Publications by authors named "Jiong-Wei Wang"

48 Publications

Modulating albumin-mediated transport of peptide-drug conjugates for antigen-specific Treg induction.

J Control Release 2022 Jun 19. Epub 2022 Jun 19.

Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands. Electronic address:

The therapeutic potential of antigen-specific regulatory T cells (Treg) has been extensively explored, leading to the development of several tolerogenic vaccines. Dexamethasone-antigen conjugates represent a prominent class of tolerogenic vaccines that enable coordinated delivery of antigen and dexamethasone to target immune cells. The importance of nonspecific albumin association towards the biodistribution of antigen-adjuvant conjugates has gained increasing attention, by which hydrophobic and electrostatic interactions govern the association capacity. Using an ensemble of computational and experimental techniques, we evaluate the impact of charged residues adjacent to the drug conjugation site in dexamethasone-antigen conjugates (Dex-K/E4-OVA323, K: lysine, E: glutamate) towards their albumin association capacity and induction of antigen-specific Treg. We find that Dex-K4-OVA323 possesses a higher albumin association capacity than Dex-E4-OVA323, leading to enhanced liver distribution and antigen-presenting cell uptake. Furthermore, using an OVA323-specific adoptive-transfer mouse model, we show that Dex-K4-OVA323 selectively upregulated OVA323-specific Treg cells, whereas Dex-E4-OVA323 exerted no significant effect on Treg cells. Our findings serve as a guide to optimize the functionality of dexamethasone-antigen conjugate amid switching vaccine epitope sequences. Moreover, our study demonstrates that moderating the residues adjacent to the conjugation sites can serve as an engineering approach for future peptide-drug conjugate development.
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http://dx.doi.org/10.1016/j.jconrel.2022.06.025DOI Listing
June 2022

Reactive Oxygen Species Scavenging Nanomedicine for The Treatment of Ischemic Heart Disease.

Adv Mater 2022 Apr 25:e2202169. Epub 2022 Apr 25.

Department of Diagnostic Radiology and Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Ischemic heart disease (IHD) is the leading cause of disability and mortality worldwide. Reactive oxygen species (ROS) have been shown to play key roles in the progression of diabetes, hypertension, and hypercholesterolemia which are independent risk factors that lead to atherosclerosis and the development of IHD. Engineered biomaterial-based nanomedicines are under extensive investigation and exploration, serving as smart and multifunctional nanocarriers for synergistic therapeutic effect. Capitalizing on the cell/molecule-targeting drug delivery, nanomedicines present enhanced specificity and safety with favorable pharmacokinetics and pharmacodynamics. In this review, we focus on introducing the roles of ROS in both IHD and its risk factors, highlighting cardiovascular medications that have antioxidant properties, summarizing the advantages, properties, and recent achievements of nanomedicines that have the ROS scavenging capacity for the treatment of diabetes, hypertension, hypercholesterolemia, atherosclerosis, ischemia/reperfusion, and myocardial infarction. Finally, this review will discuss the current challenges of nanomedicines for ROS scavenging treatment of IHD and possible future directions from a clinical perspective. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/adma.202202169DOI Listing
April 2022

Enhanced skin penetration of berberine from proniosome gel attenuates pain and inflammation in a mouse model of osteoarthritis.

Biomater Sci 2022 Mar 29;10(7):1752-1764. Epub 2022 Mar 29.

Department of Pharmacy, National University of Singapore, Science Drive 2, S15#05, Singapore 117543.

Dermal delivery of bioactive molecules remains an attractive route of administration in osteoarthritis (OA) due to the local accumulation of drugs while avoiding their systemic side effects. In this study we propose a proniosome gel comprising non-ionic surfactants that self-assemble into de-hydrated vesicles for the delivery of the natural anti-inflammatory compound berberine. By modulating the hydrating ability of the proniosome gel, berberine can be efficiently released with minimal mechanical force. A combination of sorbitan oleate (S80) and polyethlene glycol sorbitan monolaurate (T20) in a sorbitan stearate (S60)-based proniosome enables a readily hydrated gel to deliver berberine into the skin, as confirmed by skin permeation studies. Concurrently, an model of OA using primary mouse chondrocytes demonstrated that the release of berberine at a concentration as low as 1 μg mL is sufficient to restore the production of sulphated glycosaminoglycans (sGAG) to levels comparable to healthy chondrocytes while avoiding the cytotoxic concentrations (IC = 33 μg mL) on skin keratinocytes. In a mouse model of OA, the optimized formulation is able to attenuate inflammation and pain and minimize cartilage degeneration. Taken together, these data demonstrate the feasibility of adopting proniosome gels as a suitable platform to deliver active molecules for the management of osteoarthritis.
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http://dx.doi.org/10.1039/d1bm01733kDOI Listing
March 2022

Impact of following a healthy dietary pattern with co-consuming wolfberry on number and function of blood outgrowth endothelial cells from middle-aged and older adults.

Food Funct 2022 Jan 4;13(1):76-90. Epub 2022 Jan 4.

Department of Food Science & Technology, Faculty of Science, National University of Singapore, Singapore.

Blood outgrowth endothelial cells (BOECs) have received growing attention in relation to cardiovascular disease (CVD). However, the effect of diet intervention, a primary strategy for CVD prevention, on BOECs is not reported. This study aims to investigate the effect of following a healthy dietary pattern (HDP) with or without wolfberry consumption, healthy food with potential cardiovascular benefits, on the number and function of BOECs in middle-aged and older adults. Twenty-four subjects consumed either an HDP only ( = 9) or an HDP supplemented with 15 g day wolfberries ( = 15) for 16 weeks. At pre- and post-intervention, vascular health biomarkers and composite CVD risk indicators were assessed. BOECs were derived from peripheral blood mononuclear cells and their angiogenic and migration activities were measured. Isolated BOECs have typical endothelial cobblestone morphology, express von Willebrand factor and KDR. Consuming an HDP improved the BOEC colony's growth rate, which was demonstrated by significant time effects in the colony's culture time between passages 1 and 2 ( = 0.038). Both interventions increased BOECs' tube formation capacity. Moreover, HDP intervention contributed to a time effect on BOEC migration activity ( = 0.040 for ). Correlation analysis revealed that BOEC colony number was positively associated with blood pressure, atherogenic index, vascular age, and Framingham risk score. In conclusion, adherence to an HDP improved BOECs' function in middle-aged and older populations, while additional wolfberry consumption did not provide an enhanced effect. Our results provide mechanistic dissection on the beneficial effects on BOECs of dietary pattern modification.
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http://dx.doi.org/10.1039/d1fo02369aDOI Listing
January 2022

Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice.

Int J Mol Sci 2021 Oct 30;22(21). Epub 2021 Oct 30.

Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands.

Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency ( = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, < 0.05), increased contractility (QRS and QTc, < 0.05), and less inflammation (e.g., interleukins 6 and 1β, < 0.05) after TAC compared to WT animals ( = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 ± 0.8 vs. 16.6 ± 0.7 mg/mm, < 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight/tibia length correlated with expression of TLR4 in these animals (r = 0.078, = 0.005). Our data suggest that TLR2 deficiency ameliorates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes.
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http://dx.doi.org/10.3390/ijms222111823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583975PMC
October 2021

Wirelessly operated bioelectronic sutures for the monitoring of deep surgical wounds.

Nat Biomed Eng 2021 10 15;5(10):1217-1227. Epub 2021 Oct 15.

Department of Electrical and Computer Engineering, National University of Singapore, Singapore, Singapore.

Monitoring surgical wounds post-operatively is necessary to prevent infection, dehiscence and other complications. However, the monitoring of deep surgical sites is typically limited to indirect observations or to costly radiological investigations that often fail to detect complications before they become severe. Bioelectronic sensors could provide accurate and continuous monitoring from within the body, but the form factors of existing devices are not amenable to integration with sensitive wound tissues and to wireless data transmission. Here we show that multifilament surgical sutures functionalized with a conductive polymer and incorporating pledgets with capacitive sensors operated via radiofrequency identification can be used to monitor physicochemical states of deep surgical sites. We show in live pigs that the sutures can monitor wound integrity, gastric leakage and tissue micromotions, and in rodents that the healing outcomes are equivalent to those of medical-grade sutures. Battery-free wirelessly operated bioelectronic sutures may facilitate post-surgical monitoring in a wide range of interventions.
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http://dx.doi.org/10.1038/s41551-021-00802-0DOI Listing
October 2021

Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis.

Theranostics 2021 3;11(19):9243-9261. Epub 2021 Sep 3.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

The coagulation protein tissue factor (TF) regulates inflammation and angiogenesis via its cytoplasmic domain in infection, cancer and diabetes. While TF is highly abundant in the heart and is implicated in cardiac pathology, the contribution of its cytoplasmic domain to post-infarct myocardial injury and adverse left ventricular (LV) remodeling remains unknown. Myocardial infarction was induced in wild-type mice or mice lacking the TF cytoplasmic domain (TF∆CT) by occlusion of the left anterior descending coronary artery. Heart function was monitored with echocardiography. Heart tissue was collected at different time-points for histological, molecular and flow cytometry analysis. Compared with wild-type mice, TF∆CT had a higher survival rate during a 28-day follow-up after myocardial infarction. Among surviving mice, TF∆CT mice had better cardiac function and less LV remodeling than wild-type mice. The overall improvement of post-infarct cardiac performance in TF∆CT mice, as revealed by speckle-tracking strain analysis, was attributed to reduced myocardial deformation in the peri-infarct region. Histological analysis demonstrated that TF∆CT hearts had in the infarct area greater proliferation of myofibroblasts and better scar formation. Compared with wild-type hearts, infarcted TF∆CT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1) - Rac1 axis. In particular, infarcted TF∆CT hearts displayed markedly lower ratios of inflammatory M1 macrophages and reparative M2 macrophages (M1/M2). experiment with primary macrophages demonstrated that deletion of the TF cytoplasmic domain inhibited macrophage polarization toward the M1 phenotype. Furthermore, infarcted TF∆CT hearts presented markedly higher peri-infarct vessel density associated with enhanced endothelial cell proliferation and higher expression of PAR2 and PAR2-associated pro-angiogenic pathway factors. Finally, the overall cardioprotective effects observed in TF∆CT mice could be abolished by subcutaneously infusing a cocktail of PAR1-activating peptide and PAR2-inhibiting peptide via osmotic minipumps. Our findings demonstrate that the TF cytoplasmic domain exacerbates post-infarct cardiac injury and adverse LV remodeling via differential regulation of inflammation and angiogenesis. Targeted inhibition of the TF cytoplasmic domain-mediated intracellular signaling may ameliorate post-infarct LV remodeling without perturbing coagulation.
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http://dx.doi.org/10.7150/thno.63354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490508PMC
February 2022

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers.

Cell Death Discov 2021 Sep 27;7(1):265. Epub 2021 Sep 27.

Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)-positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.
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http://dx.doi.org/10.1038/s41420-021-00635-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476547PMC
September 2021

Mapping Drug-Induced Neuropathy through In-Situ Motor Protein Tracking and Machine Learning.

J Am Chem Soc 2021 09 1;143(36):14907-14915. Epub 2021 Sep 1.

Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.

Chemotherapy can induce toxicity in the central and peripheral nervous systems and result in chronic adverse reactions that impede continuous treatment and reduce patient quality of life. There is a current lack of research to predict, identify, and offset drug-induced neurotoxicity. Rapid and accurate assessment of potential neuropathy is crucial for cost-effective diagnosis and treatment. Here we report dynamic near-infrared upconversion imaging that allows intraneuronal transport to be traced in real time with millisecond resolution, but without photobleaching or blinking. Drug-induced neurotoxicity can be screened prior to phenotyping, on the basis of subtle abnormalities of kinetic characteristics in intraneuronal transport. Moreover, we demonstrate that combining the upconverting nanoplatform with machine learning offers a powerful tool for mapping chemotherapy-induced peripheral neuropathy and assessing drug-induced neurotoxicity.
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http://dx.doi.org/10.1021/jacs.1c07312DOI Listing
September 2021

Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota.

Theranostics 2021 25;11(17):8570-8586. Epub 2021 Jul 25.

College of Food Science and Engineering, Ocean University of China, 5 Yushan Road, Qingdao 266003, P. R. China.

Bovine milk constitutes an essential part of human diet, especially for children, due to its enrichment of various nutrients. We recently developed an effective protocol for the isolation of extracellular vesicles from milk (mEVs) and discovered that mEVs contained large amounts of immune-active proteins and modulated the gut immunity and microbiota in healthy mice. Here, we aimed to explore the therapeutic effects of mEVs on inflammatory bowel disease. MicroRNAs and protein content in mEVs were analyzed by RNA sequencing and proteomics, respectively, followed by functional annotation. Ulcerative colitis (UC) was induced by feeding mice with dextran sulfate sodium. Intestinal immune cell populations were phenotyped by flow cytometry, and the gut microbiota was analyzed 16S rRNA sequencing. We showed that abundant proteins and microRNAs in mEVs were involved in the regulation of immune and inflammatory pathways and that oral administration of mEVs prevented colon shortening, reduced intestinal epithelium disruption, inhibited infiltration of inflammatory cells and tissue fibrosis in a mouse UC model. Mechanistically, mEVs attenuated inflammatory response inhibiting TLR4-NF-κB signaling pathway and NLRP3 inflammasome activation. Furthermore, mEVs were able to correct cytokine production disorder and restore the balance between T helper type 17 (Th17) cells and interleukin-10Foxp3 regulatory T (Treg) cells in the inflamed colon. The disturbed gut microbiota in UC was also partially recovered upon treatment with mEVs. The correlation between the gut microbiota and cytokines suggests that mEVs may modulate intestinal immunity influencing the gut microbiota. These findings reveal that mEVs alleviate colitis by regulating intestinal immune homeostasis inhibiting TLR4-NF-κB and NLRP3 signaling pathways, restoring Treg/Th17 cell balance, and reshaping the gut microbiota.
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http://dx.doi.org/10.7150/thno.62046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344018PMC
January 2022

Lyophilization Preserves the Intrinsic Cardioprotective Activity of Bioinspired Cell-Derived Nanovesicles.

Pharmaceutics 2021 Jul 9;13(7). Epub 2021 Jul 9.

Department of Pharmacy, National University of Singapore, Singapore 117559, Singapore.

Recently, bioinspired cell-derived nanovesicles (CDNs) have gained much interest in the field of nanomedicine due to the preservation of biomolecular structure characteristics derived from their parent cells, which impart CDNs with unique properties in terms of binding and uptake by target cells and intrinsic biological activities. Although the production of CDNs can be easily and reproducibly achieved with any kind of cell culture, application of CDNs for therapeutic purposes has been greatly hampered by their physical and chemical instability during long-term storage in aqueous dispersion. In the present study, we conceived a lyophilization approach that would preserve critical characteristics regarding stability (vesicles' size and protein content), structural integrity, and biological activity of CDNs for enabling long-term storage in freeze-dried form. Compared to the lyoprotectant sucrose, trehalose-lyoprotected CDNs showed significantly higher glass transition temperature and lower residual moisture content. As assessed by ATR-FTIR and far-UV circular dichroism, lyophilization in the presence of the lyoprotectant effectively maintained the secondary structure of cellular proteins. After reconstitution, lyoprotected CDNs were efficiently associated with HeLa cells, CT26 cells, and bone marrow-derived macrophages at a rate comparable to the freshly prepared CDNs. In vivo, both lyoprotected and freshly prepared CDNs, for the first time ever reported, targeted the injured heart, and exerted intrinsic cardioprotective effects within 24 h, attributable to the antioxidant capacity of CDNs in a myocardial ischemia/reperfusion injury animal model. Taken together, these results pave the way for further development of CDNs as cell-based therapeutics stabilized by lyophilization that enabled long-term storage while preserving their activity.
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http://dx.doi.org/10.3390/pharmaceutics13071052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309024PMC
July 2021

Extracellular vesicles in cardiovascular disease.

Adv Clin Chem 2021 1;103:47-95. Epub 2020 Oct 1.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Cardiovascular Research Institute, National University Heart Centre Singapore, Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Electronic address:

Cardiovascular disease remains the leading cause of morbidity and mortality globally. Extracellular vesicles (EVs), a group of heterogeneous nanosized cell-derived vesicles, have attracted great interest as liquid biopsy material for biomarker discovery in a variety of diseases including cardiovascular disease. Because EVs inherit bioactive components from parent cells and are able to transfer their contents to recipient cells, EVs hold great promise as potential cell-free therapeutics and drug delivery systems. However, the development of EV-based diagnostics, therapeutics or drug delivery systems has been challenging due to the heterogenicity of EVs in biogenesis, size and cellular origin, the lack of standardized isolation and purification methods as well as the low production yield. In this review, we will provide an overview of the recent advances in EV-based biomarker discovery, highlight the potential usefulness of EVs and EV mimetics for therapeutic treatment and drug delivery in cardiovascular disease. In view of the fast development in this field, we will also discuss the challenges of current methodologies for isolation, purification and fabrication of EVs and potential alternatives.
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http://dx.doi.org/10.1016/bs.acc.2020.08.006DOI Listing
August 2021

Nanomedicine at the crossroads - A quick guide for IVIVC.

Adv Drug Deliv Rev 2021 12 24;179:113829. Epub 2021 Jun 24.

National University of Singapore, Department of Pharmacy, 5 Science Drive 2, 117545 Singapore. Electronic address:

For many years, nanomedicine is pushing the boundaries of drug delivery. When applying these novel therapeutics, safety considerations are not only a key concern when entering clinical trials but also an important decision point in product development. Standing at the crossroads, nanomedicine may be able to escape the niche markets and achieve wider acceptance by the pharmaceutical industry. While there is a new generation of drug delivery systems, the extracellular vesicles, standing on the starting line, unresolved issues and new challenges emerge from their translation from bench to bedside. Some key features of injectable nanomedicines contribute to the predictability of the pharmacological and toxicological effects. So far, only a few of the physicochemical attributes of nanomedicines can be justified by a direct mathematical relationship between the in vitro and the in vivo responses. To further develop extracellular vesicles as drug carriers, we have to learn from more than 40 years of clinical experience in liposomal delivery and pass on this knowledge to the next generation. Our quick guide discusses relationships between physicochemical characteristics and the in vivo response, commonly referred to as in vitro-in vivo correlation. Further, we highlight the key role of computational methods, lay open current knowledge gaps, and question the established design strategies. Has the recent progress improved the predictability of targeted delivery or do we need another change in perspective?
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http://dx.doi.org/10.1016/j.addr.2021.113829DOI Listing
December 2021

Therapeutic and diagnostic targeting of fibrosis in metabolic, proliferative and viral disorders.

Adv Drug Deliv Rev 2021 08 15;175:113831. Epub 2021 Jun 15.

Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Department of Targeted Therapeutics, University of Twente, Enschede, the Netherlands. Electronic address:

Fibrosis is a common denominator in many pathologies and crucially affects disease progression, drug delivery efficiency and therapy outcome. We here summarize therapeutic and diagnostic strategies for fibrosis targeting in atherosclerosis and cardiac disease, cancer, diabetes, liver diseases and viral infections. We address various anti-fibrotic targets, ranging from cells and genes to metabolites and proteins, primarily focusing on fibrosis-promoting features that are conserved among the different diseases. We discuss how anti-fibrotic therapies have progressed over the years, and how nanomedicine formulations can potentiate anti-fibrotic treatment efficacy. From a diagnostic point of view, we discuss how medical imaging can be employed to facilitate the diagnosis, staging and treatment monitoring of fibrotic disorders. Altogether, this comprehensive overview serves as a basis for developing individualized and improved treatment strategies for patients suffering from fibrosis-associated pathologies.
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http://dx.doi.org/10.1016/j.addr.2021.113831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611899PMC
August 2021

Extracellular vesicles as a drug delivery system: A systematic review of preclinical studies.

Adv Drug Deliv Rev 2021 08 18;175:113801. Epub 2021 May 18.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore, Singapore; Cardiovascular Research Institute (CVRI), National University Heart Centre Singapore (NUHCS), 117599 Singapore, Singapore; Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, 117609 Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore. Electronic address:

During the past decades, extracellular vesicles (EVs) have emerged as an attractive drug delivery system. Here, we assess their pre-clinical applications, in the form of a systematic review. For each study published in the past decade, disease models, animal species, EV donor cell types, active pharmaceutical ingredients (APIs), EV surface modifications, API loading methods, EV size and charge, estimation of EV purity, presence of biodistribution studies and administration routes were quantitatively analyzed in a defined and reproducible way. We have interpreted the trends we observe over the past decade, to define the niches where to apply EVs for drug delivery in the future and to provide a basis for regulatory guidelines.
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http://dx.doi.org/10.1016/j.addr.2021.05.011DOI Listing
August 2021

Enhancing the cardiovascular protective effects of a healthy dietary pattern with wolfberry (Lycium barbarum): A randomized controlled trial.

Am J Clin Nutr 2021 07;114(1):80-89

Department of Food Science & Technology, Faculty of Science, National University of Singapore, Singapore, Singapore.

Background: The consumption of wolfberry (Lycium barbarum), a rich source of carotenoids and bioactive polysaccharides, may serve as a potential dietary strategy for cardiovascular disease (CVD) risk management although limited studies examined its effects as whole fruits.

Objectives: To investigate the impact of wolfberry consumption as part of a healthy dietary pattern on vascular health-related outcomes and classical CVD risk factors in middle-aged and older adults in Singapore.

Methods: This is a 16-week, parallel design, randomized controlled trial. All participants (n = 40) received dietary counselling to follow healthy dietary pattern recommendations with the wolfberry group given additional instructions to cook and consume 15 g/d whole, dried wolfberry with their main meals. Biomarkers of vascular function (flow-mediated dilation, plasma total nitrate/nitrite, endothelin-1, and intercellular adhesion molecule-1), vascular structure (carotid intima-media thickness) and vascular regeneration (endothelial progenitor cell count, plasma angiopoietin 1 and angiopoietin 2), were assessed at baseline and postintervention. Serum lipid-lipoproteins and blood pressure were evaluated every 4 weeks.

Results: All participants showed an improved compliance toward the healthy dietary pattern. This was coupled with marked rises in total nitrate/nitrite concentrations (mean change wolfberry: 3.92 ± 1.73 nmol/mL; control: 5.01 ± 2.55 nmol/L) and reductions in endothelin-1 concentrations (wolfberry: -0.19 ± 0.06 pg/mL; control: -0.15 ± 0.08 pg/mL). Compared with the control which depicted no changes from baseline, the wolfberry group had a significantly higher HDL cholesterol (0.08 ± 0.04 mmol/L), as well as lower Framingham predicted long-term CVD risk (-0.8 ± 0.5%) and vascular age (-1.9 ± 1.0 y) postintervention. No differences were observed in the other vascular health-related outcomes.

Conclusions: In middle-aged and older adults, adherence to a healthy dietary pattern improves vascular tone. Incorporating wolfberry to the diet further improves blood lipid-lipoprotein profile and may lower long-term CVD risk. This study was registered at clinicatrials.gov as NCT03535844.
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http://dx.doi.org/10.1093/ajcn/nqab062DOI Listing
July 2021

Capturing Cytokines with Advanced Materials: A Potential Strategy to Tackle COVID-19 Cytokine Storm.

Adv Mater 2021 May 10;33(20):e2100012. Epub 2021 Apr 10.

Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.

The COVID-19 pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused great impact on the global economy and people's daily life. In the clinic, most patients with COVID-19 show none or mild symptoms, while approximately 20% of them develop severe pneumonia, multiple organ failure, or septic shock due to infection-induced cytokine release syndrome (the so-called "cytokine storm"). Neutralizing antibodies targeting inflammatory cytokines may potentially curb immunopathology caused by COVID-19; however, the complexity of cytokine interactions and the multiplicity of cytokine targets make attenuating the cytokine storm challenging. Nonspecific in vivo biodistribution and dose-limiting side effects further limit the broad application of those free antibodies. Recent advances in biomaterials and nanotechnology have offered many promising opportunities for infectious and inflammatory diseases. Here, potential mechanisms of COVID-19 cytokine storm are first discussed, and relevant therapeutic strategies and ongoing clinical trials are then reviewed. Furthermore, recent research involving emerging biomaterials for improving antibody-based and broad-spectrum cytokine neutralization is summarized. It is anticipated that this work will provide insights on the development of novel therapeutics toward efficacious management of COVID-19 cytokine storm and other inflammatory diseases.
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http://dx.doi.org/10.1002/adma.202100012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250356PMC
May 2021

Extracellular Vesicle (EV) biohybrid systems for cancer therapy: Recent advances and future perspectives.

Semin Cancer Biol 2021 09 17;74:45-61. Epub 2021 Feb 17.

Department of Pharmacy, National University of Singapore, Singapore. Electronic address:

Extracellular vesicles (EVs) are a class of cell-derived lipid-bilayer membrane vesicles secreted by almost all mammalian cells and involved in intercellular communication by shuttling various biological cargoes. Over the last decade, EVs - namely exosomes and microvesicles - have been extensively explored as next-generation nanoscale drug delivery systems (DDSs). This is in large due to their endogenous origin, which enables EVs to circumvent some of the limitations associated with existing cancer therapy approaches (i.e. by preventing recognition by the immune system and improving selectivity towards tumor tissue). However, successful translation of these cell-derived vesicles into clinical applications has been hindered by several factors, among which the loading of exogenous therapeutic molecules still represents a great challenge. In order to address this issue and to further advance these biologically-derived systems as drug carriers, EV-biohybrid nano-DDSs, obtained through the fusion of EVs with conventional synthetic nano-DDSs, have recently been proposed as a valuable alternative as DDSs. Building on the idea of "combining the best of both worlds", a combination of these two unique entities aims to harness the beneficial properties associated with both EVs and conventional nano-DDSs, while overcoming the flaws of the individual components. These biohybrid systems also provide a unique opportunity for exploitation of new synergisms, often leading to improved therapeutic outcomes, thus paving the way for advancements in cancer therapy. This review aims to describe the recent developments of EV-biohybrid nano-DDSs in cancer therapy, to highlight the most promising results and breakthroughs, as well as to provide a glimpse on the possible intrinsic targeting mechanisms of EVs that can be bequeathed to their hybrid systems. Finally, we also provide some insights in the future perspectives of EV-hybrid DDSs.
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http://dx.doi.org/10.1016/j.semcancer.2021.02.006DOI Listing
September 2021

In Vivo Three-Photon Imaging of Lipids using Ultrabright Fluorogens with Aggregation-Induced Emission.

Adv Mater 2021 Mar 11;33(11):e2007490. Epub 2021 Feb 11.

Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore.

Fluorescent probes capable of in vivo lipids labeling are highly desirable for studying lipid-accumulation-related metabolic diseases, such as nonalcoholic fatty liver disease, type-2 diabetes, and atherosclerosis. However, most of the current lipid-specific fluorophores cannot be used for in vivo labeling due to their strong hydrophobicity. Herein, organic dots from bright luminogens with aggregation-induced emission (AIEgen) are developed for in vivo labeling and three-photon fluorescence imaging of lipid-rich tissues, such as fatty liver, atherosclerotic plaques in brain vasculatures, and carotid arteries. The organic dots show excellent stability in an aqueous medium with high targeting specificity to lipids and strong three-photon fluorescence in the far-red/near-infrared (NIR) region under NIR-II laser excitation, which enables efficient in vivo labeling and imaging of lipids in deep tissues. The study will inspire the development of lipid-targeting fluorophores for in vivo applications.
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http://dx.doi.org/10.1002/adma.202007490DOI Listing
March 2021

Hypoxia-induced amniotic fluid stem cell secretome augments cardiomyocyte proliferation and enhances cardioprotective effects under hypoxic-ischemic conditions.

Sci Rep 2021 01 8;11(1):163. Epub 2021 Jan 8.

Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Secretome derived from human amniotic fluid stem cells (AFSC-S) is rich in soluble bioactive factors (SBF) and offers untapped therapeutic potential for regenerative medicine while avoiding putative cell-related complications. Characterization and optimal generation of AFSC-S remains challenging. We hypothesized that modulation of oxygen conditions during AFSC-S generation enriches SBF and confers enhanced regenerative and cardioprotective effects on cardiovascular cells. We collected secretome at 6-hourly intervals up to 30 h following incubation of AFSC in normoxic (21%O, nAFSC-S) and hypoxic (1%O, hAFSC-S) conditions. Proliferation of human adult cardiomyocytes (hCM) and umbilical cord endothelial cells (HUVEC) incubated with nAFSC-S or hAFSC-S were examined following culture in normoxia or hypoxia. Lower AFSC counts and richer protein content in AFSC-S were observed in hypoxia. Characterization of AFSC-S by multiplex immunoassay showed higher concentrations of pro-angiogenic and anti-inflammatory SBF. hCM demonstrated highest proliferation with 30h-hAFSC-S in hypoxic culture. The cardioprotective potential of concentrated 30h-hAFSC-S treatment was demonstrated in a myocardial ischemia-reperfusion injury mouse model by infarct size and cell apoptosis reduction and cell proliferation increase when compared to saline treatment controls. Thus, we project that hypoxic-generated AFSC-S, with higher pro-angiogenic and anti-inflammatory SBF, can be harnessed and refined for tailored regenerative applications in ischemic cardiovascular disease.
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http://dx.doi.org/10.1038/s41598-020-80326-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794288PMC
January 2021

Cell-Derived Nanovesicles as Exosome-Mimetics for Drug Delivery Purposes: Uses and Recommendations.

Methods Mol Biol 2021 ;2211:147-170

Department of Pharmacy, National University of Singapore, Singapore, Singapore.

Cell-derived Drug Delivery Systems (DDSs), particularly exosomes, have grown in popularity and have been increasingly explored as novel DDSs, due to their intrinsic targeting capabilities. However, clinical translation of exosomes is impeded by the tedious isolation procedures and poor yield. Cell-derived nanovesicles (CDNs) have recently been produced and proposed as exosome-mimetics. Various methods for producing exosome-mimetics have been developed. In this chapter, we present a simple, efficient, and cost-effective CDNs production method that uses common laboratory equipment (microcentrifuge) and spin cups. Through a series of extrusion and size exclusion steps, CDNs are produced from in vitro cell culture and are found to highly resemble the endogenous exosomes. Thus, we envision that this strategy holds great potential as a viable alternative to exosomes in the development of ideal DDS.
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http://dx.doi.org/10.1007/978-1-0716-0943-9_11DOI Listing
March 2021

Micro cell vesicle technology (mCVT): a novel hybrid system of gene delivery for hard-to-transfect (HTT) cells.

Nanoscale 2020 Sep 28;12(35):18022-18030. Epub 2020 Aug 28.

Department of Pharmacy, National University of Singapore, Singapore.

A hybrid gene delivery platform, micro Cell Vesicle Technology (mCVT), produced from the fusion of plasma membranes and cationic lipids, is presently used to improve the transfection efficiency of hard-to-transfect (HTT) cells. The plasma membrane components of mCVTs impart specificity in cellular uptake and reduce cytotoxicity in the transfection process, while the cationic lipids complex with the genetic material and provide structural integrity to mCVTs.
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http://dx.doi.org/10.1039/d0nr03784bDOI Listing
September 2020

Extracellular vesicle Cystatin C and CD14 are associated with both renal dysfunction and heart failure.

ESC Heart Fail 2020 10 10;7(5):2240-2249. Epub 2020 Jul 10.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Aims: Extracellular vesicles (EVs) are small double-membrane plasma vesicles that play key roles in cellular crosstalk and mechanisms such as inflammation. The role of EVs in combined organ failure such as cardiorenal syndrome has not been investigated. The aim of this study is to identify EV proteins that are associated with renal dysfunction, heart failure, and their combination in dyspnoeic patients.

Methods And Results: Blood samples were prospectively collected in 404 patients presenting with breathlessness at the emergency department at National University Hospital, Singapore. Renal dysfunction was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m . The presence of heart failure was independently adjudicated by two clinicians on the basis of the criteria of the European Society of Cardiology guidelines. Protein levels of SerpinG1, SerpinF2, Cystatin C, and CD14 were measured with a quantitative immune assay within three EV sub-fractions and in plasma and were tested for their associations with renal dysfunction, heart failure, and the concurrence of both conditions using multinomial regression analysis, thereby correcting for confounders such as age, gender, ethnicity, and co-morbidities. Renal dysfunction was found in 92 patients (23%), while heart failure was present in 141 (35%). In total, 58 patients (14%) were diagnosed with both renal dysfunction and heart failure. Regression analysis showed that Cystatin C was associated with renal dysfunction, heart failure, and their combination in all three EV sub-fractions and in plasma. CD14 was associated with both renal dysfunction and the combined renal dysfunction and heart failure in all EV sub-fractions, and with presence of heart failure in the high density lipoprotein sub-fraction. SerpinG1 and SerpinF2 were associated with heart failure in, respectively, two and one out of three EV sub-fractions and in plasma, but not with renal dysfunction.

Conclusions: We provide the first data showing that Cystatin C and CD14 in circulating EVs are associated with both renal dysfunction and heart failure in patients presenting with acute dyspnoea. This suggests that EV proteins may be involved in the combined organ failure of the cardiorenal syndrome and may represent possible targets for prevention or treatment.
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http://dx.doi.org/10.1002/ehf2.12699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524227PMC
October 2020

Magnetic fields modulate metabolism and gut microbiome in correlation with Pgc-1α expression: Follow-up to an in vitro magnetic mitohormetic study.

FASEB J 2020 08 6;34(8):11143-11167. Epub 2020 Jul 6.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Exercise modulates metabolism and the gut microbiome. Brief exposure to low mT-range pulsing electromagnetic fields (PEMFs) was previously shown to accentuate in vitro myogenesis and mitochondriogenesis by activating a calcium-mitochondrial axis upstream of PGC-1α transcriptional upregulation, recapitulating a genetic response implicated in exercise-induced metabolic adaptations. We compared the effects of analogous PEMF exposure (1.5 mT, 10 min/week), with and without exercise, on systemic metabolism and gut microbiome in four groups of mice: (a) no intervention; (b) PEMF treatment; (c) exercise; (d) exercise and PEMF treatment. The combination of PEMFs and exercise for 6 weeks enhanced running performance and upregulated muscular and adipose Pgc-1α transcript levels, whereas exercise alone was incapable of elevating Pgc-1α levels. The gut microbiome Firmicutes/Bacteroidetes ratio decreased with exercise and PEMF exposure, alone or in combination, which has been associated in published studies with an increase in lean body mass. After 2 months, brief PEMF treatment alone increased Pgc-1α and mitohormetic gene expression and after >4 months PEMF treatment alone enhanced oxidative muscle expression, fatty acid oxidation, and reduced insulin levels. Hence, short-term PEMF treatment was sufficient to instigate PGC-1α-associated transcriptional cascades governing systemic mitohormetic adaptations, whereas longer-term PEMF treatment was capable of inducing related metabolic adaptations independently of exercise.
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http://dx.doi.org/10.1096/fj.201903005RRDOI Listing
August 2020

In Vivo Generation of Post-infarct Human Cardiac Muscle by Laminin-Promoted Cardiovascular Progenitors.

Cell Rep 2020 May;31(8):107714

Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore; Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.celrep.2020.107714DOI Listing
May 2020

Predicting human pharmacokinetics of liposomal temoporfin using a hybrid in silico model.

Eur J Pharm Biopharm 2020 Apr 6;149:121-134. Epub 2020 Feb 6.

Department of Pharmacy, Faculty of Science, National University of Singapore, 6 Science Drive 2, Singapore 117546, Singapore. Electronic address:

Over the years, the performance of the liposomal formulations of temoporfin, Foslip® and Fospeg®, was investigated in a broad array of cell-based assays and preclinical animal models. So far, little attention has been paid to the influence of drug release and liposomal stability on the plasma concentration-time profile. The drug release is a key attribute which impacts product quality and the in vivo efficacy of nanocarrier formulations. In the present approach, the in vitro drug release and the drug-protein transfer of Foslip® and Fospeg® was determined using the dispersion releaser technology. To analyze the stability of both formulations in physiological fluids, nanoparticle tracking analysis was applied. A comparable drug release behavior and a high physical stability with a vesicle size of approximately 92 ± 2 nm for Foslip® and at 111 ± 5 nm for Fospeg® were measured. The development of a novel hybrid in silico model resulted in an optimal representation of the in vivo data. Based on the information available for previous formulations, the model enabled a prediction of the performance of Foslip® in humans. To verify the simulations, plasma concentration-time profiles of a phase I clinical trial were used. An absolute average fold error of 1.4 was achieved. Moreover, a deconvolution of the pharmacokinetic profile into different fractions relevant for the in vivo efficacy and safety was achieved. While the total plasma concentration reached a c of 2298 ng/mL after 0.72 h, the monomolecular drug accounted for a small fraction of the photosensitizer with a c of 321 ng/mL only.
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http://dx.doi.org/10.1016/j.ejpb.2020.02.001DOI Listing
April 2020

Yin Yang 1 Suppresses Dilated Cardiomyopathy and Cardiac Fibrosis Through Regulation of and .

Circ Res 2019 10 9;125(9):834-846. Epub 2019 Sep 9.

From the Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (C.Y.T., J.X.W., P.S.C., H.T., D.L., W.C., J.J.).

Rationale: Pathogenic variations in the lamin gene () cause familial dilated cardiomyopathy (DCM). insufficiency caused by pathogenic variants is believed to be the basic mechanism underpinning -related DCM.

Objective: To assess whether silencing of cardiac causes DCM and investigate the role of Yin Yang 1 () in suppressing DCM.

Methods And Results: We developed a DCM mouse model induced by cardiac-specific short hairpin RNA. Silencing of cardiac induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of suppressed DCM and cardiac fibrosis by inducing expression and preventing upregulation of . Knockdown of upregulated attenuated the suppressive effect of on DCM and cardiac fibrosis. However, upregulation of alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of together with silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, upregulation of regulated and reporter activities and modulated and gene expression in cardiomyocytes. Downregulation of inhibited TGF-β (transforming growth factor-β)/Smad signaling in DCM hearts. Regulation of both and further suppressed TGFβ/Smad signaling. In addition, co-modulation of and reduced CD3+ T cell numbers in DCM hearts.

Conclusions: Our findings demonstrate that upregulation of or co-modulation of and offer novel therapeutic strategies for the treatment of DCM caused by insufficiency.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.314794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336364PMC
October 2019

Extracellular Vesicles in Cardiovascular Diseases: Alternative Biomarker Sources, Therapeutic Agents, and Drug Delivery Carriers.

Int J Mol Sci 2019 Jul 3;20(13). Epub 2019 Jul 3.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

Cardiovascular diseases (CVD) represent the leading cause of morbidity and mortality globally. The emerging role of extracellular vesicles (EVs) in intercellular communication has stimulated renewed interest in exploring the potential application of EVs as tools for diagnosis, prognosis, and therapy in CVD. The ubiquitous nature of EVs in biological fluids presents a technological advantage compared to current diagnostic tools by virtue of their notable stability. EV contents, such as proteins and microRNAs, represent specific signatures of cellular activation or injury. This feature positions EVs as an alternative source of biomarkers. Furthermore, their intrinsic activity and immunomodulatory properties offer EVs unique opportunities to act as therapeutic agents per se or to serve as drug delivery carriers by acting as miniaturized vehicles incorporating bioactive molecules. In this article, we aim to review the recent advances and applications of EV-based biomarkers and therapeutics. In addition, the potential of EVs as a drug delivery and theranostic platform for CVD will also be discussed.
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http://dx.doi.org/10.3390/ijms20133272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650854PMC
July 2019

In Vivo Generation of Post-infarct Human Cardiac Muscle by Laminin-Promoted Cardiovascular Progenitors.

Cell Rep 2019 03;26(12):3231-3245.e9

Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore; Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden. Electronic address:

Regeneration of injured human heart muscle is limited and an unmet clinical need. There are no methods for the reproducible generation of clinical-quality stem cell-derived cardiovascular progenitors (CVPs). We identified laminin-221 (LN-221) as the most likely expressed cardiac laminin. We produced it as human recombinant protein and showed that LN-221 promotes differentiation of pluripotent human embryonic stem cells (hESCs) toward cardiomyocyte lineage and downregulates pluripotency and teratoma-associated genes. We developed a chemically defined, xeno-free laminin-based differentiation protocol to generate CVPs. We show high reproducibility of the differentiation protocol using time-course bulk RNA sequencing developed from different hESC lines. Single-cell RNA sequencing of CVPs derived from hESC lines supported reproducibility and identified three main progenitor subpopulations. These CVPs were transplanted into myocardial infarction mice, where heart function was measured by echocardiogram and human heart muscle bundle formation was identified histologically. This method may provide clinical-quality cells for use in regenerative cardiology.
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http://dx.doi.org/10.1016/j.celrep.2019.02.083DOI Listing
March 2019

Toll-like receptor 7 deficiency promotes survival and reduces adverse left ventricular remodelling after myocardial infarction.

Cardiovasc Res 2019 Oct;115(12):1791-1803

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Aims: The Toll-like receptor 7 (TLR7) is an intracellular innate immune receptor activated by nucleic acids shed from dying cells leading to activation of the innate immune system. Since innate immune system activation is involved in the response to myocardial infarction (MI), this study aims to identify if TLR7 is involved in post-MI ischaemic injury and adverse remodelling after MI.

Methods And Results: TLR7 involvement in MI was investigated in human tissue from patients with ischaemic heart failure, as well as in a mouse model of permanent left anterior descending artery occlusion in C57BL/6J wild type and TLR7 deficient (TLR7-/-) mice. TLR7 expression was up-regulated in human and mouse ischaemic myocardium after MI. Compared to wild type mice, TLR7-/- mice had less acute cardiac rupture associated with blunted activation of matrix metalloproteinase 2, increased expression of tissue inhibitor of metalloproteinase 1, recruitment of more myofibroblasts, and the formation of a myocardial scar with higher collagen fibre density. Furthermore, inflammatory cell influx and inflammatory cytokine expression post-MI were reduced in the TLR7-/- heart. During a 28-day follow-up after MI, TLR7 deficiency resulted in less chronic adverse left ventricular remodelling and better cardiac function. Bone marrow (BM) transplantation experiments showed that TLR7 deficiency in BM-derived cells preserved cardiac function after MI.

Conclusions: In acute MI, TLR7 mediates the response to acute cardiac injury and chronic remodelling probably via modulation of post-MI scar formation and BM-derived inflammatory infiltration of the myocardium.
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http://dx.doi.org/10.1093/cvr/cvz057DOI Listing
October 2019
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