Thymosin ß4 increases cardiac cell proliferation, cell engraftment, and the reparative potency of human induced-pluripotent stem cell-derived cardiomyocytes in a porcine model of acute myocardial infarction.

Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.

Small dense low-density lipoproteins and associated risk factors in patients with stroke.

OBJECTIVE: Low-density lipoproteins (LDL) are a heterogeneous group of particles, with small, dense particles being more atherogenic. It remains controversial whether elevated plasma levels of small dense LDL (sd-LDL) are risk factors for stroke. The aim of the present study was to examine the plasma levels of sd-LDL in patients with stroke and to investigate the associations in a large Chinese case-control study. METHODS: We recruited 299 stroke patients (159 cerebral thrombosis, 42 lacunar infarction, 98 intracerebral hemorrhage) and 299 controls. The semiquantitative analysis of plasma levels of sd-LDL was performed by nondenaturing gradient gel electrophoresis. RESULTS: (1) The plasma levels of sd-LDL in patients with ischemic stroke or hemorrhagic stroke were higher than in controls. (2) Multiple regression analysis showed that there were significant relationships between sd-LDL and triglyceride, high-density lipoprotein cholesterol, LDL cholesterol, systolic blood pressure and history of diabetes, and a significant relationship between sd-LDL and stroke (r = 0.286, p < 0.001) even after adjusting for these factors. (3) Compared with the controls, the calculation of odds ratios indicated relative risk estimates of 3.111 for ischemic stroke (OR = 3.111 , 95% CI = 1.891-5.117, p < 0.001) and 3.164 for hemorrhagic stroke (OR = 3.164, 95% CI = 1.632-6.137, p < 0.01). CONCLUSION: Plasma sd-LDL was independently associated with both thrombotic and hemorrhagic stroke, suggesting it may be an independent predictor of as well as a risk factor for stroke in Chinese people, justifying clinical trials for primary and secondary prevention of stroke using statins or fibrates.