomyogenic differentiation was induced by WNT signaling molecules, yielding hiPS-CMs that were almost 90% positive for α-actinin, Nkx2.5, and cardiac troponin T. hiPS-CM sheets were created using thermoresponsive dishes and transplanted over the myocardial infarcts in a porcine model of ischemic cardiomyopathy induced by ameroid constriction of the left anterior descending coronary artery (n=6 for the iPS group receiving sheet transplantation and the sham-operated group; both groups received tacrolimus daily). Transplantation significantly improved cardiac performance and attenuated left ventricular remodeling. hiPS-CMs were detectable 8 weeks after transplantation, but very few survived long term. No teratoma formation was observed in animals that received hiPS-CM sheets. The culture system used yields a large number of highly pure hiPS-CMs, and hiPS-CM sheets could improve cardiac function after ischemic cardiomyopathy. This newly developed culture system and the hiPS-CM sheets may provide a basis for the clinical use of hiPS cells in cardiac regeneration therapy.
    Circulation 09/2012; 126(11 Suppl 1):S29-37. · 15.20 Impact Factor
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    ABSTRACT: Myoblast sheet transplantation for cardiac failure is a promising therapy to enhance cardiac function via paracrine mechanism. However, their efficacies of treatment showed a gradual decline. The gene modification of the implanted myoblast is important in improving the long-term results of the treatment. Elastin fiber enhances the extensibility of the infarcted wall and can prevent left ventricular dilation. We therefore hypothesized that the elastin gene modification of the implanted myoblast could strengthen and maintain the long-term improvement effects of cardiac function. In this study, we evaluated long-term follow-up benefits of functional myoblast sheets that secrete elastin in an infarcted model. The animal models were divided into three groups: a group transplanted with nontransfected, wild-type, skeletal myoblast-type sheets (WT-rSkM); group transplanted with myoblast sheets that secreted elastin fragments (ELN-rSkM); and a control group (ligation only). Cardiac function was examined by echocardiography, and cardiac remodeling after infarction was evaluated by histological examination. The cardiac function was significantly improved and the left ventricle end-diastolic dimensions were significantly reduced in the ELN-rSkM group. Histological analysis showed that left ventricular remodeling was attenuated in the ELN-rSkM group and that elastic fiber was formed in the epicardial area of ELN-rSkM group. The functionalization of myoblast sheet by elastin gene transfer showed the long-term improvement of cardiac function. Expressed recombinant elastin fiber prevented the dilation of the left ventricular chamber after myocardial infarction. The functional myoblast sheet transplantation maintained the treatment effect by the paracrine effect of myoblast and the formed recombinant elastin.
    Molecular and Cellular Biochemistry 06/2012; 368(1-2):203-14. · 2.33 Impact Factor
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    ABSTRACT: Cell-based therapies are promising strategies for myocardial repair following myocardial infarction. Induced pluripotent stem (iPS) cells have the potential to generate many cardiomyocytes, and they hold significant promise for the application of regenerative medicine to heart failure. Here, we developed cardiac tissue sheets, termed bioengineered myocardium (BM), from mouse iPS cells and measured cardiac performance following BM implantation in a rat chronic myocardial infarction model. Immunostaining analyses revealed that the α-actinin(+) cell population was isolated with more than 99% purity under specific culture conditions. To evaluate the contribution of BM to the improvements in cardiac performance, we induced myocardial infarction in 30 F344/NJcl-rnu/rnu rats by left anterior descending coronary ligation. The rats were randomly divided into two groups, 2 weeks after ligation: a BM implantation group (n = 15) and a sham group (n = 15). Echocardiography and catheter examination showed that the BM implantation significantly improved cardiac function and attenuated cardiac remodeling compared with the sham group. Histological analyses demonstrated that the implanted BM survived at the epicardial implantation site 4 weeks after implantation. The implanted BM survived and attenuated left ventricular remodeling in the rat chronic myocardial infarction model. Thus, BM derived from iPS cells might be a promising new treatment for heart failure.
    STEM CELLS TRANSLATIONAL MEDICINE 05/2012; 1(5):430-7. · 3.60 Impact Factor
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    ABSTRACT: Impairment of diastolic function and late remodeling are concerns after left ventricular restoration (LVR) for ischemic cardiomyopathy. This study aims to evaluate the effects of combined surgery of myoblast sheets (MS) implantation and LVR. Rat myocardial infarction model was established 2 weeks after left anterior descending artery ligation. They were divided into three groups: sham operation (n=15; group sham), LVR by plicating the infracted area (n=15; group LVR), and MS implantation with LVR (n=15; group LVR+MS). Serial echocardiographic study revealed significant LV redilatation and decrease of ejection fraction 4 weeks after LVR in group LVR. MS implantation combined with LVR prevented those later deteriorations of LV function in group LVR+MS. Four weeks after the operation, a hemodynamic assessment using a pressure-volume loop showed significantly preserved diastolic function in group LVR+MS; end-diastolic pressure (LVR vs. LVR+MS: 9.0±6.6 mm Hg vs. 2.0±1.0 mm Hg, P<0.05), end-diastolic pressure-volume relationship (LVR vs. LVR+MS 42±23 vs. 13±6, P<0.05). Histological examination revealed cellular hypertrophy and LV fibrosis were significantly less and vascular density was significantly higher in group LVR+MS than in the other two groups. Reverse transcription polymerase chain reaction demonstrated significantly suppressed expression of transforming growth factor-beta, Smad2, and reversion-inducing cysteine-rich protein with Kazal motifs in group LVR+MS. MS implantation decreased cardiac fibrosis by suppressing the profibrotic gene expression and attenuated the impairment of diastolic function and the late remodeling after LVR. It is suggesting that MS implantation may improve long-term outcome of LVR for ischemic heart disease.
    Transplantation 04/2012; 93(11):1108-15. · 3.78 Impact Factor

Publication Stats

449 Citations
191.82 Total Impact Points

Institutions

  • 2008–2014
    • Osaka City University
      • • Department of Cardiovascular Surgery
      • • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
  • 2009–2013
    • Osaka University
      • • Division of Cardiovascular Surgery
      • • Department of Biotechnology
      • • Department of Chemical Science and Engineering
      Suita, Osaka-fu, Japan