Bio

Honors & Awards


  • Western States Affiliate Postdoctoral Fellowship, American Heart Association (2015-2016)

Professional Education


  • Doctor of Philosophy, University College London (2011)
  • Master of Science, University of Manchester (2008)
  • Bachelor of Science, Unlisted University (2006)

Stanford Advisors


Publications

Journal Articles


  • Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism. European heart journal Gu, M., Mordwinkin, N. M., Kooreman, N. G., Lee, J., Wu, H., Hu, S., Churko, J. M., Diecke, S., Burridge, P. W., He, C., Barron, F. E., Ong, S., Gold, J. D., Wu, J. C. 2015; 36 (13): 806-816

    Abstract

    High-fat diet-induced obesity (DIO) is a major contributor to type II diabetes and micro- and macro-vascular complications leading to peripheral vascular disease (PVD). Metabolic abnormalities of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from obese individuals could potentially limit their therapeutic efficacy for PVD. The aim of this study was to compare the function of iPSC-ECs from normal and DIO mice using comprehensive in vitro and in vivo assays.Six-week-old C57Bl/6 mice were fed with a normal or high-fat diet. At 24 weeks, iPSCs were generated from tail tip fibroblasts and differentiated into iPSC-ECs using a directed monolayer approach. In vitro functional analysis revealed that iPSC-ECs from DIO mice had significantly decreased capacity to form capillary-like networks, diminished migration, and lower proliferation. Microarray and ELISA confirmed elevated apoptotic, inflammatory, and oxidative stress pathways in DIO iPSC-ECs. Following hindlimb ischaemia, mice receiving intramuscular injections of DIO iPSC-ECs had significantly decreased reperfusion compared with mice injected with control healthy iPSC-ECs. Hindlimb sections revealed increased muscle atrophy and presence of inflammatory cells in mice receiving DIO iPSC-ECs. When pravastatin was co-administered to mice receiving DIO iPSC-ECs, a significant increase in reperfusion was observed; however, this beneficial effect was blunted by co-administration of the nitric oxide synthase inhibitor, N(ω)-nitro-l-arginine methyl ester.This is the first study to provide evidence that iPSC-ECs from DIO mice exhibit signs of endothelial dysfunction and have suboptimal efficacy following transplantation in a hindlimb ischaemia model. These findings may have important implications for future treatment of PVD using iPSC-ECs in the obese population.

    View details for DOI 10.1093/eurheartj/ehu411

    View details for PubMedID 25368203

  • Variable activation of the DNA damage response pathways in patients undergoing single-photon emission computed tomography myocardial perfusion imaging. Circulation. Cardiovascular imaging Hee Lee, W., Nguyen, P., Hu, S., Liang, G., Ong, S., Han, L., Sanchez-Freire, V., Lee, A. S., Vasanawala, M., Segall, G., Wu, J. C. 2015; 8 (2)

    Abstract

    Although single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) has improved the diagnosis and risk stratification of patients with suspected coronary artery disease, it remains a primary source of low-dose radiation exposure for cardiac patients. To determine the biological effects of low-dose radiation from SPECT MPI, we measured the activation of the DNA damage response pathways using quantitative flow cytometry and single-cell gene expression profiling.Blood samples were collected from patients before and after SPECT MPI (n=63). Overall, analysis of all recruited patients showed no marked differences in the phosphorylation of proteins (H2AX, protein 53, and ataxia telangiectasia mutated) after SPECT. The majority of patients also had either downregulated or unchanged expression in DNA damage response genes at both 24 and 48 hours post-SPECT. Interestingly, a small subset of patients with increased phosphorylation had significant upregulation of genes associated with DNA damage, whereas those with no changes in phosphorylation had significant downregulation or no difference, suggesting that some patients may potentially be more sensitive to low-dose radiation exposure.Our findings showed that SPECT MPI resulted in a variable activation of the DNA damage response pathways. Although only a small subset of patients had increased protein phosphorylation and elevated gene expression postimaging, continued care should be taken to reduce radiation exposure to both the patients and operators.

    View details for DOI 10.1161/CIRCIMAGING.114.002851

    View details for PubMedID 25609688

  • Response to Letter Regarding Article, "Cross Talk of Combined Gene and Cell Therapy in Ischemic Heart Disease: Role of Exosomal MicroRNA Transfer". Circulation Ong, S. G., Lee, W. H., Huang, M., Dey, D., Kodo, K., Sanchez-Freire, V., Gold, J. D., Wu, J. C. 2015; 131 (12): e385

    View details for DOI 10.1161/CIRCULATIONAHA.114.014467

    View details for PubMedID 25802264

  • MicroRNA-mediated Regulation of Differentiation and Trans-differentiation in Stem Cells. Advanced drug delivery reviews Ong, S. G., Lee, W. H., Kodo, K., Wu, J. C. 2015

    Abstract

    MicroRNAs (miRNAs) are key components of a broadly conserved post-transcriptional mechanism that controls gene expression by targeting mRNAs. miRNAs regulate diverse biological processes, including the growth and differentiation of stem cells as well as the regulation of both endogenous tissue repair that has critical implications in the development of regenerative medicine approaches. In this review, we first describe key features of miRNA biogenesis and their role in regulating self-renewal, and then discuss the involvement of miRNAs in the determination of cell fate decisions. We highlight the role of miRNAs in the emergent field of reprogramming and trans-differentiation of somatic cells that could further our understanding of miRNA biology and regenerative medicine applications. Finally, we describe potential techniques for proper delivery of miRNAs in target cells.

    View details for DOI 10.1016/j.addr.2015.04.004

    View details for PubMedID 25887992

  • HIF-1 reduces ischaemia-reperfusion injury in the heart by targeting the mitochondrial permeability transition pore CARDIOVASCULAR RESEARCH Ong, S., Lee, W. H., Theodorou, L., Kodo, K., Lim, S. Y., Shukla, D. H., Briston, T., Kiriakidis, S., Ashcroft, M., Davidson, S. M., Maxwell, P. H., Yellon, D. M., Hausenloy, D. J. 2014; 104 (1): 24-36

    View details for DOI 10.1093/cvr/cvu172

    View details for Web of Science ID 000343317000005

  • Effect of human donor cell source on differentiation and function of cardiac induced pluripotent stem cells. Journal of the American College of Cardiology Sanchez-Freire, V., Lee, A. S., Hu, S., Abilez, O. J., Liang, P., Lan, F., Huber, B. C., Ong, S., Hong, W. X., Huang, M., Wu, J. C. 2014; 64 (5): 436-448

    Abstract

    Human-induced pluripotent stem cells (iPSCs) are a potentially unlimited source for generation of cardiomyocytes (iPSC-CMs). However, current protocols for iPSC-CM derivation face several challenges, including variability in somatic cell sources and inconsistencies in cardiac differentiation efficiency.This study aimed to assess the effect of epigenetic memory on differentiation and function of iPSC-CMs generated from somatic cell sources of cardiac versus noncardiac origins.Cardiac progenitor cells (CPCs) and skin fibroblasts from the same donors were reprogrammed into iPSCs and differentiated into iPSC-CMs via embryoid body and monolayer-based differentiation protocols.Differentiation efficiency was found to be higher in CPC-derived iPSC-CMs (CPC-iPSC-CMs) than in fibroblast-derived iPSC-CMs (Fib-iPSC-CMs). Gene expression analysis during cardiac differentiation demonstrated up-regulation of cardiac transcription factors in CPC-iPSC-CMs, including NKX2-5, MESP1, ISL1, HAND2, MYOCD, MEF2C, and GATA4. Epigenetic assessment revealed higher methylation in the promoter region of NKX2-5 in Fib-iPSC-CMs compared with CPC-iPSC-CMs. Epigenetic differences were found to dissipate with increased cell passaging, and a battery of in vitro assays revealed no significant differences in their morphological and electrophysiological properties at early passage. Finally, cell delivery into a small animal myocardial infarction model indicated that CPC-iPSC-CMs and Fib-iPSC-CMs possess comparable therapeutic capabilities in improving functional recovery in vivo.This is the first study to compare differentiation of iPSC-CMs from human CPCs versus human fibroblasts from the same donors. The authors demonstrate that although epigenetic memory improves differentiation efficiency of cardiac versus noncardiac somatic cell sources in vitro, it does not contribute to improved functional outcome in vivo.

    View details for DOI 10.1016/j.jacc.2014.04.056

    View details for PubMedID 25082575

  • Cross Talk of Combined Gene and Cell Therapy in Ischemic Heart Disease: Role of Exosomal MicroRNA Transfer. Circulation Ong, S. G., Lee, W. H., Huang, M., Dey, D., Kodo, K., Sanchez-Freire, V., Gold, J. D., Wu, J. C. 2014; 130 (11 Suppl 1): S60-9

    Abstract

    Despite the promise shown by stem cells for restoration of cardiac function after myocardial infarction, the poor survival of transplanted cells has been a major issue. Hypoxia-inducible factor-1 (HIF1) is a transcription factor that mediates adaptive responses to ischemia. Here, we hypothesize that codelivery of cardiac progenitor cells (CPCs) with a nonviral minicircle plasmid carrying HIF1 (MC-HIF1) into the ischemic myocardium can improve the survival of transplanted CPCs.After myocardial infarction, CPCs were codelivered intramyocardially into adult NOD/SCID mice with saline, MC-green fluorescent protein, or MC-HIF1 versus MC-HIF1 alone (n=10 per group). Bioluminescence imaging demonstrated better survival when CPCs were codelivered with MC-HIF1. Importantly, echocardiography showed mice injected with CPCs+MC-HIF1 had the highest ejection fraction 6 weeks after myocardial infarction (57.1±2.6%; P=0.002) followed by MC-HIF1 alone (48.5±2.6%; P=0.04), with no significant protection for CPCs+MC-green fluorescent protein (44.8±3.3%; P=NS) when compared with saline control (38.7±3.2%). In vitro mechanistic studies confirmed that cardiac endothelial cells produced exosomes that were actively internalized by recipient CPCs. Exosomes purified from endothelial cells overexpressing HIF1 had higher contents of miR-126 and miR-210. These microRNAs activated prosurvival kinases and induced a glycolytic switch in recipient CPCs, giving them increased tolerance when subjected to in vitro hypoxic stress. Inhibiting both of these miRs blocked the protective effects of the exosomes.In summary, HIF1 can be used to modulate the host microenvironment for improving survival of transplanted cells. The exosomal transfer of miRs from host cells to transplanted cells represents a unique mechanism that can be potentially targeted for improving survival of transplanted cells.

    View details for DOI 10.1161/CIRCULATIONAHA.113.007917

    View details for PubMedID 25200057

  • Cortical bone-derived stem cells: a novel class of cells for myocardial protection. Circulation research Ong, S., Wu, J. C. 2013; 113 (5): 480-483

    View details for DOI 10.1161/CIRCRESAHA.113.302083

    View details for PubMedID 23948579

  • Development of Poly(beta-amino ester)-Based Biodegradable Nanoparticles for Nonviral Delivery of Minicircle DNA ACS NANO Keeney, M., Ong, S., Padilla, A., Yao, Z., Goodman, S., Wu, J. C., Yang, F. 2013; 7 (8): 7241-7250

    Abstract

    Gene therapy provides a powerful tool for regulating cellular processes and tissue repair. Minicircle (MC) DNA are supercoiled DNA molecules free of bacterial plasmid backbone elements and have been reported to enhance prolonged gene expression compared to conventional plasmids. Despite the great promise of MC DNA for gene therapy, methods for safe and efficient MC DNA delivery remain lacking. To overcome this bottleneck, here we report the development of a poly(β-amino ester) (PBAE)-based, biodegradable nanoparticulate platform for efficient delivery of MC DNA driven by a Ubc promoter in vitro and in vivo. By synthesizing and screening a small library of 18 PBAE polymers with different backbone and end-group chemistry, we identified lead cationic PBAE structures that can complex with minicircle DNA to form nanoparticles, and delivery efficiency can be further modulated by tuning PBAE chemistry. Using human embryonic kidney 293 cells and mouse embryonic fibroblasts as model cell types, we identified a few PBAE polymers that allow efficient MC delivery at levels that are comparable or even surpassing Lipofectamine 2000. The biodegradable nature of PBAE-based nanoparticles facilitates in vivo applications and clinical translation. When injected via intraperitoneal route in vivo, MC alone resulted in high transgene expression, and a lead PBAE/MC nanoparticle formulation achieved a further 2-fold increase in protein expression compared to MC alone. Together, our results highlight the promise of PBAE-based nanoparticles as promising nonviral gene carriers for MC delivery, which may provide a valuable tool for broad applications of MC DNA-based gene therapy.

    View details for DOI 10.1021/nn402657d

    View details for Web of Science ID 000323810600089

    View details for PubMedID 23837668

  • Hypoxia-inducible factor as a therapeutic target for cardioprotection PHARMACOLOGY & THERAPEUTICS Ong, S., Hausenloy, D. J. 2012; 136 (1): 69-81

    Abstract

    Hypoxia inducible factor (HIF) is an oxygen-sensitive transcription factor that enables aerobic organisms to adapt to hypoxia. This is achieved through the transcriptional activation of up to 200 genes, many of which are critical to cell survival. Under conditions of normoxia, the hydroxylation of HIF by prolyl hydroxylase domain-containing (PHD) enzymes targets it for polyubiquitination and proteosomal degradation by the von Hippel-Lindau protein (VHL). However, under hypoxic conditions, PHD activity is inhibited, thereby allowing HIF to accumulate and translocate to the nucleus, where it binds to the hypoxia-responsive element sequences of target gene promoters. Experimental studies suggest that HIF may act as a mediator of ischemic preconditioning, and that the genetic or pharmacological stabilization of HIF under normoxic conditions, may protect the heart against the detrimental effects of acute ischemia-reperfusion injury. The mechanisms underlying the cardioprotective effect of HIF are unclear, but it may be attributed to the transcriptional activation of genes associated with cardioprotection such as erythropoietin, heme oxygenase-1, and inducible nitric oxide synthase or it may be due to reprogramming of cell metabolism. In this review article, we highlight the role of HIF in mediating both adaptive and pathological processes in the heart, as well as focusing on the therapeutic potential of the HIF-signaling pathway as a target for cardioprotection.

    View details for DOI 10.1016/j.pharmthera.2012.07.005

    View details for Web of Science ID 000309034600006

    View details for PubMedID 22800800

  • Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Smith, C. C., Dixon, R. A., Wynne, A. M., Theodorou, L., Ong, S., Subrayan, S., Davidson, S. M., Hausenloy, D. J., Yellon, D. M. 2010; 299 (4): H1265-H1270

    Abstract

    Leptin-induced protection against myocardial ischemia-reperfusion (I/R) injury involves the activation of the reperfusion injury salvage kinase pathway, incorporating phosphatidylinositol 3-kinase-Akt/protein kinase B and p44/42 MAPK, and the inhibition of the mitochondrial permeability transition pore (MPTP). Recently published data indicate that the JAK/STAT signaling pathway, which mediates the metabolic actions of leptin, also plays a pivotal role in cardioprotection. Consequently, in the present study we considered the possibility that JAK/STAT signaling linked to the MPTP may be involved in modulating the cardioprotective actions of leptin. Employing rat in vitro models (Langendorff-perfused hearts and cardiomyocytes) of I/R injury, we investigated the actions of leptin (10 nM), administered at reperfusion, in the presence or absence of the JAK2 inhibitor, AG-490 (5 μM). Leptin reduced infarct size significantly (control, 60.05 ± 7.41% vs. leptin treated, 29.9 ± 3.24%, P < 0.05), protection being abolished by AG-490. Time course studies revealed that leptin caused a 171% (P < 0.001) increase in STAT3/tyrosine-705 phosphorylation at 2.5 min reperfusion; however, increases were not seen at 5, 10, 15, or 30 min reperfusion. Contrasting with STAT3, Akt/serine-473 phosphorylation was not significantly increased until 15 min into the reperfusion phase (140%, P < 0.05). AG-490 blocked the leptin-induced rise in STAT3 phosphorylation seen at 2.5 min reperfusion but did not influence Akt/serine-473 phosphorylation at 15 min. Leptin reduced the MPTP opening (P < 0.001), which was blocked by AG-490. This is the first study to yield evidence that JAK/STAT signaling linked to the MPTP plays a role in leptin-induced cardioprotection. Under the experimental conditions employed, STAT3 phosphorylation appears to have occurred earlier during reperfusion than that of Akt. Further research into the interactions between these two signaling pathways in the setting of I/R injury is, however, required.

    View details for DOI 10.1152/ajpheart.00092.2010

    View details for Web of Science ID 000283857300034

    View details for PubMedID 20656889

  • Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning CARDIOVASCULAR RESEARCH Hausenloy, D. J., Lim, S. Y., Ong, S., Davidson, S. M., Yellon, D. M. 2010; 88 (1): 67-74

    Abstract

    It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2.Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout. We have demonstrated that under basal conditions, non-pathological mPTP opening occurs (indicated by the percent reduction in mitochondrial calcein fluorescence). This effect was greater in WT cardiomyocytes compared with CYPD-/- ones (53 ± 2% WT vs. 17 ± 3% CYPD-/-; P < 0.01) and was augmented by hypoxic preconditioning (HPC) (70 ± 9% WT vs. 56 ± 1% CYPD-/-; P < 0.01). HPC reduced cell death following simulated ischaemia-reperfusion injury in WT (23.2 ± 3.5% HPC vs. 43.7 ± 3.2% WT; P < 0.05) but not CYPD-/- cardiomyocytes (19.6 ± 1.4% HPC vs. 24.4 ± 2.6% control; P > 0.05). HPC generated mitochondrial ROS in WT (four-fold increase; P < 0.05) but not CYPD-/- cardiomyocytes. HPC induced significant Akt phosphorylation in WT cardiomyocytes (two-fold increase; P < 0.05), an effect which was abrogated by ciclosporin-A (a CYPD inhibitor) and N-2-mercaptopropionyl glycine (a ROS scavenger). Finally, in vivo IPC of adult murine hearts resulted in significant phosphorylation of Akt and Erk1/2 in WT but not CYPD-/- hearts.The CYPD component of the mPTP is required by IPC to generate mitochondrial ROS and phosphorylate Akt and Erk1/2, major steps in the IPC signalling pathway.

    View details for DOI 10.1093/cvr/cvq113

    View details for Web of Science ID 000281714600010

    View details for PubMedID 20400621

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