Publications by authors named "Desy S Lee"

6 Publications

  • Page 1 of 1

Cardiac-specific microRNA-125b deficiency induces perinatal death and cardiac hypertrophy.

Sci Rep 2021 01 27;11(1):2377. Epub 2021 Jan 27.

Cardiovascular Division, Institute of Biomedical Science, Academia Sinica, National Taiwan University College of Medicine, 128 Academia Road, Sec. 2, Nankang, Taipei, 115, Taiwan.

MicroRNA-125b, the first microRNA to be identified, is known to promote cardiomyocyte maturation from embryonic stem cells; however, its physiological role remains unclear. To investigate the role of miR-125b in cardiovascular biology, cardiac-specific miR-125b-1 knockout mice were generated. We found that cardiac-specific miR-125b-1 knockout mice displayed half the miR-125b expression of control mice resulting in a 60% perinatal death rate. However, the surviving mice developed hearts with cardiac hypertrophy. The cardiomyocytes in both neonatal and adult mice displayed abnormal mitochondrial morphology. In the deficient neonatal hearts, there was an increase in mitochondrial DNA, but total ATP production was reduced. In addition, both the respiratory complex proteins in mitochondria and mitochondrial transcription machinery were impaired. Mechanistically, using transcriptome and proteome analysis, we found that many proteins involved in fatty acid metabolism were significantly downregulated in miR-125b knockout mice which resulted in reduced fatty acid metabolism. Importantly, many of these proteins are expressed in the mitochondria. We conclude that miR-125b deficiency causes a high mortality rate in neonates and cardiac hypertrophy in adult mice. The dysregulation of fatty acid metabolism may be responsible for the cardiac defect in the miR-125b deficient mice.
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http://dx.doi.org/10.1038/s41598-021-81700-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840921PMC
January 2021

The roles of non-coding RNAs in cardiac regenerative medicine.

Noncoding RNA Res 2017 Jun 7;2(2):100-110. Epub 2017 Jun 7.

Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.

The emergence of non-coding RNAs (ncRNAs) has challenged the central dogma of molecular biology that dictates that the decryption of genetic information starts from transcription of DNA to RNA, with subsequent translation into a protein. Large numbers of ncRNAs with biological significance have now been identified, suggesting that ncRNAs are important in their own right and their roles extend far beyond what was originally envisaged. ncRNAs do not only regulate gene expression, but are also involved in chromatin architecture and structural conformation. Several studies have pointed out that ncRNAs participate in heart disease; however, the functions of ncRNAs still remain unclear. ncRNAs are involved in cellular fate, differentiation, proliferation and tissue regeneration, hinting at their potential therapeutic applications. Here, we review the current understanding of both the biological functions and molecular mechanisms of ncRNAs in heart disease and describe some of the ncRNAs that have potential heart regeneration effects.
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http://dx.doi.org/10.1016/j.ncrna.2017.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096405PMC
June 2017

Solving the puzzle of pluripotent stem cell-derived cardiomyocyte maturation: piece by piece.

Ann Transl Med 2017 Mar;5(6):143

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

There is a growing need for models which can serve as platforms for drug screening and basic research. Human adult cardiomyocytes cannot be readily obtained or cultured, and so pluripotent stem cell-derived cardiomyocytes appear to be an attractive option. Unfortunately, these cells are structurally and functionally immature-more comparable to foetal cardiomyocytes than adult. A recent study by Ruan ., provides new insights into accelerating the maturation process and takes us a step closer to solving the puzzle of pluripotent stem cell-derived cardiomyocyte maturation.
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http://dx.doi.org/10.21037/atm.2017.01.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395477PMC
March 2017

Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes.

Cell Rep 2015 Sep 10;12(12):1960-7. Epub 2015 Sep 10.

Institute of Clinical Medicine, National Cheng Kung University, Tainan 704, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Division of Cardiovascular Surgery, National Taiwan University Hospital, Taipei 100, Taiwan. Electronic address:

Pluripotent-cell-derived cardiomyocytes have great potential for use in research and medicine, but limitations in their maturity currently constrain their usefulness. Here, we report a method for improving features of maturation in murine and human embryonic-stem-cell-derived cardiomyocytes (m/hESC-CMs). We found that coculturing m/hESC-CMs with endothelial cells improves their maturity and upregulates several microRNAs. Delivering four of these microRNAs, miR-125b-5p, miR-199a-5p, miR-221, and miR-222 (miR-combo), to m/hESC-CMs resulted in improved sarcomere alignment and calcium handling, a more negative resting membrane potential, and increased expression of cardiomyocyte maturation markers. Although this could not fully phenocopy all adult cardiomyocyte characteristics, these effects persisted for two months following delivery of miR-combo. A luciferase assay demonstrated that all four miRNAs target ErbB4, and siRNA knockdown of ErbB4 partially recapitulated the effects of miR-combo. In summary, a combination of miRNAs induced via endothelial coculture improved ESC-CM maturity, in part through suppression of ErbB4 signaling.
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http://dx.doi.org/10.1016/j.celrep.2015.08.042DOI Listing
September 2015

Bcl3 Bridges LIF-STAT3 to Oct4 Signaling in the Maintenance of Naïve Pluripotency.

Stem Cells 2015 Dec 18;33(12):3468-80. Epub 2015 Sep 18.

Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.

Leukemia inhibitory factor (LIF) regulates mouse embryonic stem cell (mESC) pluripotency through STAT3 activation, but the downstream signaling remains largely unelucidated. Using cDNA microarrays, we verified B cell leukemia/lymphoma 3 (Bcl3) as the most significantly downregulated factor following LIF withdrawal in mESCs. Bcl3 knockdown altered mESC morphology, reduced expression of pluripotency genes including Oct4, Sox2, and Nanog, and downregulated DNA binding of acetylated histone 3 and RNA polymerase II on the Oct4 promoter. Conversely, Bcl3 overexpression partially prevented cell differentiation and promoted Oct4 and Nanog promoter activities. Furthermore, coimmunoprecipitation and chromatin immunoprecipitation experiments demonstrated that Bcl3 regulation of mESC pluripotency may be through its association with Oct4 and β-catenin and its promoter binding capability. These results establish that Bcl3 positively regulates pluripotency genes and thus shed light on the mechanism of Bcl3 as a downstream molecule of LIF/STAT3 signaling in pluripotency maintenance.
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http://dx.doi.org/10.1002/stem.2201DOI Listing
December 2015

Fibroblast growth factor-10 promotes cardiomyocyte differentiation from embryonic and induced pluripotent stem cells.

PLoS One 2010 Dec 28;5(12):e14414. Epub 2010 Dec 28.

Institute of Clinical Medicine and Research Center for Clinical Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan.

Background: The fibroblast growth factor (FGF) family is essential to normal heart development. Yet, its contribution to cardiomyocyte differentiation from stem cells has not been systemically studied. In this study, we examined the mechanisms and characters of cardiomyocyte differentiation from FGF family protein treated embryonic stem (ES) cells and induced pluripotent stem (iPS) cells.

Methodology/principal Findings: We used mouse ES cells stably transfected with a cardiac-specific α-myosin heavy chain (αMHC) promoter-driven enhanced green fluorescent protein (EGFP) and mouse iPS cells to investigate cardiomyocyte differentiation. During cardiomyocyte differentiation from mouse ES cells, FGF-3, -8, -10, -11, -13 and -15 showed an expression pattern similar to the mesodermal marker Brachyury and the cardiovascular progenitor marker Flk-1. Among them, FGF-10 induced cardiomyocyte differentiation in a time- and concentration-dependent manner. FGF-10 neutralizing antibody, small molecule FGF receptor antagonist PD173074 and FGF-10 and FGF receptor-2 short hairpin RNAs inhibited cardiomyocyte differentiation. FGF-10 also increased mouse iPS cell differentiation into cardiomyocyte lineage, and this effect was abolished by FGF-10 neutralizing antibody or PD173074. Following Gene Ontology analysis, microarray data indicated that genes involved in cardiac development were upregulated after FGF-10 treatment. In vivo, intramyocardial co-administration of FGF-10 and ES cells demonstrated that FGF-10 also promoted cardiomyocyte differentiation.

Conclusion/significance: FGF-10 induced cardiomyocyte differentiation from ES cells and iPS cells, which may have potential for translation into clinical applications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014414PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011000PMC
December 2010
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