Publications by authors named "Christopher Y T Yen"

6 Publications

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MicroRNA let-7-TGFBR3 signalling regulates cardiomyocyte apoptosis after infarction.

EBioMedicine 2019 Aug 7;46:236-247. Epub 2019 Aug 7.

Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan; Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United States; Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan. Electronic address:

Background: Myocardial infarction (MI) is a life-threatening disease, often leading to heart failure. Defining therapeutic targets at an early time point is important to prevent heart failure.

Methods: MicroRNA screening was performed at early time points after MI using paired samples isolated from the infarcted and remote myocardium of pigs. We also examined the microRNA expression in plasma of MI patients and pigs. For mechanistic studies, AAV9-mediated microRNA knockdown and overexpression were administrated in mice undergoing MI.

Findings: MicroRNAs let-7a and let-7f were significantly downregulated in the infarct area within 24 h post-MI in pigs. We also observed a reduction of let-7a and let-7f in plasma of MI patients and pigs. Inhibition of let-7 exacerbated cardiomyocyte apoptosis, induced a cardiac hypertrophic phenotype, and resulted in worsened left ventricular ejection fraction. In contrast, ectopic let-7 overexpression significantly reduced those phenotypes and improved heart function. We then identified TGFBR3 as a target of let-7, and found that induction of Tgfbr3 in cardiomyocytes caused apoptosis, likely through p38 MAPK activation. Finally, we showed that the plasma TGFBR3 level was elevated after MI in plasma of MI patients and pigs.

Interpretation: Together, we conclude that the let-7-Tgfbr3-p38 MAPK signalling plays an important role in cardiomyocyte apoptosis after MI. Furthermore, microRNA let-7 and Tgfbr3 may serve as therapeutic targets and biomarkers for myocardial damage. FUND: Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis, Thematic Research Program and the Summit Research Program, Taiwan.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712055PMC
August 2019

Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair.

Circulation 2019 01;139(5):647-659

Program in Molecular Medicine, National Yang Ming University and Academia Sinica, Taipei, Taiwan (T.W.H.T., P.C.C.H.).

Background: The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated.

Methods: To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI.

Results: Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate.

Conclusions: Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035235DOI Listing
January 2019

The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling.

Theranostics 2018 9;8(12):3176-3188. Epub 2018 May 9.

Institute of Biomedical Sciences, Academia Sinica, Taiwan.

Lapatinib (LAP) is a crucial alternative to trastuzumab upon the onset of drug resistance during treatment of metastatic human epidermal growth factor receptor 2-positive breast cancer. Like trastuzumab, LAP is commonly used alongside anthracyclines as a combination therapy, due to enhanced anti-cancer efficacy. However, this is notably associated with cardiotoxicity so it is imperative to understand the mechanisms driving this cardiotoxicity and develop cardioprotective strategies. To this end, here we utilize human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), which exhibit several characteristics representative of cardiomyocytes that make them breakthrough models to study drug toxicity. We investigated LAP- and doxorubicin (DOX)-induced toxicity in hPSC-CMs and evaluated the involvement of inducible nitric oxide (NO) synthase (iNOS). The significance of iNOS-mediated cardiotoxicity was furthermore evaluated in animal studies. LAP synergistically increased DOX toxicity in hPSC-CMs in a dose- and time-dependent manner. At concentrations that were otherwise non-apoptotic when administered separately, LAP significantly potentiated DOX-induced hPSC-CM apoptosis. This was accompanied by increased iNOS expression and pronounced production of NO. iNOS inhibition significantly reduced hPSC-CM sensitivity to LAP and DOX co-treatment (LAP-plus-DOX), leading to reduced apoptosis. Consistent with our observations , delivery of an iNOS inhibitor in mice treated with LAP-plus-DOX attenuated myocardial apoptosis and systolic dysfunction. Moreover, inhibition of iNOS did not compromise the anti-cancer potency of LAP-plus-DOX in a murine breast cancer xenograft model. Our findings suggest that iNOS inhibition is a promising cardioprotective strategy to accompany HER2-inhibitor/anthracycline combination therapies. Furthermore, these results support the promise of hPSC-CMs as a platform for investigating cardiotoxicity and developing cardioprotectants as a whole.
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http://dx.doi.org/10.7150/thno.23207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010982PMC
August 2019

Mechanisms of pluripotency maintenance in mouse embryonic stem cells.

Cell Mol Life Sci 2017 05 20;74(10):1805-1817. Epub 2016 Dec 20.

Institute of Biomedical Sciences, Academia Sinica, IBMS Rm.417, 128 Academia Road, Section 2, Nankang, Taipei, 115, Taiwan.

Mouse embryonic stem cells (mESCs), characterized by their pluripotency and capacity for self-renewal, are driven by a complex gene expression program composed of several regulatory mechanisms. These mechanisms collaborate to maintain the delicate balance of pluripotency gene expression and their disruption leads to loss of pluripotency. In this review, we provide an extensive overview of the key pillars of mESC pluripotency by elaborating on the various essential transcription factor networks and signaling pathways that directly or indirectly support this state. Furthermore, we consider the latest developments in the role of epigenetic regulation, such as noncoding RNA signaling or histone modifications.
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http://dx.doi.org/10.1007/s00018-016-2438-0DOI Listing
May 2017

Reloadable multidrug capturing delivery system for targeted ischemic disease treatment.

Sci Transl Med 2016 11;8(365):365ra160

Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.

Human clinical trials of protein therapy for ischemic diseases have shown disappointing outcomes so far, mainly because of the poor circulatory half-life of growth factors in circulation and their low uptake and retention by the targeted injury site. The attachment of polyethylene glycol (PEG) extends the circulatory half-lives of protein drugs but reduces their extravasation and retention at the target site. To address this issue, we have developed a drug capture system using a mixture of hyaluronic acid (HA) hydrogel and anti-PEG immunoglobulin M antibodies, which, when injected at a target body site, can capture and retain a variety of systemically injected PEGylated therapeutics at that site. Furthermore, repeated systemic injections permit "reloading" of the capture depot, allowing the use of complex multistage therapies. This study demonstrates this capture system in both murine and porcine models of critical limb ischemia. The results show that the reloadable HA/anti-PEG system has the potential to be clinically applied to patients with ischemic diseases, who require sequential administration of protein drugs for optimal outcomes.
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http://dx.doi.org/10.1126/scitranslmed.aah6228DOI Listing
November 2016

Arrhythmogenesis: a Roadblock to Cardiac Stem Cell Therapy.

Curr Treat Options Cardiovasc Med 2016 Oct;18(10):61

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Opinion Statement: Despite significant advances in the treatment of ischemic heart disease (IHD), it remains the leading cause of mortality worldwide. Undoubtedly, methods for regenerating the injured human heart are urgently needed, and whilst exciting progress has been made from utilizing stem cell therapy for cardiac regeneration, several major challenges still remain. In particular, one major safety issue is the occurrence of potentially life-threatening ventricular arrhythmias after cell therapy. Several drivers may be responsible for this, ranging from the potential inherent arrhythmogenicity of delivered stem cells to that of the underlying IHD. Therefore, it is imperative to thoroughly assess the risk-to-benefit ratio of such treatments prior to the clinical application. As such, despite the considerable progress made in stem cell therapy over the past decades, many obstacles still lie ahead.
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http://dx.doi.org/10.1007/s11936-016-0481-7DOI Listing
October 2016
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