Winston S N Shim

Publications (14)36.61 Total impact

• Article: Different expression of large-conductance calcium-activated K+ channels in human internal mammary and radial arteries.

  Yangzhen Shao, Reginald Liew, Bingcai Guan, Philip E H Wong, Winston S N Shim, Yeowleng Chua, Guowei He
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  ABSTRACT: In this study, we investigated and compared the electrophysiological and molecular properties of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels between human internal mammary arteries (IMA) and radial arteries (RA). IMA and RA sections were obtained from 79 patients (including 9 females) undergoing coronary artery bypass graft surgery. We examined the effects of K(+) channel blockers tetraethylammonium (TEA), iberiotoxin (IBTX), and 4-aminopyridine (4-AP) on isolated smooth muscle cells (SMCs) using patch clamping. Both TEA (1 mM) and IBTX (0.1 µM) significantly decreased K(+) currents in IMA SMCs and RA SMCs, while 4-AP (1 mM) only had a weak effect. IBTX had a greater K(+)-blocking effect on IMA SMCs than on RA SMCs. Consistently, TEA and IBTX evoked significant constriction of both intact vascular rings. IBTX had a greater constrictor effect on IMA rings (18.5 ± 6.7%, n= 8) than on RA rings (10.6 ± 3.1%, n= 8), P< 0.05. RT-PCR and western blot analysis demonstrated that gene and protein expression of the α-subunit of BK(Ca) channels from IMA was greater than that from RA. The density of BK(Ca) channels is greater in human IMA than in RA resulting in greater BK(Ca) currents in SMCs from IMA. This may partly explain the finding of less spasm in IMA grafts than in RA grafts. Our results may be of value in determining the best anti-spasm agent to use peri-operatively.
  Cardiovascular research 02/2011; 89(2):329-35. · 5.80 Impact Factor
• Article: Dose-dependent systolic contribution of differentiated stem cells in post-infarct ventricular function.

  Winston S N Shim, Genevieve Tan, Yacui Gu, Ling Qian, Shiqi Li, Ying Ying Chung, Sze Yun Lim, Eugene Sim, Seng Chye Chuah, Philip Wong
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  ABSTRACT: Differentiation of bone marrow stem cells toward cardiomyocytes has been widely reported in vitro. However, optimum cell types and mechanisms leading to functional improvement in cardiac cell therapy remain unresolved. There is limited evidence showing a dose-dependent effect of transplanted cells in contributing to functional recovery. This study showed that cell transplantation of differentiated cardiomyocyte-like cells (CLCs) and undifferentiated mesenchymal stem cells (MSCs) dose-dependently improved left ventricular function in a rat myocardial infarction model. At 1 week after infarction in Wistar rats, 1 × 10(6) MSCs (n = 9) or CLCs (n = 9) and 5 × 10(6) MSCs (n = 18) or CLCs (n = 15) were injected into peri-infarcted myocardium to study their effect after 6 weeks. High-dose CLCs exhibited a dose-response that was significantly more effective than MSCs in recovering cardiac contractility. Superiority of CLCs over MSCs was demonstrated in load-independent measurement of the end-systolic pressure-volume relationship and pre-load recruitable stroke work, but not in the end-diastolic pressure-volume relationship. These findings showed a unique systolic role of CLCs in contractility recovery. Functional improvement mediated by MSCs was mainly derived from preservation of endogenous myocyte function and restriction of chamber dilatation by enhancing intramyocardial angiogenesis during post-infarct ventricular remodeling. Engrafted CLCs showed better survival, were strategically integrated into myofiber-associated collagen V matrix, and exhibited mature sarcomeric cross-striations. Vascular differentiation, but not cardiac, was observed with MSCs. These cell type-specific effects suggest that committing stem cells to a cardiac phenotype ex vivo promoted mechanical and functional integration of CLCs into the myofibrillar syncytium of infarcted myocardium.
  The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 12/2010; 29(12):1415-26. · 3.54 Impact Factor
• Article: Myoblast transplantation for cardiac repair: from automyoblast to allomyoblast transplantation.

  Changfa Guo, Husnain Kh Haider, Chunsheng Wang, Ru-San Tan, Winston S N Shim, Philip Wong, Eugene K W Sim
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  ABSTRACT: We sought to compare host immune cell kinetics, survival profile of donor skeletal myoblasts, and skeletal myoblast graft efficacy after autologous and allogeneic skeletal myoblast transplantation into a rat model of myocardial infarction. One week after myocardial infarction, 128 animals were divided into four groups: group 1 (n = 24, receiving medium only), group 2 (n = 24, receiving medium and cyclosporine), group 3 (n = 40, autologous skeletal myoblast transplantation), and group 4 (n = 40, allogeneic skeletal myoblast transplantation with cyclosporine treatment). Rats were euthanized 10 minutes, 1 day, and 4, 7, and 28 days later. Host immune cell kinetics were assessed by immunohistochemical studies for macrophages, and CD4+ and CD8+ lymphocytes. Donor skeletal myoblast survival was confirmed by tracking prelabeled signals, and quantified by beta-gal assay. Heart function was evaluated by echocardiography. A transient immune cell infiltration was demonstrated in group 3, with macrophage infiltration on day 1 and day 4, CD8+ cell infiltration on day 4 and day 7, and CD4+ cell infiltration on day 4. In group 4, immunocyte infiltration was slightly more severe than that in group 3. Automyoblasts and allomyoblasts showed no significant difference of survival from day 1 to day 7 (p > 0.10); however, on day 28, automyoblasts showed better survival than allomyoblasts (p < 0.05). Transplantation of allomyoblasts increased systolic heart function and limited heart dilation after myocardial injury to a similar degree as automyoblasts (p > 0.10). The use of allomyoblasts is feasible and effective for cardiac repair with immunosuppressive treatment as compared with automyoblasts.
  The Annals of thoracic surgery 01/2009; 86(6):1841-8. · 3.74 Impact Factor
• Article: Structural stability of neoangiogenic intramyocardial microvessels supports functional recovery in chronic ischemic myocardium.

  Winston S N Shim, Sze Yun Lim, Shi Qi Li, Yacui Gu, Hwee Choo Ong, In Chin Song, Seng Chye Chuah, Philip Wong
  [show abstract] [hide abstract]
  ABSTRACT: We hypothesize that combining angiopoietin-1 (ANG-1) or ANG-2 with vascular endothelial growth factor (VEGF) improves myocardial perfusion and contractile function by modulating vascular adaptation of neoangiogenic microvessels in a chronic ischemic swine model. Four weeks after occlusion of the left circumflex coronary artery (LCx), animals were injected with AdVEGF(165) (n=6), AdVEGF(165)+AdANG-1 (n=6), AdVEGF(165)+AdANG-2 (n=6) or control vector (n=5) into the left ventricular posterolateral wall. Regional perfusion by fluorescent microspheres and segmental myocardial tissue velocity by tissue Doppler imaging (TDI) were assessed at baseline, 4 weeks post occlusion and 4 weeks post therapy. Despite similar vascular growth following VEGF+ANG-1 and VEGF+ANG-2 treatments, transmural myocardial contractility improved only when VEGF was paired with ANG-1. In contrast, regional systolic function deteriorated uniformly across subepicardial, mid-myocardial and subendocardial segments in VEGF and VEGF+ANG-2 treated groups. Contractile improvement was associated with enhanced vascular stability through augmented arteriole formation, tight structural integration between VE-cadherin and beta-catenin at endothelial junctions and improved cross-talk between endothelium and myocardium. Structural stability of developing intramyocardial microvessels contributes to systolic function during ischemic neovascularization. Coordinated regulation of angiogenic revascularization that supports vascular stability is a key aspect in improving therapeutic outcomes in ischemic myocardium.
  Journal of Molecular and Cellular Cardiology 08/2008; 45(1):70-80. · 5.17 Impact Factor
• Article: Myoblast-based cardiac repair: xenomyoblast versus allomyoblast transplantation.

  Changfa Guo, Husnain Kh Haider, Winston S N Shim, Ru-San Tan, Lei Ye, Shujia Jiang, Peter K Law, Philip Wong, Eugene K W Sim
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  ABSTRACT: We sought to investigate immune cell kinetics in relation to skeletal myoblast survival and heart function improvement after nonautologous skeletal myoblast transplantation in a rat model of myocardial infarction. One week after myocardial infarction, 208 Wistar rats were grouped into group 1 (n = 24, receiving 150 muL of medium only), group 2 (n = 24, receiving 150 muL of medium and cyclosporine [INN: ciclosporin]), group 3 (n = 40, human skeletal myoblast transplantation), group 4 (n = 40, human skeletal myoblast transplantation with cyclosporine treatment), group 5 (n = 40, rat skeletal myoblast transplantation), and group 6 (n = 40, rat skeletal myoblast transplantation with cyclosporine treatment). The hearts were harvested at 10 minutes and 1, 4, 7, and 28 days after cell transplantation. Skeletal myoblast survival was confirmed by means of immunohistochemical studies and quantified by using real-time polymerase chain reaction. Host immune responses were assessed by immunostaining for macrophages and CD4+ and CD8+ lymphocytes. Heart function was evaluated by means of echocardiographic analysis. The majority of macrophages and lymphocytes infiltrated in the acute phase (from day 1 to day 7) and then subsided by day 28. The donor skeletal myoblasts survived and differentiated well in all skeletal myoblast transplantation groups. Allogeneic skeletal myoblasts showed a superior survival rate than xenogeneic skeletal myoblasts (P < .01). Cyclosporine inhibited the infiltration of the immunocytes, enhanced skeletal myoblast survival, and improved heart performance compared with that seen in the groups not receiving cyclosporine treatment (P < .05). Allomyoblasts survive better than do xenomyoblasts after transplantation into infarcted myocardium. After inhibition of immunocyte infiltration by means of immunosuppressive treatment, skeletal myoblast survival is enhanced, with improved heart performance. These findings suggest the feasibility of nonautologous myoblast transplantation with immunosuppressive treatment.
  The Journal of thoracic and cardiovascular surgery 11/2007; 134(5):1332-9. · 3.41 Impact Factor
• Article: Angiopoietin: a TIE(d) balance in tumor angiogenesis.

  Winston S N Shim, Ivy A W Ho, Philip E H Wong
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  ABSTRACT: Angiopoietins (ANG-1 and ANG-2) and their TIE-2 receptor tyrosine kinase have wide-ranging effects on tumor malignancy that includes angiogenesis, inflammation, and vascular extravasation. These multifaceted pathways present a valuable opportunity in developing novel inhibition strategies for cancer treatment. However, the regulatory role of ANG-1 and ANG-2 in tumor angiogenesis remains controversial. There is a complex interplay between complementary yet conflicting roles of both the ANGs in shaping the outcome of angiogenesis. Embryonic vascular development suggests that ANG-1 is crucial in engaging interaction between endothelial and perivascular cells. However, recruitment of perivascular cells by ANG-1 has recently been implicated in its antiangiogenic effect on tumor growth. It is becoming clear that TIE-2 signaling may function in a paracrine and autocrine manner directly on tumor cells because the receptor has been increasingly found in tumor cells. In addition, alpha(5)beta(1) and alpha(v)beta(5) integrins were recently recognized as functional receptors for ANG-1 and ANG-2. Therefore, both the ligands may have wide-ranging functions in cellular activities that affect overall tumor development. Collectively, these TIE-2-dependent and TIE-2-independent activities may account for the conflicting findings of ANG-1 and ANG-2 in tumor angiogenesis. These uncertainties have impeded development of a clear strategy to target this important angiogenic pathway. A better understanding of the molecular basis of ANG-1 and ANG-2 activity in the pathophysiologic regulation of angiogenesis may set the stage for novel therapy targeting this pathway.
  Molecular Cancer Research 08/2007; 5(7):655-65. · 4.29 Impact Factor
• Article: Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model.

  Winston S N Shim, Wei Li, Li Zhang, Shiqi Li, Hwee Choo Ong, In-Chin Song, Akanksha Bapna, Ruowen Ge, Yean Teng Lim, Seng Chye Chuah, Eugene K W Sim, Philip Wong
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  ABSTRACT: This study investigates the long-term angiogenic effects of ANG-1 and VEGF in a swine chronic myocardial ischemia model. Four-weeks after gradual occlusion of the left circumflex coronary artery by ameroid constrictor, animals were injected with recombinant adenoviral vectors carrying either human ANG-1 (n=9), human VEGF(165) (n=10) or empty vector (n=7) into the left ventricle free wall supplied by the constricted artery. Left ventricular perfusion in animals that received AdANG-1 (3.25+/-0.16 ml/min/g, p<0.05) recovered robustly 4 weeks after gene transfer while ischemia persisted in the AdVEGF (1.09+/-0.13 ml/min/g) and empty vector (1.20+/-0.03 ml/min/g) groups. Microvascular densities in the left ventricles of animals that received AdANG-1 (19.61+/-1.76/0.572 mm(2) myocardial tissue, p<0.05) and AdVEGF (18.17+/-1.43/0.572 mm(2) myocardial tissue, p<0.05) were significantly higher than animals that received empty vector (13.53+/-0.92/0.572 mm(2) myocardial tissue) 12 weeks after gene transfer. ANG-1, but not VEGF, contributed to enhanced regional perfusion by increasing arteriolar density (1.9+/-0.4/0.572 mm(2) myocardial tissue vs. 0.7+/-0.2/0.572 mm(2) myocardial tissue, p<0.05) of large-sized (50-100 microm) arterioles. These data demonstrate that gene transfer of ANG-1 and VEGF enhances angiogenesis, but ANG-1 promotes sustained improvement of ventricular perfusion that expedites recovery of ischemic myocardium via arteriogenesis.
  Journal of Biomedical Science 07/2006; 13(4):579-91. · 2.01 Impact Factor
• Article: Ex vivo differentiation of human adult bone marrow stem cells into cardiomyocyte-like cells.

  Winston S N Shim, Shujia Jiang, Philip Wong, Jack Tan, Yeow Leng Chua, Yong Seng Tan, Yoong Kong Sin, Chong Hee Lim, Terrance Chua, Ming Teh, Te Chih Liu, Eugene Sim
  [show abstract] [hide abstract]
  ABSTRACT: Bone marrow mesenchymal stem cells have been shown to transdifferentiate into cardiomyocytes after 5-azacytidine treatment or co-culturing with rodent cardiomyocytes. We investigate if adult human bone marrow stem cells can be differentiated ex vivo into cardiomyocyte-like cells (CLCs) independent of cytotoxic agents or co-culturing technique. Sternal bone marrow was collected from 16 patients undergoing coronary artery bypass surgery. Mesenchymal stem cells were differentiated in a cardiomyogenic differentiation medium containing insulin, dexamethasone, and ascorbic acid. Differentiation towards CLCs was determined by induced expression of cardiomyocyte-specific proteins. Differentiated CLCs expressed multiple structural and contractile proteins that are associated with cardiomyocytes. Thin filament associated myofibrillar proteins were detected early in the cells, with cardiac troponin I, sarcomeric tropomyosin, and cardiac titin among the first expressed. Some CLCs were found to develop into a nascent cardiomyocyte phenotype with cross-striated myofibrils characterized by alpha-actinin-positive Z bands after 4-5 passages in differentiated culture. These lineage-defined CLCs may be potentially useful for repairing damaged myocardium.
  Biochemical and Biophysical Research Communications 12/2004; 324(2):481-8. · 2.48 Impact Factor
• Article: Chronic Effects of Transmyocardial Laser Revascularization in the Nonischemic Myocardium:

  Jaro Hubacek, Eugene K.W. Sim, Li Zhang, Winston S.N. Shim
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  ABSTRACT: Abstract Background: Transmyocardial laser revascularization (TMLR) has been shown to induce angiogenesis and improve regional myocardial blood flow. However, the biological response to laser of different energy doses in nonischemic myocardium has not been well studied. We study the time course of histological appearance following high- and low-energy TMLR in a rodent model of normal myocardium. Methods: The animals were randomized to two groups (high-energy (1.4 J/pulse) TMLR group and low-energy (0.6 J/ pulse) TMLR group). TMLR was applied to the anterolateral wall of the left ventricle. Then the animals were sacrificed (one every 2 or 3 days up to 6 weeks, then one every week) to give a series of hearts from 1 week to 12 weeks following TMLR. Results: No patent laser channels were identified. All laser channel remnants were composed of granulation tissue, fibrosis, and various amounts of vascular structures. Changes in vascular density demonstrated a similar pattern in both groups over time. The initial increase in vascular density within the laser channel remnants and the surrounding areas was more marked in group I than in group II. Gradual decline of vascular density occurred during a later follow-up. More fibrosis and less vasculature were demonstrated 12 weeks after laser therapy in group I. Conclusion: Angiogenic response to the Holmium:YAG laser in the nonischemic myocardium is nonspecific and unsustainable. TMLR might chronically impair the myocardium function by enhancing regional scar formation. Therefore, we should clearly identify the ischemic area for laser therapy. Reduction of laser energy might prevent this potential complication. (J Card Surg 2004;19:161-166)
  Journal of Cardiac Surgery 02/2004; 19(2):161 - 166. · 0.87 Impact Factor
• Article: Angiopoietin 1 promotes tumor angiogenesis and tumor vessel plasticity of human cervical cancer in mice.

  Winston S N Shim, Ming Teh, Akanksha Bapna, Injune Kim, Gou-Young Koh, Peter O P Mack, Ruowen Ge
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  ABSTRACT: Angiopoietins have been increasingly implicated to play important roles in blood vessel formation, remodeling, maturation, and maintenance. However, their roles in tumor angiogenesis and hence tumor growth and metastasis still remain uncertain. In this work, angiopoietin 1 expression was amplified in human cervical cancer HeLa cells by stable transfection or recombinant human adenovirus-mediated gene transfer. We show that increased angiopoietin 1 expression promoted in vivo growth of human cervical cancers in mice by promoting tumor angiogenesis and inhibiting tumor cell apoptosis. Furthermore, we also show for the first time that overexpression of angiopoietin 1 also leads to increased tumor vessel plasticity with a large number of vessels lacking periendothelial supporting cells. These results indicate that angiopoietin 1 promotes tumor angiogenesis and tumor vessel plasticity of human cervical cancer in mice.
  Experimental Cell Research 11/2002; 279(2):299-309. · 3.58 Impact Factor
• Article: Chronic effects of transmyocardial laser revascularization in the nonischemic myocardium: a word of caution.

  Jaro Hubacek, Eugene K W Sim, Li Zhang, Winston S N Shim
  [show abstract] [hide abstract]
  ABSTRACT: Transmyocardial laser revascularization (TMLR) has been shown to induce angiogenesis and improve regional myocardial blood flow. However, the biological response to laser of different energy doses in nonischemic myocardium has not been well studied. We study the time course of histological appearance following high- and low-energy TMLR in a rodent model of normal myocardium. The animals were randomized to two groups (high-energy (1.4 J/pulse) TMLR group and low-energy (0.6 J/ pulse) TMLR group). TMLR was applied to the anterolateral wall of the left ventricle. Then the animals were sacrificed (one every 2 or 3 days up to 6 weeks, then one every week) to give a series of hearts from 1 week to 12 weeks following TMLR. RESULTs: No patent laser channels were identified. All laser channel remnants were composed of granulation tissue, fibrosis, and various amounts of vascular structures. Changes in vascular density demonstrated a similar pattern in both groups over time. The initial increase in vascular density within the laser channel remnants and the surrounding areas was more marked in group I than in group II. Gradual decline of vascular density occurred during a later follow-up. More fibrosis and less vasculature were demonstrated 12 weeks after laser therapy in group I. Angiogenic response to the Holmium:YAG laser in the nonischemic myocardium is nonspecific and unsustainable. TMLR might chronically impair the myocardium function by enhancing regional scar formation. Therefore, we should clearly identify the ischemic area for laser therapy. Reduction of laser energy might prevent this potential complication.
  Journal of Cardiac Surgery 19(2):161-6. · 0.87 Impact Factor
• Article: Therapeutic angiogenesis for coronary artery disease.

  Eugene K W Sim, Li Zhang, Winston S N Shim, Y L Lim, Ruowen Ge
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  ABSTRACT: Therapeutic angiogenesis may be a realistic approach in treating ischemic heart disease. VEGF is a major angiogenic factor involved in physiological as well as pathological angiogenesis. The ability of VEGF to promote angiogenesis in animal and clinical studies has been studied extensively. However, it is becoming clear that VEGF alone may not be sufficient to effectively complete the angiogenesis process. The use of more than one growth factor may be more pertinent in creating a sustainable angiogenic effect with clinically significant outcome. The challenge is to find complementary partners in angiogenesis to better affect the outcome of the process. To this end, we have been studying the effects of other angiogenic factors such as angiopoietin-1 (Ang-1) in a chronic ischemic porcine model. Single intramyocardial introduction of adenovirus-mediated gene transfer of Ang-1 into the left ventricle free wall has been found to enhance angiogenesis by augmenting the formation of new capillaries that manifested in improved total blood flow in the myocardium. A combined therapeutic angiogenesis study involving VEGF and Ang-1 is currently underway. Due to their unique complementary properties, it is expected that the combination will not merely enhance angiogenesis but will also lead to healthy and mature vascular network in the ischemic myocardium.
  Journal of Cardiac Surgery 17(4):350-4. · 0.87 Impact Factor
• Article: Structural stability of neoangiogenic intramyocardial microvessels supports functional recovery in chronic ischemic myocardium

  Winston S.N. Shim, Sze Yun Lim, Shi Qi Li, Yacui Gu, Hwee Choo Ong, In Chin Song, Seng Chye Chuah, Philip Wong
  [show abstract] [hide abstract]
  ABSTRACT: We hypothesize that combining angiopoietin-1 (ANG-1) or ANG-2 with vascular endothelial growth factor (VEGF) improves myocardial perfusion and contractile function by modulating vascular adaptation of neoangiogenic microvessels in a chronic ischemic swine model. Four weeks after occlusion of the left circumflex coronary artery (LCx), animals were injected with AdVEGF165 (n = 6), AdVEGF165+AdANG-1 (n = 6), AdVEGF165+AdANG-2 (n = 6) or control vector (n = 5) into the left ventricular posterolateral wall. Regional perfusion by fluorescent microspheres and segmental myocardial tissue velocity by tissue Doppler imaging (TDI) were assessed at baseline, 4 weeks post occlusion and 4 weeks post therapy. Despite similar vascular growth following VEGF+ANG-1 and VEGF+ANG-2 treatments, transmural myocardial contractility improved only when VEGF was paired with ANG-1. In contrast, regional systolic function deteriorated uniformly across subepicardial, mid-myocardial and subendocardial segments in VEGF and VEGF+ANG-2 treated groups. Contractile improvement was associated with enhanced vascular stability through augmented arteriole formation, tight structural integration between VE-cadherin and β-catenin at endothelial junctions and improved cross-talk between endothelium and myocardium. Structural stability of developing intramyocardial microvessels contributes to systolic function during ischemic neovascularization. Coordinated regulation of angiogenic revascularization that supports vascular stability is a key aspect in improving therapeutic outcomes in ischemic myocardium.
  Journal of Molecular and Cellular Cardiology.
• Article: Ex vivo differentiation of human adult bone marrow stem cells into cardiomyocyte-like cells

  Winston S.N. Shim, Shujia Jiang, Philip Wong, Jack Tan, Yeow Leng Chua, Yong Seng Tan, Yoong Kong Sin, Chong Hee Lim, Terrance Chua, Ming Teh, Te Chih Liu, Eugene Sim
  [show abstract] [hide abstract]
  ABSTRACT: Bone marrow mesenchymal stem cells have been shown to transdifferentiate into cardiomyocytes after 5-azacytidine treatment or co-culturing with rodent cardiomyocytes. We investigate if adult human bone marrow stem cells can be differentiated ex vivo into cardiomyocyte-like cells (CLCs) independent of cytotoxic agents or co-culturing technique. Sternal bone marrow was collected from 16 patients undergoing coronary artery bypass surgery. Mesenchymal stem cells were differentiated in a cardiomyogenic differentiation medium containing insulin, dexamethasone, and ascorbic acid. Differentiation towards CLCs was determined by induced expression of cardiomyocyte-specific proteins. Differentiated CLCs expressed multiple structural and contractile proteins that are associated with cardiomyocytes. Thin filament associated myofibrillar proteins were detected early in the cells, with cardiac troponin I, sarcomeric tropomyosin, and cardiac titin among the first expressed. Some CLCs were found to develop into a nascent cardiomyocyte phenotype with cross-striated myofibrils characterized by α-actinin-positive Z bands after 4–5 passages in differentiated culture. These lineage-defined CLCs may be potentially useful for repairing damaged myocardium.
  Biochemical and Biophysical Research Communications.