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Stem cell therapy has been proved to be an effective approach to ameliorate the heart remodeling post myocardial infarction (MI). However, poor cell engraftment and survival in ischemic myocardium limits the successful use of cellular therapy for treating MI. Here, we sought to transplant adipose derived-mesenchymal stem cells (AD-MSCs) with a hydrogel (NapFF-NO), naphthalene covalently conjugated a short peptide, FFGGG, and β-galactose caged nitric oxide (NO) donor, which can release NO molecule in response to β-galactosidase. AD-MSCs, either from transgenic mice that constitutively express GFP and firefly luciferase (Fluc), or express Fluc under the control of VEGFR2 promoter, were co-transplanted with NapFF-NO hydrogel into murine MI models. Improved cell survival and enhanced cardiac function were confirmed by bioluminescence imaging (BLI) and echocardiogram respectively. Moreover, increasing VEGFR2-luc expression was also tracked in real-time in vivo, indicating NapFF-NO hydrogel stimulated VEGF secretion of AD-MSCs. To investigate the therapeutic mechanism of NapFF-NO hydrogel, cell migration assay, paracrine action of AD-MSCs, and histology analysis were carried out. Our results revealed that condition medium from AD-MSCs cultured with NapFF-NO hydrogel could promote endothelial cell migration. Additionally, AD-MSCs showed significant improvement secretion of angiogenic factors VEGF and SDF-1α in the presence of NapFF-NO hydrogel. Finally, postmortem analysis confirmed that transplanted AD-MSCs with NapFF-NO hydrogel could ameliorate heart function by promoting angiogenesis and attenuating ventricular remodeling. In conclusion, NapFF-NO hydrogel can obviously improve therapeutic efficacy of AD-MSCs for MI by increasing cell engraftment and angiogenic paracrine action., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Netrin-1 is typically known as a neuronal guidance factor. Studies have reported the proangiogenic, antiapoptotic, and antiinflammatory properties of Netrin-1. A critical role for Netrin-1 in ischemic organ damage, myocardial infarction (MI) in particular, has also been demonstrated, making Netrin-1 a potential therapeutic target for the treatment of cardiovascular diseases (CVDs). Mesenchymal stem cells (MSCs) have shown promising therapeutic efficacy in preclinical studies. However, limited clinical success was observed, mainly due to poor MSC survival. Given the reported beneficial impact of Netrin-1 in tissue repair and cell survival, we examined the effects of Netrin-1 in MSC therapy against MI-induced ischemic cardiac injury in rats and type 2 diabetic (T2D) mice. MSCs were isolated and Netrin-1-expressing MSCs were obtained by transduction with a Netrin-1-encoding retroviral vector. The Netrin-1-MSCs were then delivered intramyocardially to the infarct sites of rats and T2D mice with MI. Thirty days after MSC implantation, changes at the infarct area, level of collagen deposition, and cardiac hypertrophy were assessed. Molecular mechanisms underlying the effects of Netrin-1 were also investigated. Attenuated MI-induced myocardial dysfunction was observed after Netrin-1-MSC treatment. Protective effects of the Netrin-1-MSCs were attributable primarily to better MSC survival and migration, which is mediated by Netrin-1-induced phosphorylation of p44/42 mitogen-activated protein kinase. Netrin-1-stimulated nitric oxide production was also responsible, which could promote neovessel formation and progenitor cell mobilization in vivo. We report a protective role for Netrin-1 against MI-induced ischemic injuries, reinstating its promising potential as a therapeutic target for CVDs and, more importantly, for patients with CVD with coexisting diabetes.

Aims: Parthenogenetic embryonic stem cells (pESCs) derived from artificially activated oocytes without fertilization presumably raise minimal ethical concerns and may serve as attractive candidates for regenerative medicine. Here we investigated whether pESCs could repair myocardial infarction (MI), in comparison to embryonic stem cells (ESCs)., Methods and Results: A total of 89 mice that survived coronary artery ligation randomly received an intramyocardial injection of undifferentiated pESCs, ESCs, or saline. Sham-operated mice (n = 21) that received no treatment served as control animals. After 7 days, transplantation of pESCs increased expression of pro-angiogenic factors and reduced leucocyte infiltration. By 14 and 30 days post-MI, similar to treatment with ESCs, treatment with pESCs efficiently prevented cardiac remodelling and enhanced angiogenesis, in contrast to saline-treated hearts. Improved heart contractile function was also notable 30 days following transplantation of pESCs. Immunofluorescence staining revealed that tissues regenerated from pESCs in the infarcted myocardium were positive for markers of cardiomyocytes, endothelial cells, and smooth muscle cells. Unlike ESC-treated mice, which exhibited a high incidence of teratoma (6 of 34), the pESC-treated mice showed no teratomas (0 of 30) 30 days following transplantation., Conclusion: Transplantation of pESCs could attenuate cardiac dysfunction and adverse ventricular remodelling post-MI, suggesting that pESCs may provide promising therapeutic sources for MI in females.