Human Long Noncoding RNA Regulation of Stem Cell Potency and Differentiation

Lee, Seahyoung,Seo, Hyang-Hee,Lee, Chang Youn,Lee, Jiyun,Shin, Sunhye,Kim, Sang Woo,Lim, Soyeon,Hwang, Ki-Chul Hindawi 2017 Stem cells international Vol.2017 No.-

<P>Because of their capability of differentiation into lineage-specific cells, stem cells are an attractive therapeutic modality in regenerative medicine. To develop an effective stem cell-based therapeutic strategy with predictable results, deeper understanding of the underlying molecular mechanisms of stem cell differentiation and/or pluripotency maintenance is required. Thus, reviewing the key factors involved in the transcriptional and epigenetic regulation of stem cell differentiation and maintenance is important. Accumulating data indicate that long noncoding RNAs (lncRNAs) mediate numerous biological processes, including stem cell differentiation and maintenance. Here, we review recent findings on the human lncRNA regulation of stem cell potency and differentiation. Although the clinical implication of these lncRNAs is only beginning to be elucidated, it is anticipated that lncRNAs will become important therapeutic targets in the near future.</P>

microRNA-133a attenuates cardiomyocyte hypertrophy by targeting PKCδ and Gq

Lee, Se-Yeon,Lee, Chang Youn,Ham, Onju,Moon, Jae Yoon,Lee, Jiyun,Seo, Hyang-Hee,Shin, Sunhye,Kim, Sang Woo,Lee, Seahyoung,Lim, Soyeon,Hwang, Ki-Chul Springer-Verlag 2018 MOLECULAR AND CELLULAR BIOCHEMISTRY - Vol.439 No.1

Suppression of miR-181a attenuates H ₂ O ₂ -induced death of mesenchymal stem cells by maintaining hexokinase II expression

Lee, Seahyoung,Yun, Ina,Ham, Onju,Lee, Se-Yeon,Lee, Chang Yeon,Park, Jun-Hee,Lee, Jiyun,Seo, Hyang-Hee,Choi, Eunhyun,Hwang, Ki-Chul BioMed Central 2015 BIOLOGICAL RESEARCH Vol.48 No.1

<P><B>Background</B></P><P>Low survival rate of transplanted cells compromises the efficacy of cell therapy. Hexokinase II (HKII) is known to have anti-apoptotic activity through its interaction with mitochondria. The objective was to identify miRNAs targeting HKII and investigate whether miRNA-mediated modulation of HKII could improve the survival of mesenchymal stem cells (MSCs) exposed to H<SUB>2</SUB>O<SUB>2</SUB>. The expression of HKII in MSCs exposed to H<SUB>2</SUB>O<SUB>2</SUB> was evaluated, and HKII-targeting miRNA was screened based on miRNA-target prediction databases. The effect of H<SUB>2</SUB>O<SUB>2</SUB> on the expression of the selected HKII-targeting miRNA was examined and the effect of modulation of the selected HKII-targeting miRNA using anti-miRNA on H<SUB>2</SUB>O<SUB>2</SUB>-induced apoptosis of MSC was evaluated.</P><P><B>Results</B></P><P>H<SUB>2</SUB>O<SUB>2</SUB> (600 μM) induced cell death of MSCs and decreased mitochondrial HKII expression. We have identified miR-181a as a HKII-targeting miRNA and H<SUB>2</SUB>O<SUB>2</SUB> increased the expression of miR-181a in MSCs. Delivery of anti-miR-181a, which neutralizes endogenous miR-181a, significantly attenuated H<SUB>2</SUB>O<SUB>2</SUB>-induced decrease of HKII expression and disruption of mitochondrial membrane potential, improving the survival of MSCs exposed to H<SUB>2</SUB>O<SUB>2</SUB>.</P><P><B>Conclusions</B></P><P>These findings suggest that H<SUB>2</SUB>O<SUB>2</SUB>-induced up-regulation of miR-181a contributes to the cell death of MSCs by down-regulating HKII. Neutralizing miR-181a can be an effective way to prime MSCs for transplantation into ischemic tissues.</P>

Cell Adhesion and Long-Term Survival of Transplanted Mesenchymal Stem Cells: A Prerequisite for Cell Therapy

Lee, Seahyoung,Choi, Eunhyun,Cha, Min-Ji,Hwang, Ki-Chul Hindawi Publishing Corporation 2015 Oxidative medicine and cellular longevity Vol.2015 No.-

<P>The literature provides abundant evidence that mesenchymal stem cells (MSCs) are an attractive resource for therapeutics and have beneficial effects in regenerating injured tissues due to their self-renewal ability and broad differentiation potential. Although the therapeutic potential of MSCs has been proven in both preclinical and clinical studies, several questions have not yet been addressed. A major limitation to the use of MSCs in clinical applications is their poor viability at the site of injury due to the harsh microenvironment and to anoikis driven by the loss of cell adhesion. To improve the survival of the transplanted MSCs, strategies to regulate apoptotic signaling and enhance cell adhesion have been developed, such as pretreatment with cytokines, growth factors, and antiapoptotic molecules, genetic modifications, and hypoxic preconditioning. More appropriate animal models and a greater understanding of the therapeutic mechanisms of MSCs will be required for their successful clinical application. Nevertheless, the development of stem cell therapies using MSCs has the potential to treat degenerative diseases. This review discusses various approaches to improving MSC survival by inhibiting anoikis.</P>

Looking into a Conceptual Framework of ROS–miRNA–Atrial Fibrillation

Lee, Seahyoung,Choi, Eunhyun,Cha, Min-Ji,Hwang, Ki-Chul MDPI 2014 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.15 No.12

<P>Atrial fibrillation (AF) has been recognized as a major cause of cardiovascular-related morbidity and mortality. MicroRNAs (miRNAs) represent recent additions to the collection of biomolecules involved in arrhythmogenesis. Reactive oxygen species (ROS) have been independently linked to both AF and miRNA regulation. However, no attempts have been made to investigate the possibility of a framework composed of ROS–miRNA–AF that is related to arrhythmia development. Therefore, this review was designed as an attempt to offer a new approach to understanding AF pathogenesis. The aim of this review was to find and to summarize possible connections that exist among AF, miRNAs and ROS to understand the interactions among the molecular entities underlying arrhythmia development in the hopes of finding unappreciated mechanisms of AF. These findings may lead us to innovative therapies for AF, which can be a life-threatening heart condition. A systemic literature review indicated that miRNAs associated with AF might be regulated by ROS, suggesting the possibility that miRNAs translate cellular stressors, such as ROS, into AF pathogenesis. Further studies with a more appropriate experimental design to either prove or disprove the existence of an ROS–miRNA–AF framework are strongly encouraged.</P>

PPARδ activation inhibits angiotensin II induced cardiomyocyte hypertrophy by suppressing intracellular Ca²⁺ signaling pathway

Lee, Kuy-Sook,Park, Jin-Hee,Lee, Seahyoung,Lim, Hyun-Joung,Park, Hyun-Young Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of cellular biochemistry Vol.106 No.5

<P>Peroxisome proliferator-activated receptors δ (PPARδ) is known to be expressed ubiquitously, and the predominant PPAR subtype of cardiac cells. However, relatively less is known regarding the role of PPARδ in cardiac cells except that PPARδ ligand treatment protects cardiac hypertrophy by inhibiting NF-κB activation. Thus, in the present study, we examined the effect of selective PPARδ ligand L-165041 on angiotensin II (AngII) induced cardiac hypertrophy and its underlying mechanism using cardiomyocyte. According to our data, L-165041 (10 µM) inhibited AngII-induced [<SUP>3</SUP>H] leucine incorporation, induction of the fetal gene atrial natriuretic factor (ANF) and increase of cardiomyocyte size. Previous studies have implicated the activation of focal adhesion kinase (FAK) in the progress of cardiomyocyte hypertrophy. L-165041 pretreatment significantly inhibited AngII-induced intracellular Ca<SUP>2+</SUP> increase and subsequent phosphorylation of FAK. Further experiment using Ca<SUP>2+</SUP> ionophore A23187 confirmed that Ca<SUP>2+</SUP> induced FAK phosphorylation, and this was also blocked by L-165041 pretreatment. In addition, overexpression of PPARδ using adenovirus significantly inhibited AngII-induced intracellular Ca<SUP>2+</SUP> increase and FAK expression, while PPARδ siRNA treatment abolished the effect of L-165041. These data indicate that PPARδ ligand L-165041 inhibits AngII induced cardiac hypertrophy by suppressing intracellular Ca<SUP>2+</SUP>/FAK/ERK signaling pathway in a PPARδ dependent mechanism. J. Cell. Biochem. 106: 823–834, 2009. © 2009 Wiley-Liss, Inc.</P>

Looking for Pyroptosis-Modulating miRNAs as a Therapeutic Target for Improving Myocardium Survival

Lee, Seahyoung,Choi, Eunhyun,Cha, Min-Ji,Hwang, Ki-Chul Hindawi Publishing Corporation 2015 MEDIATORS OF INFLAMMATION Vol.2015 No.-

<P>Pyroptosis is the most recently identified type of regulated cell death with inflammatory response and has characteristics distinct from those of apoptosis or necrosis. Recently, independent studies have reported that small noncoding RNAs termed microRNAs (miRNAs) are involved in the regulation of pyroptosis. Nevertheless, only a handful of empirical data regarding miRNA-dependent regulation of pyroptosis is currently available. This review is aimed to provide a current update on the role of miRNAs in pyroptosis and to offer suggestions for future studies probing miRNAs as a linker connecting pyroptosis to various cardiovascular diseases (CVDs) and their potential as a therapeutic target for preventing excessive cell death of myocardium during CVDs.</P>

Rapid Induction of Osteogenic Markers in Mesenchymal Stem Cells by Adipose-Derived Stromal Vascular Fraction Cells

Choi, Jung-Won,Shin, Sunhye,Lee, Chang Youn,Lee, Jiyun,Seo, Hyang-Hee,Lim, Soyeon,Lee, Seahyoung,Kim, Il-Kwon,Lee, Hoon-Bum,Kim, Sang Woo,Hwang, Ki-Chul S. KARGER AG 2017 CELLULAR PHYSIOLOGY AND BIOCHEMISTRY Vol.44 No.1

<P>Background/Aims: Stromal vascular fraction (SVF) cells are a mixed cell population, and their regenerative capacity has been validated in various therapeutic models. The purpose of this study was to investigate the regenerative mechanisms utilized by implanted SVF cells. Using an in vitro co-culture system, we sought to determine whether SVF implantation into impaired tissue affects endogenous mesenchymal stem cell (MSC) differentiation; MSCs can differentiate into a variety of cell types, and they have a strong regenerative capacity despite their low numbers in impaired tissue. Methods: Adipose-derived SVF cells obtained from four donors were co-cultured with bone marrow-derived MSCs, and the differential expression of osteogenic markers and osteogenic differentiation inducers over time was analyzed in mono-cultured MSCs and MSCs co-cultured with SVF cells. Results: The co-cultivation of MSCs with SVF cells significantly and mutually induced the expression of osteogenic-specific markers via paracrine and/or autocrine regulation but did not induce adipocyte, chondrocyte or myoblast marker expression. More surprisingly, subsequent osteogenesis and/or comparable effects were rapidly induced within 48 h. Conclusion: To the best of our knowledge, this is the first study in which osteogenesis and/or comparable effects were rapidly induced in bone marrow-derived MSCs and adipose-derived SVF cells through co-cultivation. Our findings suggest that the positive effects of SVF implantation into impaired bone may be attributed to the rapid induction of MSC osteogenesis, and the transplantation of co-cultured and preconditioned SVF cells and/or MSCs may be more effective than the transplantation of untreated cells for the treatment of bone defects. (c) 2017 The Author(s) Published by S. Karger AG, Basel</P>

7-cyclopentyl-5-(4-phenoxyphenyl)−7H-pyrrolo[2,3-d] pyrimidin-4-ylamine inhibits the proliferation and migration of vascular smooth muscle cells by suppressing ERK and Akt pathways

Seo, Hyang-Hee,Kim, Sang Woo,Lee, Chang Youn,Lim, Kyu Hee,Lee, Jiyun,Lim, Soyeon,Lee, Seahyoung,Hwang, Ki-Chul Elsevier 2017 european journal of pharmacology Vol.798 No.-

<P>Excessive vascular smooth muscle cell (VSMC) proliferation and migration after vascular injury significantly contributes to the development of occlusive vascular disease. Therefore, inhibiting the proliferation and migration of VSMCs is a validated therapeutic modality for occlusive vascular disease such as atherosclerosis and restenosis. In the present study, we screened chemical compounds for their anti -proliferative effects on VSMCs using multiple approaches, such as MTT assays, wound healing assays, and trans -well migration assays. Our data indicate that 7-cyclopenty1-5-(4-phenoxypheny1)-7H-pyrrolo[2,3-d] pyrimidin-4-ylamine, a lymphocyte -specific protein tyrosine kinase (Lck) inhibitor, significantly inhibited both VSMC proliferation and migration. 7-cyclopenty1-5-(4-phenoxypheny1)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine suppresses VSMC proliferation and migration via down -regulating the protein kinase B (Akt) and extracellular signal regulated kinase (ERK) pathways, and it significantly decreased the expression of proliferating cell nuclear antigen (PCNA) and cyclin Dl and, the phosphorylation of retinoblastoma protein (pRb). Additionally, 7-cyclopenty1-5-(4phenoxypheny1)-7H-pyrrolo[2,3-d] pyrimidin-4-ylamine suppressed the migration of VSMCs from endothelium -removed aortic rings, as well as neointima formation following rat carotid balloon injury. The present study identified 7-cyclopenty1-5-(4-phenoxypheny1)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine as a potent VSMC proliferation and migration inhibitor and warrants further studies to elucidate its more detailed molecular mechanisms, such as its primary target, and to further validate its in vivo efficacy as a therapeutic agent for pathologic vascular conditions, such as restenosis and atherosclerosis.</P>

Effects of donor age on human adipose-derived adherent stromal cells under oxidative stress conditions

Kim, Sang Woo,Choi, Jung-Won,Lee, Chang Youn,Lee, Jiyun,Shin, Sunhye,Lim, Soyeon,Lee, Seahyoung,Kim, Il-Kwon,Lee, Hoon-Bum,Hwang, Ki-Chul Cambridge Medical Publications Ltd 2018 The Journal of international medical research Vol.46 No.3

<P><B>Objective</B></P><P>Adipose-derived stromal vascular fractions (SVFs) are heterogeneous complex populations of cells with therapeutic efficacy for tissue generation and vascular stabilization. SVFs have cardiomyogenic potential, and many researchers have examined the possibility of SVF transplantation for heart disease. In cell-based therapies, donor age affects the regenerative capability, cell yield, and differentiation potential of adult tissues; however, opposing or controversial results have been found in humans. We examined whether SVF transplantation into impaired heart tissue shows differential effects according to donor age.</P><P><B>Methods</B></P><P>We investigated differences in protein expression in human umbilical vein endothelial cells (HUVECs) co-cultured with adipose-derived adherent stromal cells (ADASs) from donors of different ages [>40-year-olds (40s group) and >60-year-olds (60s group)] under oxidative stress conditions.</P><P><B>Results</B></P><P>Although co-culturing HUVECs with ADASs ameliorated inflammation due to increased oxidative stress conditions, few differences were observed between the ADASs from the 40s and 60s groups. Moreover, the Database for Annotation, Visualization, and Integrated Discovery classification tool revealed differentially expressed genes in the Kyoto Encyclopedia of Genes and Genomes pathway associated with cytokine–cytokine receptor interaction in response to ADASs.</P><P><B>Conclusion</B></P><P>Protein expression profiles were unchanged in HUVECs induced by isolated ADASs from donors of different ages under oxidative stress conditions.</P>