Lihan Wang

Temperature-dependent photoluminescence of quasialigned Al-doped ZnO nanorods

Temperature-dependent photoluminescence (PL) properties of quasialigned Al-doped ZnO nanorods grown by thermal evaporation method were investigated. The ionization energy of the Al donor was determined to be ∼90meV. A PL peak at 3.315eV was observed at low temperature and was tentatively related to excitons bound to surface defects. The emission, along with its first longitudinal optical phonon replica, persists up to room temperature and dominates the near band edge (NBE) emission of the nanorods. The doping of Al results in a redshift of ∼0.04eV of the room-temperature NBE emission of the ZnO nanorods.

Leptin Signaling Is Required for Augmented Therapeutic Properties of Mesenchymal Stem Cells Conferred by Hypoxia Preconditioning

Hypoxia preconditioning enhances the therapeutic effect of mesenchymal stem cells (MSCs). However, the mechanism underlying hypoxia‐induced augmentation of the protective effect of MSCs on myocardial infarction (MI) is poorly understood. We show that hypoxia‐enhanced survival, mobility, and protection of cocultured cardiomyocytes were paralleled by increased expression of leptin and cell surface receptor CXCR4. The enhanced activities were abolished by either knockdown of leptin with a selective shRNA or by genetic deficiency of leptin or its receptor in MSCs derived, respectively, from ob/ob or db/db mice. To characterize the role of leptin in the regulation of MSC functions by hypoxia and its possible contribution to enhanced therapeutic efficacy, cell therapy using MSCs derived from wild‐type, ob/ob, or db/db mice was implemented in mouse models of acute MI. Augmented protection by hypoxia pretreatment was only seen with MSCs from wild‐type mice. Parameters that were differentially affected by hypoxia pretreatment included MSC engraftment, c‐Kit+ cell recruitment to the infarct, vascular density, infarct size, and long‐term contractile function. These data show that leptin signaling is an early and essential step for the enhanced survival, chemotaxis, and therapeutic properties of MSCs conferred by preculture under hypoxia. Leptin may play a physiological role in priming MSCs resident in the bone marrow endosteum for optimal response to systemic signaling molecules and subsequent tissue repair. Stem Cells 2014;32:2702–2713

SIRT1 ameliorates age-related senescence of mesenchymal stem cells via modulating telomere shelterin

Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD+-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation. These results suggest that SIRT1 plays a key role in modulating age-induced MSCs senescence. Aging-related proteins, P16 and P21 may be downstream effectors of the SIRT1-mediated anti-aging effects. SIRT1 protected MSCs from age-related DNA damage, induced telomerase reverse transcriptase (TERT) expression and enhanced telomerase activity but did not affect telomere length. SIRT1 positively regulated the expression of tripeptidyl peptidase 1 (TPP1), a component of the shelterin pathway that protects chromosome ends from DNA damage. Together, the results demonstrate that SIRT1 quenches age-related MSCs senescence by mechanisms that include enhanced TPP1 expression, increased telomerase activity and reduced DNA damage.

Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA-21

Our group recently reported positive therapeutic benefit of human endometrium‐derived mesenchymal stem cells (EnMSCs) delivered to infarcted rat myocardium, an effect that correlated with enhanced secretion of protective cytokines and growth factors compared with parallel cultures of human bone marrow MSCs (BMMSCs). To define more precisely the molecular mechanisms of EnMSC therapy, in the present study, we assessed in parallel the paracrine and therapeutic properties of MSCs derived from endometrium, bone marrow, and adipose tissues in a rat model of myocardial infarction (MI). EnMSCs, BMMSCs, and adipose‐derived MSCs (AdMSCs) were characterized by fluorescence‐activated cell sorting (FACS). Paracrine and cytoprotective actions were assessed in vitro by coculture with neonatal cardiomyocytes and human umbilical vein endothelial cells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superior cardioprotection relative to BMMSCs or AdMSCs and supported enhanced microvessel density. Inhibitor studies indicated that the enhanced paracrine actions of EnMSCs were mediated by secreted exosomes. Analyses of exosomal microRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR‐21 expression was selectively enhanced in exosomes derived from EnMSCs. Selective antagonism of miR‐21 by anti‐miR treatment abolished the antiapoptotic and angiogenic effects of EnMSCs with parallel effects on phosphatase and tensin homolog (PTEN), a miR‐21 target and downstream Akt. The results of the present study confirm the superior cardioprotection by EnMSCs relative to BMMSCs or AdMSCs and implicates miR‐21 as a potential mediator of EnMSC therapy by enhancing cell survival through the PTEN/Akt pathway. The endometrium might be a preferential source of MSCs for cardiovascular cell therapy. Stem Cells Translational Medicine 2017;6:209–222

Human endometrial stem cells confer enhanced myocardial salvage and regeneration by paracrine mechanisms

Human endometrial stem cells (EnSCs) have the potential to be ‘off the shelf’ clinical reagents for the treatment of heart failure. Here, using an immunocompetent rat model of myocardial infarction (MI), we provide evidence that the functional benefits of EnSC transplantation are principally and possibly exclusively through a paracrine effect. Human EnSCs were delivered by intramyocardial injection into rats 30 min. after coronary ligation. EnSC therapy significantly preserved viable myocardium in the infarct zone and improved cardiac function at 28 days. Despite increased viable myocardium and vascular density, there was scant evidence of differentiation of EnSCs into any cardiovascular cell type. Cultured human EnSCs expressed a distinctive profile of cytokines that enhanced the survival, proliferation and function of endothelial cells in vitro. When injected into the peri‐infarct zone, human EnSCs activated AKT, ERK1/2 and STAT3 and inhibited the p38 signalling pathway. EnSC therapy decreased apoptosis and promoted cell proliferation and c‐kit+ cell recruitment in vivo. Myocardial protection and enhanced post‐infarction regeneration by EnSCs is mediated primarily by paracrine effects conferred by secreted cytokines that activate survival pathways and recruit endogenous progenitor stem cells. Menstrual blood provides a potentially limitless source of biologically competent ‘off the shelf’ EnSCs for allogeneic myocardial regenerative medicine.

Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis

Autophagy is the basic catabolic progress involved in cell degradation of unnecessary or dysfunctional cellular components. It has been proven that autophagy could be utilized for cell survival under stresses. Hypoxic-preconditioning (HPC) could reduce apoptosis induced by ischemia and hypoxia/serum deprivation (H/SD) in bone marrow-derived mesenchymal stem cells (BMSCs). Previous studies have shown that both leptin signaling and autophagy activation were involved in the protection against apoptosis induced by various stress, including ischemia-reperfusion. However, it has never been fully understood how leptin was involved in the protective effects conferred by autophagy. In the present study, we demonstrated that HPC can induce autophagy in BMSCs by increased LC3-II/LC3-I ratio and autophagosome formation. Interestingly, similar effects were also observed when BMSCs were pretreated with rapamycin. The beneficial effects offered by HPC were absent when BMSCs were incubated with autophagy inhibitor, 3-methyladenine (3-MA). In addition, down-regulated leptin expression by leptin-shRNA also attenuated HPC-induced autophagy in BMSCs, which in turn was associated with increased apoptosis after exposed to sustained H/SD. Furthermore, increased AMP-activated protein kinase phosphorylation and decreased mammalian target of rapamycin phosphorylation that were observed in HPC-treated BMSCs can also be attenuated by down-regulation of leptin expression. Our data suggests that leptin has impact on HPC-induced autophagy in BMSCs which confers protection against apoptosis under H/SD, possibly through modulating both AMPK and mTOR pathway.

Rational synthesis and tunable optical properties of quasialigned Zn1−xMgxO nanorods

Quasialigned, single-crystal Zn1−xMgxO (x=0–0.32) nanorods were synthesized on Si substrates by thermal evaporation. Zn1−xMgxO nanorods grew along the [0001] crystal direction and had uniform hexagonal planes with diameters of 420–120nm. The predominant ultraviolet luminescence could be tuned from 379 (x=0) to 305nm (x=0.32) at room temperature. This blueshift indicated the band gap engineering in Zn1−xMgxO nanorods. Temperature-dependent photoluminescence was used to illustrate the free-exciton emission from Zn1−xMgxO nanorods. The exciton binding energy decreased from 59 (x=0) to 49meV (x=0.18) and then increased to 54meV (x=0.32).

Preconditioning via Angiotensin Type 2 Receptor Activation Improves Therapeutic Efficacy of Bone Marrow Mononuclear Cells for Cardiac Repair

Background The therapeutic efficiency of bone marrow mononuclear cells (BMMNCs) autologous transplantation for myocardial infarction (MI) remains low. Here we developed a novel strategy to improve cardiac repair by preconditioning BMMNCs via angiotensin II type 2 receptor (AT2R) stimulation. Methods and Results Acute MI in rats led to a significant increase of AT2R expression in BMMNCs. Preconditioning of BMMNCs via AT2R stimulation directly with an AT2R agonist CGP42112A or indirectly with angiotensin II plus AT1R antagonist valsartan led to ERK activation and increased eNOS expression as well as subsequent nitric oxide generation, ultimately improved cardiomyocyte protection in vitro as measured by co-culture approach. Intramyocardial transplantation of BMMNCs preconditioned via AT2R stimulation improved survival of transplanted cells in ischemic region of heart tissue and reduced cardiomyocyte apoptosis and inflammation at 3 days after MI. At 4 weeks after transplantation, compared to DMEM and non-preconditioned BMMNCs group, AT2R stimulated BMMNCs group showed enhanced vessel density in peri-infarct region and attenuated infarct size, leading to global heart function improvement. Conclusions Preconditioning of BMMNCs via AT2R stimulation exerts protective effect against MI. Stimulation of AT2R in BMMNCs may provide a new strategy to improving therapeutic efficiency of stem cells for post MI cardiac repair.

Transplantation of SIRT1-engineered aged mesenchymal stem cells improves cardiac function in a rat myocardial infarction model

BACKGROUND Previous studies have demonstrated that biological aging has a negative influence on the therapeutic effects of mesenchymal stem cells (MSCs)-based therapy. Using a rat myocardial infarction (MI) model, we tested the hypothesis that silent mating type information regulation 2 homolog 1 (SIRT1) may ameliorate the phenotype and improve the function of aged MSCs and thus enhance the efficacy of aged MSCs-based therapy. METHODS Sixty female rats underwent left anterior descending coronary artery ligation and were randomly assigned to receiving: intramyocardial injection of cell culture medium (DMEM group); SIRT1 overexpression vector-treated aged MSCs (SIRT1-aged MSCs group) obtained from aged male SD rats or empty vector-treated aged MSCs (vector-aged MSCs group). Another 20 sham-operated rats that underwent open-chest surgery without coronary ligation or any other intervention served as controls. RESULTS SIRT1-aged MSC group exhibited enhanced blood vessel density in the border zone of MI hearts, which was associated with reduced cardiac remodeling, leading to improved cardiac performance. Consistent with the in vivo data, our in vitro experiments also demonstrated that SIRT1 overexpression ameliorated aged MSCs senescent phenotype and recapitulated the pro-angiogenesis property of MSCs and conferred the anti-stress response capabilities, as indicated by increases in pro-angiogenic factors, angiopoietin 1 (Ang1) and basic fibroblast growth factor (bFGF), expressions and a decrease in anti-angiogenic factor thrombospondin-1 (TBS1) at mRNA levels, and increases in Bcl-2/Bax ratio at protein level. CONCLUSIONS Up-regulating SIRT1 expression could enhance the efficacy of aged MSCs-based therapy for MI as it relates to the amelioration of senescent phenotype and hence improved biological function of aged MSCs.

Lack of an Association Between Interleukin-6 −174G/C Polymorphism and Circulating Interleukin-6 Levels in Normal Population: A Meta-Analysis

Interleukin-6 (IL-6) signaling may play a causal role in the development of coronary heart disease. However, the relationship between IL-6 genotypes and plasma levels of IL-6 appears to be complex. To help clarify the inconsistent findings, we conducted a meta-analysis of the published genetic association studies of the -174 G/C polymorphisms in the IL-6 gene and the circulating IL-6 levels in a normal population. In this meta-analysis, no significant association of IL-6 -174G/C polymorphism and circulating IL-6 levels in a normal population was observed. However, when compared among GG, GC, and CC genotypes, heterogeneity existed among the studies. Sensitivity analysis revealed that, the independent study by Shen et al. influenced the heterogeneity in the homozygous and heterozygous comparison. Although Shen et al.s study was excluded, no significant association was observed between IL-6 -174G/C polymorphism and circulating IL-6 levels in a normal population [homozygous comparison (GG vs. CC): the pooled standard mean difference (SMD) was -0.01, 95% confidence interval (CI): -0.1-0.08; heterozygous comparison (GC vs. GG or CC): the pooled SMD (GG vs. GC) was -0.05, 95%CI: -0.11-0.01, and the pooled SMD (CC vs. GC) was 0.03, 95%CI: -0.03-0.1]. Under the dominant model, the pooled SMD was -0.05, 95%CI: -0.11-0.01). The meta-analysis provides evidence that the -174G/C polymorphism in the IL-6 gene is not significantly associated with circulating IL-6 levels in a normal population.