Song-Yan Liao

MR diffusion tensor imaging study of postinfarct myocardium structural remodeling in a porcine model

This study aimed to investigate postinfarct left ventricular (LV) fiber structural alterations by ex vivo diffusion tensor imaging (DTI) in a porcine heart model. In vivo cardiac MR imaging was first performed to measure ventricular function in six adult pigs with septal infarction near apex induced by the LAD ligation 13 weeks earlier. Hearts were then excised from the infarct pigs (n = 6) and six intact controls (n = 6) and fixed in formalin. High‐resolution DTI was employed to examine changes in fractional anisotropy (FA), apparent diffusion coefficient (ADC), and transmural helix angle distribution in the infarct, adjacent and remote regions as compared to the sham regions in the controls. FA values were found to decrease in the infarct and differ between the adjacent and remote regions. ADC increase in the infarct region was substantial, while changes in the adjacent and remote regions were insignificant. Structurally, the double‐helix myocardial structure shifted toward more left‐handed around the infarcted myocardium. Accordingly, the histological analysis revealed clear fiber structural degradation in the adjacent region. These findings confirmed the subtle alterations in the myocardial fiber quality and structure not only in the infarcted but also in the surrounding noninfarcted myocardium or borderzone. Magn Reson Med 58:687–695, 2007.

Effects of iron oxide nanoparticles on cardiac differentiation of embryonic stem cells

The therapeutic potential of transplantation of embryonic stem cells (ESCs) in animal model of myocardial infarction has been consistently demonstrated. The development of superparamagnetic iron oxide (SPIO) nanoparticles labeling and cardiac magnetic resonance imaging (MRI) have been increasingly used to track the migration of transplanted cells in vivo allowing cell fate determination. However, the impact of SPIO- labeling on cell phenotype and cardiac differentiation capacity of ESCs remains unclear. In this study, we demonstrated that ESCs labeled with SPIO compared to their unlabeled counterparts had similar cardiogenic capacity, and SPIO-labeling did not affect calcium-handling property of ESC-derived cardiomyocytes. Moreover, transplantation of SPIO-labeled ESCs via direct intra-myocardial injection to infarct myocardium resulted in significant improvement in heart function. These findings demonstrated the feasibility of in vivo ESC tracking using SPIO-labeling and cardiac MRI without affecting the cardiac differentiation potential and functional properties of ESCs.

Proarrhythmic risk of embryonic stem cell–derived cardiomyocyte transplantation in infarcted myocardium

BACKGROUND Cellular replacement strategies using embryonic stem cells (ESCs) and their cardiac derivatives are emerging as novel experimental therapeutic paradigms for the treatment of post-myocardial infarction (MI) left ventricular (LV) dysfunction; however, their potential proarrhythmic risk remains unclear. OBJECTIVE The purpose of this study was to investigate the functional effect and proarrhythmic risk of ESC transplantation in a mouse model of MI. METHODS We compared the functional effects and proarrhythmic risk of direct intramyocardial transplantation of 3 × 10(5) undifferentiated mouse ESCs (MI+ESC group, n = 33) and mouse ESC-derived cardiomyocytes (MI+ESC-CM group, n = 40) versus culture medium (MI group, n = 33) at the infarct border zone in a mouse model of acute MI. LV performance was assessed with serial cardiac magnetic resonance imaging (MRI) at 1 and 3 week(s) post-MI, and invasive LV pressure measurement was assessed (dP/dt) at 4 weeks before sacrifice for histological examination. Furthermore, electrophysiological study was also performed in another set of animals in each group (n = 24) to assess for proarrhythmias after transplantation. RESULTS In vitro cellular electrophysiological study demonstrated that ESC-CMs exhibit arrhythmogenesis including automaticity, lengthened action potential duration, and depolarized resting membrane potential. At 4 weeks, the MI+ESC-CM group (21/40, 53%) had a higher mortality rate compared with those in the MI group (10/33, 30%, P = .08) and in the MI+ESC group (7/33, 21%, P = .012). Electrophysiological study showed a significantly higher incidence of inducible ventricular tachyarrhythmias in the MI+ESC-CM group (13/24, 54%) compared with in the MI group (6/24, 21%, P = .039) and in the MI+ESC group (5/24, 21%, P = .017). Cardiac MRI showed similar improvement in LV ejection fraction in the MI+ESC and MI+ESC-CM groups compared with in the MI group at 1 week (27.5% ± 3.8%; 30.3% ± 5.2% vs. 12.4% ± 1.4%; P < .05) and 3 weeks (29.8% ± 3.9%; 27.0% ± 4.8% vs. 10.6% ± 2.8%; P < .05) post-MI, respectively. Furthermore, invasive hemodynamic assessment at 4 weeks showed significant similar improvement in LV +dP/dt in the MI+ESC (2,644 ± 391 mmHg/s, P < .05) and MI+ESC-CM groups (2,539 ± 389 mmHg/s; P < .05) compared with in the MI group (2,042 ± 406 mmHg/s). CONCLUSIONS Our results demonstrate that transplantation of undifferentiated ESCs and ESC-CMs provides similar improvement in cardiac function post-MI. However, transplantation of ESC-CMs is associated with a significantly higher prevalence of inducible ventricular tachyarrhythmias and early mortality than transplantations with ESCs.

MR study of the effect of infarct size and location on left ventricular functional and microstructural alterations in porcine models

To investigate the effect of infarct size and location on left ventricular (LV) functional and microstructural alterations in well‐established porcine models.

Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy

Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) can protect cardiomyocytes against anthracycline-induced cardiomyopathy (AIC) through paracrine effects. Nonetheless the paracrine effects of human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) on AIC are poorly understood. In vitro studies reveal that doxorubicin (Dox)-induced reactive oxidative stress (ROS) generation and cell apoptosis in neonatal rat cardiomyocytes (NRCMs) are significantly reduced when treated with conditioned medium harvested from BM-MSCs (BM-MSCs-CdM) or iPSC-MSCs (iPSC-MSCs-CdM). Compared with BM-MSCs-CdM, NRCMs treated with iPSC-MSCs-CdM exhibit significantly less ROS and cell apoptosis in a dose-dependent manner. Transplantation of BM-MSCs-CdM or iPSC-MSCs-CdM into mice with AIC remarkably attenuated left ventricular (LV) dysfunction and dilatation. Compared with BM-MSCs-CdM, iPSC-MSCs-CdM treatment showed better alleviation of heart failure, less cardiomyocyte apoptosis and fibrosis. Analysis of common and distinct cytokines revealed that macrophage migration inhibitory factor (MIF) and growth differentiation factor-15 (GDF-15) were uniquely overpresented in iPSC-MSC-CdM. Immunodepletion of MIF and GDF-15 in iPSC-MSCs-CdM dramatically decreased cardioprotection. Injection of GDF-15/MIF cytokines could partially reverse Dox-induced heart dysfunction. We suggest that the potent paracrine effects of iPSC-MSCs provide novel “cell-free” therapeutic cardioprotection against AIC, and that MIF and GDF-15 in iPSC-MSCs-CdM are critical for these enhanced cardioprotective effects.

Improved Cell Survival and Paracrine Capacity of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells Promote Therapeutic Potential for Pulmonary Arterial Hypertension

Although transplantation of adult bone marrow mesenchymal stem cells (BM-MSCs) holds promise in the treatment for pulmonary arterial hypertension (PAH), the poor survival and differentiation potential of adult BM-MSCs have limited their therapeutic efficiency. Here, we compared the therapeutic efficacy of human embryonic stem cell-derived MSCs (hESC-MSCs) with adult BM-MSCs for the treatment of PAH in an animal model. One week following monocrotaline (MCT)-induced PAH, mice were randomly assigned to receive phosphate-buffered saline (MCT group); 3.0 × 106 human BM-derived MSCs (BM-MSCs group) or 3.0 × 106 hESC-derived MSCs (hESC-MSCs group) via tail vein injection. At 3 weeks posttransplantation, the right ventricular systolic pressure (RVSP), degree of RV hypertrophy, and medial wall thickening of pulmonary arteries were lower=, and pulmonary capillary density was higher in the hESC-MSC group as compared with BM-MSC and MCT groups (all p < 0.05). At 1 week posttransplantation, the number of engrafted MSCs in the lungs was found significantly higher in the hESC-MSC group than in the BM-MSC group (all p < 0.01). At 3 weeks posttransplantation, implanted BM-MSCs were undetectable whereas hESC-MSCs were not only engrafted in injured pulmonary arteries but had also undergone endothelial differentiation. In addition, protein profiling of hESC-MSC- and BM-MSC-conditioned medium revealed a differential paracrine capacity. Classification of these factors into bioprocesses revealed that secreted factors from hESC-MSCs were preferentially involved in early embryonic development and tissue differentiation, especially blood vessel morphogenesis. We concluded that improved cell survival and paracrine capacity of hESC-MSCs provide better therapeutic efficacy than BM-MSCs in the treatment for PAH.

Thoracic Spinal Cord Stimulation Improves Cardiac Contractile Function and Myocardial Oxygen Consumption in a Porcine Model of Ischemic Heart Failure

Thoracic Spinal Cord Stimulation. Background: Prior experimental studies show that thoracic spinal cord stimulation (SCS) improves left ventricular (LV) ejection fraction (LVEF). The mechanism of this improvement in the LV contractile function after SCS and its effects on the myocardial oxygen consumption remains unknown.

Hyperthyroidism-induced left ventricular diastolic dysfunction: implication in hyperthyroidism-related heart failure

Background  Heart failure occurs in 6% of hyperthyroid patients. Nonetheless, only half of those with hyperthyroidism‐related heart failure have impaired left ventricular (LV) systolic function. Thus, diastolic dysfunction may play an important role in the pathogenesis.

Stem cells for myocardial repair

There is a growing interest in the clinical application for stem cell as a novel therapy for treatment of acute myocardial infarction and chronic myocardial ischaemia. The initial premise is the transplanted exogenous stem cells can engraft and integrate with host myocardium for cardiac regeneration. However, recent experimental studies suggest that multiple mechanisms, including remodelling of extracellular matrix, enhancement of neovascularisation and recruitment of endogenous stem cells are more likely to contribute to the beneficial effects of stem cell therapy that direct trans-differentiation of stem cells into functional myocardium. Among different potential cell sources, bone marrow-derived cells and skeletal myoblasts have been tested in pilot clinical trials. Phase I/II randomised controlled clinical trials suggest that intracoronary or intramyocardial injection of bone marrow-derived cells may be safe and feasible strategies for treatment of acute myocardial infarction as well as chronic myocardial ischaemia. In addition, these studies show a modest, but significant improvement in left ventricular ejection fraction and clinical status of patients after cell transplantation. Nevertheless, most of these studies included a relatively small sample size (<200) and short duration of follow-up (<6 months), and the clinical efficacy of stem cell therapy need to be confirmed by future clinical trials. Furthermore, the optimal timing, cell types and mode of delivery need to be addressed, and strategies to improve cell survival and engraftment should also be developed to overcome the potential hurdles related to cell-based therapy.

iPSC-MSCs with High Intrinsic Miro1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-induced Cardiomyopathy

Summary Mesenchymal stem cells (MSCs) can donate mitochondria and rescue anthracycline-induced cardiomyocyte (CM) damage, although the underlying mechanisms remain elusive. We determined that the superior efficiency of mitochondrial transfer by human induced-pluripotent-stem-cell-derived MSCs (iPSC-MSCs) compared with bone marrow-derived MSCs (BM-MSCs) is due to high expression of intrinsic Rho GTPase 1 (MIRO1). Further, due to a higher level of TNFαIP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-α)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-α/NF-κB/TNFαIP2 signaling pathway. Inhibition of TNFαIP2 or MIRO1 in iPSC-MSCs reduced the efficiency of mitochondrial transfer and decreased CMs protection. Compared with BM-MSCs, transplantation of iPSC-MSCs into a mouse model of anthracycline-induced cardiomyopathy resulted in more human mitochondrial retention and bioenergetic preservation in heart tissue. Efficacious transfer of mitochondria from iPSC-MSCs to CMs, due to higher MIRO1 expression and responsiveness to TNF-α-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.