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Takatoshi Sato,
Yoshitaka Iso,
Taro Uyama,
Keisuke Kawachi,
Kohei Wakabayashi,
Yasutoshi Omori,
Teruko Soda,
Makoto Shoji,
Shinji Koba, Shin-Ichiro Yokoyama,
Noboru Fukuda,
Satoshi Saito,
Takashi Katagiri,
Youichi Kobayashi,
Youichi Takeyama,
Akihiro Umezawa,
Hiroshi Suzuki
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ABSTRACT: Few reports have examined the effects of adult bone marrow multipotent stromal cells (MSCs) on large animals, and no useful method has been established for MSC implantation. In this study, we investigate the effects of MSC infusion from the coronary vein in a swine model of chronic myocardial infarction (MI). MI was induced in domestic swine by placing beads in the left coronary artery. Bone marrow cells were aspirated and then cultured to isolate the MSCs. At 4 weeks after MI, MSCs labeled with dye (n=8) or vehicle (n=5) were infused retrogradely from the anterior interventricular vein without any complications. Left ventriculography (LVG) was performed just before and at 4 weeks after cell infusion. The ejection fraction (EF) assessed by LVG significantly decreased from baseline up to a follow-up at 4 weeks in the control group (P<0.05), whereas the cardiac function was preserved in the MSC group. The difference in the EF between baseline and follow-up was significantly greater in the MSC group than in the control group (P<0.05). The MSC administration significantly promoted neovascularization in the border areas compared with the controls (P<0.0005), though it had no affect on cardiac fibrosis. A few MSCs expressed von Willebrand factor in a differentiation assay, but none of them expressed troponin T. In quantitative gene expression analysis, basic fibroblast growth factor and vascular endothelial growth factor (VEGF) levels were significantly higher in the MSC-treated hearts than in the controls (P<0.05, respectively). Immunohistochemical staining revealed VEGF production in the engrafted MSCs. In vitro experiment demonstrated that MSCs significantly stimulated endothelial capillary network formation compared with the VEGF protein (P<0.0001). MSC infusion via the coronary vein prevented the progression of cardiac dysfunction in chronic MI. This favorable effect appeared to derive not from cell differentiation, but from enhanced neovascularization by angiogenic factors secreted from the MSCs.
Laboratory Investigation 01/2011; 91(4):553-64. · 3.64 Impact Factor
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Kazuhiro Hagikura,
Noboru Fukuda, Shin-ichiro Yokoyama,
Li Yuxin,
Yoshiaki Kusumi,
Taro Matsumoto,
Yukihiro Ikeda,
Satoshi Kunimoto,
Tadateru Takayama,
Medet Jumabay,
Masako Mitsumata,
Satoshi Saito,
Atsushi Hirayama,
Hideo Mugishima
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ABSTRACT: Although transplantation of mononuclear cells (MNCs) induces angiogenesis in myocardial infarction, transplantation requires a large amount of bone marrow or peripheral blood cells. We examined the effects of transplantation of peripheral MNCs expressing an exogenous vascular endothelial growth factor (VEGF) gene in a pig model of acute myocardial infarction (AMI).
MNCs were isolated from 20 ml peripheral blood from pigs and transfected with 10 microg of human VEGF165 plasmid (phVEGF). Myocardial infarction was induced by occlusion of the mid portion of the left anterior descending coronary artery (LAD) in anesthetized pigs. At 4 h after total occlusion, 5 x 10(6) VEGF-transfected MNCs were retrogradely transplanted into the pig via the coronary vein. Cardiac function, neovascularization and histology of the ischemic tissue were evaluated 4 weeks after transplantation.
MNCs expressing hVEGF and infused via the coronary vein were efficiently delivered the heart in pigs with myocardial infarction. Transplantation of MNCs expressing hVEGF significantly increased left ventricular (LV) function, collateral vessels, and capillary density in heart from AMI model pigs. Transplantation of MNCs expressing hVEGF increased the wall thickness of the scar in the heart after AMI.
Retrograde transplantation of peripheral blood MNCs expressing hVEGF efficiently induced angiogenesis and improved the impaired LV function in hearts of pigs with AMI. These findings indicate that angiogenic cells and gene therapy may be useful to treat ischemic heart disease.
International journal of cardiology 02/2009; 142(1):56-64. · 7.08 Impact Factor
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Taro Kawano,
Junko Honye,
Tadateru Takayama, Shin-ichiro Yokoyama,
Masaaki Chiku,
Hideyuki Ando,
Masayoshi Endo,
Makoto Ichikawa,
Nobuaki Ishii,
Yasuo Watanabe,
Ichiro Watanabe,
Satoshi Saito
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ABSTRACT: To identify subclinical high-risk plaques is potentially important because those vulnerable plaques may have a greater likelihood of rupture and subsequent thrombosis. The aim of this study is to reveal the histology of angioscopic yellow plaques known as vulnerable plaques by intravascular ultrasound radiofrequency data analysis.
Thirty-one coronary plaques in 21 patients, which were non-culprit, de novo, angiographically non-obstructive (<50%) lesions, were analyzed with Virtual Histology - intravascular ultrasound (VH-IVUS) and coronary angioscopy. These plaques were prospectively divided into 4 groups (Grade 0 to 3) by the yellow color intensity and we compared plaque morphology, echogenicity and composition among their groups.
Morphology and echogenicity evaluated by standard gray-scale IVUS were not significantly different among those groups. On analyzing plaque composition by VH-IVUS, mean percentage of necrotic core was significantly larger in yellow plaque (Grade 2 and 3) than white plaque (Grade 0).
Angioscopic yellow plaque included a larger amount of necrotic core analyzed by VH-IVUS than white plaque.
International journal of cardiology 03/2008; 125(1):74-8. · 7.08 Impact Factor
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ABSTRACT: Recently, there has been noteworthy progress in the field of cardiac regeneration therapy. We previously reported that brown adipose tissue (BAT) contained cardiac progenitor cells that were relevant to the regeneration of damaged myocardium. In this study, we found that CD133-positive, but not c-Kit- or Sca-1-positive, cells in BAT differentiated into cardiomyocytes (CMs) with a high frequency. Moreover, we found that CD133(+) brown adipose tissue-derived cells (BATDCs) effectively induced bone marrow cells (BMCs) into CMs. BMCs are considered to have the greatest potential as a source of CMs, and two sorts of stem cell populations, the MSCs and hematopoietic stem cells (HSCs), have been reported to differentiate into CMs; however, it has not been determined which population is a better source of CMs. Here we show that CD133-positive BATDCs induce BMCs into CMs, not through cell fusion but through bivalent cation-mediated cell-to-cell contact when cocultured. Moreover, BMCs induced by BATDCs are able to act as CM repletion in an in vivo infarction model. Finally, we found that CD45(-)CD31(-) CD105(+) nonhematopoietic cells, when cocultured with BATDCs, generated more than 20 times the number of CMs compared with lin(-)c-Kit(+) HSCs. Taken together, these data suggest that CD133-positive BATDCs are a useful tool as CM inducers, as well as a source of CMs, and that the nonhematopoietic fraction in bone marrow is also a major source of CMs. Disclosure of potential conflicts of interest is found at the end of this article.
Stem Cells 06/2007; 25(5):1326-33. · 7.78 Impact Factor
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ABSTRACT: Recently, there has been noteworthy progress in the field of cardiac regeneration therapy. We previously reported that brown adipose tissue (BAT) contained cardiac progenitor cells that were relevant to the regeneration of damaged myocardium. In this study, we found that CD133-positive, but not c-Kit- or Sca-1-positive, cells in BAT differentiated into cardiomyocytes (CMs) with a high frequency. Moreover, we found that CD133+ brown adipose tissue-derived cells (BATDCs) effectively induced bone marrow cells (BMCs) into CMs. BMCs are considered to have the greatest potential as a source of CMs, and two sorts of stem cell populations, the MSCs and hematopoietic stem cells (HSCs), have been reported to differentiate into CMs; however, it has not been determined which population is a better source of CMs. Here we show that CD133-positive BATDCs induce BMCs into CMs, not through cell fusion but through bivalent cation-mediated cell-to-cell contact when cocultured. Moreover, BMCs induced by BATDCs are able to act as CM repletion in an in vivo infarction model. Finally, we found that CD45−CD31− CD105+ nonhematopoietic cells, when cocultured with BATDCs, generated more than 20 times the number of CMs compared with lin−c-Kit+ HSCs. Taken together, these data suggest that CD133-positive BATDCs are a useful tool as CM inducers, as well as a source of CMs, and that the nonhematopoietic fraction in bone marrow is also a major source of CMs.Disclosure of potential conflicts of interest is found at the end of this article.
Stem Cells 04/2007; 25(5):1326 - 1333. · 7.78 Impact Factor
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ABSTRACT: Umbilical cord blood (CB) is a promising source for regeneration therapy in humans. Recently, it was shown that CB was a source of mesenchymal stem cells as well as hematopoietic stem cells, and further that the mesenchymal stem cells could differentiate into a number of cells types of mesenchymal lineage, such as cardiomyocytes (CMs), osteocytes, chondrocytes, and fat cells. Previously, we reported that brown adipose tissue derived cells (BATDCs) differentiated into CMs and these CMs could adapt functionally to repair regions of myocardial infarction. In this study, we examined whether CB mononuclear cells (CBMNCs) could effectively differentiate into CMs by coculturing them with BATDCs and determined which population among CBMNCs differentiated into CMs. The results show that BATDCs effectively induced CBMNCs that were non-hematopoietic stem cells (HSCs) (educated CB cells: e-CBCs) into CMs in vitro. E-CBCs reconstituted infarcted myocardium more effectively than non-educated CBMNCs or CD34-positive HSCs. Moreover, we found that e-CBCs after 3 days coculturing with BATDCs induced the most effective regeneration for impaired CMs. This suggests that e-CBCs have a high potential to differentiate into CMs and that adequate timing of transplantation supports a high efficiency for CM regeneration. This strategy might be a promising therapy for human cardiac disease.
Biochemical and Biophysical Research Communications 03/2007; 353(1):182-8. · 2.48 Impact Factor
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Yuxin Li,
Noboru Fukuda, Shin-Ichiro Yokoyama,
Yoshiaki Kusumi,
Kazuhiro Hagikura,
Taro Kawano,
Tadateru Takayama,
Taro Matsumoto,
Aya Satomi,
Junko Honye,
Hideo Mugishima,
Masako Mitsumata,
Satoshi Saito
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ABSTRACT: Although granulocyte colony-stimulating factor (G-CSF) has been shown to prevent cardiac remodeling after acute myocardial infarction, the mechanism and safety of G-CSF treatment acute myocardial infarction remain controversial. The purpose of the present study was to investigate in a rat model the mechanisms underlying the beneficial effect of G-CSF in acute myocardial infarction and to determine whether G-CSF treatment aggravates vascular remodeling of injured artery after acute myocardial infarction. Sprague-Dawley rats received transplanted bone marrow cells from green fluorescent protein (GFP) transgenic rats. Acute myocardial infarction was induced by ligation of the left coronary artery. After 24 h, the right carotid artery was injured with a balloon catheter. G-CSF (100 microg/kg/day) or saline was injected subcutaneously for 5 consecutive days after induction of acute myocardial infarction. G-CSF treatment significantly improved left ventricle function and reduced infarct size in rats with acute myocardial infarction. Expression of mRNA for the angiogenic cytokines was significantly higher in the infarction border area in the G-CSF group than in the control group. The surviving cardiomyocytes in infarction area were more in the G-CSF group. GFP-positive cells were gathered in the infarction border area in both groups; G-CSF did not increase cardiac homing of GFP-positive bone marrow cells in contrast to control group. Most GFP-positive cells were CD68-positive (macrophages). It was difficult to find bone marrow-derived cardiomyocytes in the infarcted area. G-CSF treatment inhibited neointima formation and increased reendothelialization of the injured artery. GFP-positive cells were identified most in the adventitia of the injured artery. A few cells in the neointima and reendothelialization were GFP positive. In conclusion, administration of G-CSF appears to be effective for treatment of left ventricular remodeling after acute myocardial infarction and does not aggravate vascular remodeling. The effect of G-CSF on cardiac and vascular remodeling may occur mainly through a direct action on the heart and arteries.
European Journal of Pharmacology 12/2006; 549(1-3):98-106. · 2.52 Impact Factor
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Yuxin Li,
Noboru Fukuda,
Satoshi Kunimoto, Shin-ichiro Yokoyama,
Kazuhiro Hagikura,
Taro Kawano,
Tadateru Takayama,
Junko Honye,
Naohiko Kobayashi,
Hideo Mugishima,
Satoshi Saito,
Kazuo Serie
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ABSTRACT: Although the use of drug-eluting stents (DESs) has been shown to limit neointima hyperplasia, currently available DESs may adversely affect reendothelialization, possibly precipitating cardiac events. We evaluated the effect of an antisense oligodeoxynucleotide (ODN) targeted to the platelet-derived growth factor (PDGF) A-chain on in-stent restenosis in pig coronary artery.
A bare metal stent coated with phosphorothioate-linked antisense ODN or nonsense ODN, or a bare metal stent without ODN (control), was implanted in the mid segment of the left anterior descending artery (LAD). Twenty-eight days after implantation, angiography and intravascular ultrasound (IVUS) were performed, the LAD was removed, and stenosis was evaluated pathologically.
Volumetric stenosis ratios were 64 +/- 11.9, 44 +/- 3.4, and 26 +/- 3.8% in coronary arteries implanted with control, nonsense ODN-coated, and antisense ODN-coated stents, respectively. In angioscopic findings, the lumen surface was smooth in the stented segments in all groups. Struts of antisense ODN-coated stents were observed embedded in the neointima, whereas embedding was not observed in nonsense ODN-coated stents or control stents, indicating a decrease in hyperplasia in response to antisense ODN treatment. Pathologic findings showed 77 +/- 5.8, 68 +/- 12.2, and 38 +/- 5.3% stenosis in coronary arteries implanted with control stents, nonsense ODN-coated stents, and antisense ODN-coated stents, respectively. A continuous lining of endothelial cells was observed along the lumen of coronary arteries implanted with antisense ODN-coated stents.
Stent-based delivery of an antisense ODN targeted to the PDGF A-chain effectively inhibits neointima formation after stent implantation in pig coronary artery by suppressing VSMC hyperplasia and preserving endothelialization. Antisense-ODNs may provide a therapy for in-stent restenosis of the coronary artery.
Journal of Cardiovascular Pharmacology 11/2006; 48(4):184-90. · 2.29 Impact Factor
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ABSTRACT: Cardiomyocyte (CM) regeneration is limited in adult life and is not sufficient to prevent myocardial infarction. Hence, the identification of a useful source of CM progenitors is of great interest for possible use in regenerative therapy. Mesenchymal stem cells in bone marrow, embryonic stem cells, and skeletal myoblasts are known sources of CM repletion; however, there are a number of critical problems for clinical application. In this study, we succeeded to identify CM progenitor cells in brown adipose tissue (BAT). Moreover, we showed that CM progenitor cells in BAT that existed in CD29-positive population could differentiate into CM with high efficiency. To confirm the in vivo effect of CD29(+)BAT-derived cells (BATDCs), we transplanted these cells into infarct border zone of an acute myocardial infarction model in rat. Results clearly indicated that implantation of CD29(+) BATDCs led to the reduction of the infarction area and improvement of left ventricular function by replacing newly developed CMs in comparison with that by CD29(+) white adipose tissue-derived cells or control saline. These findings suggest that BATDCs are one of the useful sources for a new strategy in CM regeneration.
Biochemical and Biophysical Research Communications 05/2006; 342(2):662-70. · 2.48 Impact Factor
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Shin-Ichiro Yokoyama,
Noboru Fukuda,
Yuxin Li,
Kazuhiro Hagikura,
Tadateru Takayama,
Satoshi Kunimoto,
Junko Honye,
Satoshi Saito,
Mika Wada,
Aya Satomi,
Maiko Kato,
Hideo Mugishima,
Yoshiaki Kusumi,
Masako Mitsumata,
Toyoaki Murohara
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ABSTRACT: Bone marrow cells implantation (BMI) has been reported to efficiently improve ischemic heart disease. However, BMI strategies are generally invasive. To establish a BMI strategy for ischemic heart disease, we performed implantation of autologous cryopreserved mononuclear cells (MNCs) from bone marrow (BM) retrogradely into the myocardium via the coronary vein in pigs with acute myocardial infarction (AMI) and old myocardial infarction (OMI).
BM cells were harvested from the pigs' fumurs. MNCs were collected by centrifugation and were cryopreserved. Anterior myocardial infarction was induced by occlusion of the midportion of the left anterior descending coronary artery without surgical intervention. Frozen BM cells were quickly thawed and injected retrogradely via the coronary vein into the myocardium through a single balloon infusion catheter 6 h and 2 weeks after the induction of infarction. Four weeks after implantation, coronary arteriograms were obtained, cardiac function was analyzed with the use of a conductance catheter, and histopathologic analysis was performed with a confocal laser microscope. Plasma levels of natriuretic peptides and angiogenic growth factors were measured after BMI.
Flow cytometric analysis revealed that 90% of cryopreserved BM cells were viable in vitro. Labeled BM cells were entirely distributed around in the infarcted area of maycardium in pigs. BMI increased collateral neovascuralization in infarcted hearts. BMI significantly improved cardiac function in AMI with BMI and OMI with BMI groups. BMI also increased the formation of microcapillary arteries in infarcted hearts. Levels of natriuretic peptides were significantly decreased, and levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2) were significantly increased after BMI. Confocal laser microscopy revealed the presence of proliferative and activated myocardial cells in infarcted hearts after BMI.
The retrograde infusion of cryopreserved BM cells into myocardium efficiently induced angiogenesis and improved cardiac function in pigs with AMI or OMI. These results suggest that the present strategy of BMI will be safe and feasible as an angiogenic cell therapy for ischemic heart disease.
Journal of Molecular and Cellular Cardiology 02/2006; 40(1):24-34. · 5.17 Impact Factor
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Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital 02/2005; 32(1):108-9. · 0.65 Impact Factor
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Yuxin Li,
Junko Honye,
Satoshi Saito,
Tadateru Takayama, Shin-Ichiro Yokoyama,
Tadahiro Saruya,
Motoko Kotani,
Kazuo Harasawa,
Hideyuki Ando,
Masayoshi Endo,
Katsuo Kanmatsuse
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ABSTRACT: We evaluated two different intravascular ultrasound (IVUS) systems, Atlantis and Intrafocus, to verify their accuracy and reproducibility. In an in vivo study on 20 consecutive patients with coronary artery diseases, the minimum lumen diameter (MLD), vessel diameter, lumen area (LA), vessel area, plaque area, and area stenosis rate (% AS) were respectively measured. In an in vitro study, MLD and LA were measured in four metal tubes with different diameters. All of the measured values except for % AS by Atlantis were significantly larger than the values obtained with Intrafocus. Nonuniform rotational distortion (NURD) was estimated as 34% in Atlantis and 1% in Intrafocus. The measurements by Atlantis were larger than the true values while the measurements by Intrafocus were less than the true values in all four metal tubes. These findings suggest that we should clearly avoid the use of different IVUS systems in the same study.
Catheterization and Cardiovascular Interventions 07/2004; 62(2):175-80. · 2.29 Impact Factor
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ABSTRACT: Endothelial progenitor cells (EPCs) are present in the mononuclear cells (MNCs) of umbilical cord blood and peripheral blood. To establish the efficiency of angiogenic cell and gene therapies, we transfected the human vascular endothelial growth factor (hVEGF) gene into cord blood MNCs to enhance endothelialization. MNCs from cord blood and peripheral blood were isolated and transfected with pCR3 expressing hVEGF165 or GFP by the Hemagglutinating Virus of Japan (HVJ)-envelope and the cells were cultured in endothelium basal medium-2. The number of attached cells from cord blood was higher than that from peripheral blood. Attached cells expressed Flk-1, VE-cadherin, PECAM-1, CD34, and Tie-2. The increase in the number of attached cells was transient with the transfection of vascular endothelial growth factor (VEGF) gene early in the experimental period. Flt-1 mRNA was not expressed early in the culture period, but was expressed at 2 weeks after separation. VEGF gene transfer into MNCs at 12 days after separation, i.e., when Flt-1 mRNA was expressed continuously, increased the number of attached cells. We evaluated the effects of the transplantation of cord blood MNCs expressing the hVEGF gene on regional blood flow in an ischemic area in a rat model of chronic hindlimb ischemia. Blood flow was significantly improved in nude rats that received transplanted control MNCs. Transplantation of cord blood MNCs transfected with the hVEGF gene yielded greater improvements in blood flow. These results indicate that the hVEGF gene enhances endothelialization of EPCs, and that the transplantation of cord blood MNCs transfected with the VEGF gene may be feasible for the treatment of ischemic diseases as a type of angiogenic cell and gene therapy.
Hypertension Research 03/2004; 27(2):119-28. · 2.58 Impact Factor
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ABSTRACT: We designed and synthesized a chimeric DNA-RNA hammerhead ribozyme targeting transforming growth factor (TGF)-beta 1 mRNA and found that this ribozyme effectively and specifically inhibited growth of vascular smooth muscle cells. We examined the effects of the chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta 1 mRNA on neointima formation and investigated the underlying mechanism to develop a possible gene therapy for coronary artery restenosis after percutaneous transluminal coronary angioplasty. Expression of mRNAs encoding TGF-beta 1, p27kip1, and connective tissue growth factor (CTGF) in carotid artery increased after balloon injury. Fluorescein-isothiocyanate (FITC)-labeled ribozyme was taken up into the midlayer smooth muscle of the injured carotid artery. Both 2 and 5 mg of ribozyme reduced neointima formation by 65% compared to that of controls. Ribozyme markedly decreased expression of TGF-beta 1 mRNA and protein in injured vessel. Mismatch ribozyme had no effect on expression of TGF-beta 1 mRNA protein in injured vessel. Ribozyme markedly decreased expression of fibronectin, p27kip1, and CTGF mRNAs in injured vessel, whereas a mismatch ribozyme had no effect on these mRNAs. These findings indicate that the chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta 1 mRNA inhibits neointima formation in rat carotid artery after balloon injury with suppression of TGF-beta 1 and inhibition of extracellular matrix and CTGF. In conclusion, the hammerhead ribozyme against TGF-beta 1 may have promise as a therapy for coronary artery restenosis after percutaneous transluminal coronary angioplasty.
European Journal of Pharmacology 02/2004; 483(2-3):207-14. · 2.52 Impact Factor
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ABSTRACT: We designed and synthesized a chimeric DNA–RNA hammerhead ribozyme targeting transforming growth factor (TGF)-β1 mRNA and found that this ribozyme effectively and specifically inhibited growth of vascular smooth muscle cells. We examined the effects of the chimeric DNA–RNA hammerhead ribozyme targeting TGF-β1 mRNA on neointima formation and investigated the underlying mechanism to develop a possible gene therapy for coronary artery restenosis after percutaneous transluminal coronary angioplasty. Expression of mRNAs encoding TGF-β1, p27kip1, and connective tissue growth factor (CTGF) in carotid artery increased after balloon injury. Fluorescein-isothiocyanate (FITC)-labeled ribozyme was taken up into the midlayer smooth muscle of the injured carotid artery. Both 2 and 5 mg of ribozyme reduced neointima formation by 65% compared to that of controls. Ribozyme markedly decreased expression of TGF-β1 mRNA and protein in injured vessel. Mismatch ribozyme had no effect on expression of TGF-β1 mRNA protein in injured vessel. Ribozyme markedly decreased expression of fibronectin, p27kip1, and CTGF mRNAs in injured vessel, whereas a mismatch ribozyme had no effect on these mRNAs. These findings indicate that the chimeric DNA–RNA hammerhead ribozyme targeting TGF-β1 mRNA inhibits neointima formation in rat carotid artery after balloon injury with suppression of TGF-β1 and inhibition of extracellular matrix and CTGF. In conclusion, the hammerhead ribozyme against TGF-β1 may have promise as a therapy for coronary artery restenosis after percutaneous transluminal coronary angioplasty.
European Journal of Pharmacology.
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Medet Jumabay,
Taro Matsumoto, Shin-ichiro Yokoyama,
Koichiro Kano,
Yoshiaki Kusumi,
Takayuki Masuko,
Masako Mitsumata,
Satoshi Saito,
Atsushi Hirayama,
Hideo Mugishima,
Noboru Fukuda
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ABSTRACT: Adipose tissue-derived stem cells have been demonstrated to differentiate into cardiomyocytes and vascular endothelial cells. Here we investigate whether mature adipocyte-derived dedifferentiated fat (DFAT) cells can differentiate to cardiomyocytes in vitro and in vivo by establishing DFAT cell lines via ceiling culture of mature adipocytes. DFAT cells were obtained by dedifferentiation of mature adipocytes from GFP-transgenic rats. We evaluated the differentiating ability of DFAT cells into cardiomyocytes by detection of the cardiac phenotype markers in immunocytochemical and RT-PCR analyses in vitro. We also examined effects of the transplantation of DFAT cells into the infarcted heart of rats on cardiomyocytes regeneration and angiogenesis. DFAT cells expressed cardiac phenotype markers when cocultured with cardiomyocytes and also when grown in MethoCult medium in the absence of cardiomyocytes, indicating that DFAT cells have the potential to differentiate to cardiomyocyte lineage. In a rat acute myocardial infarction model, transplanted DFAT cells were efficiently accumulated in infarcted myocardium and expressed cardiac sarcomeric actin at 8 weeks after the cell transplantation. The transplantation of DFAT cells significantly (p < 0.05) increased capillary density in the infarcted area when compared with hearts from saline-injected control rats. We demonstrated that DFAT cells have the ability to differentiate to cardiomyocyte-like cells in vitro and in vivo. In addition, transplantation of DFAT cells led to neovascuralization in rats with myocardial infarction. We propose that DFAT cells represent a promising candidate cell source for cardiomyocyte regeneration in severe ischemic heart disease.
Journal of Molecular and Cellular Cardiology.
