Publications by authors named "Chang Youn Lee"

47 Publications

Multiplexed targeting of miRNA-210 in stem cell-derived extracellular vesicles promotes selective regeneration in ischemic hearts.

Exp Mol Med 2021 Apr 20;53(4):695-708. Epub 2021 Apr 20.

Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea.

Extracellular vesicles (EVs) are cell derivatives containing diverse cellular molecules, have various physiological properties and are also present in stem cells used for regenerative therapy. We selected a "multiplexed target" that demonstrates multiple effects on various cardiovascular cells, while functioning as a cargo of EVs. We screened various microRNAs (miRs) and identified miR-210 as a candidate target for survival and angiogenic function. We confirmed the cellular and biological functions of EV-210 (EVs derived from ASC) secreted from adipose-derived stem cells (ASCs) transfected with miR-210 (ASC). Under hypoxic conditions, we observed that ASC inhibits apoptosis by modulating protein tyrosine phosphatase 1B (PTP1B) and death-associated protein kinase 1 (DAPK1). In hypoxic endothelial cells, EV-210 exerted its angiogenic capacity by inhibiting Ephrin A (EFNA3). Furthermore, EV-210 enhanced cell survival under the control of PTP1B and induced antiapoptotic effects in hypoxic H9c2 cells. In cardiac fibroblasts, the fibrotic ratio was reduced after exposure to EV-210, but EVs derived from ASC did not communicate with fibroblasts. Finally, we observed the functional restoration of the ischemia/reperfusion-injured heart by maintaining the intercommunication of EVs and cardiovascular cells derived from ASC. These results suggest that the multiplexed target with ASC is a useful tool for cardiovascular regeneration.
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http://dx.doi.org/10.1038/s12276-021-00584-0DOI Listing
April 2021

2-Phenylethylamine (PEA) Ameliorates Corticosterone-Induced Depression-Like Phenotype via the BDNF/TrkB/CREB Signaling Pathway.

Int J Mol Sci 2020 Nov 30;21(23). Epub 2020 Nov 30.

Pharmacology and Drug Abuse Group, Convergence Toxicology Research Division, Korea Institute of Toxicology, KRICT, Daejeon 34114, Korea.

Depression is a serious medical illness that is one of the most prevalent psychiatric disorders. Corticosterone (CORT) increases depression-like behavior, with some effects on anxiety-like behavior. 2-Phenethylamine (PEA) is a monoamine alkaloid that acts as a central nervous system stimulant in humans. Here, we show that PEA exerts antidepressant effects by modulating the Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element binding protein (CREB) signaling pathway in CORT-induced depression. To investigate the potential effects of PEA on CORT-induced depression, we first treated CORT (50 μM)-induced hippocampal neurons with 100 μM PEA for 24 h. We found that treatment with CORT altered dendritic spine architecture; however, treatment with PEA rescued dendritic spine formation via regulation of BDNF/TrkB/CREB signaling. Next, we used a mouse model of CORT-induced depression. Mice were treated with CORT (20 mg/kg) for 21 days, followed by assessments of a battery of depression-like behaviors. During the final four days of CORT exposure, the mice were treated with PEA (50 mg/kg). We found that CORT injection promoted depression-like behavior and significantly decreased BDNF and TrkB expression in the hippocampus. However, treatment with PEA significantly ameliorated the behavioral and biochemical changes induced by CORT. Our findings reveal that PEA exerts antidepressant effects by modulating the BDNF/TrkB/CREB signaling pathway in a mouse model of CORT-induced depression.
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http://dx.doi.org/10.3390/ijms21239103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729630PMC
November 2020

Novel Therapeutic Effects of Pterosin B on Ang II-Induced Cardiomyocyte Hypertrophy.

Molecules 2020 Nov 12;25(22). Epub 2020 Nov 12.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea.

Pathological cardiac hypertrophy is characterized by an abnormal increase in cardiac muscle mass in the left ventricle, resulting in cardiac dysfunction. Although various therapeutic approaches are being continuously developed for heart failure, several studies have suggested natural compounds as novel potential strategies. Considering relevant compounds, we investigated a new role for Pterosin B for which the potential life-affecting biological and therapeutic effects on cardiomyocyte hypertrophy are not fully known. Thus, we investigated whether Pterosin B can regulate cardiomyocyte hypertrophy induced by angiotensin II (Ang II) using H9c2 cells. The antihypertrophic effect of Pterosin B was evaluated, and the results showed that it reduced hypertrophy-related gene expression, cell size, and protein synthesis. In addition, upon Ang II stimulation, Pterosin B attenuated the activation and expression of major receptors, Ang II type 1 receptor and a receptor for advanced glycation end products, by inhibiting the phosphorylation of PKC-ERK-NF-κB pathway signaling molecules. In addition, Pterosin B showed the ability to reduce excessive intracellular reactive oxygen species, critical mediators for cardiac hypertrophy upon Ang II exposure, by regulating the expression levels of NAD(P)H oxidase 2/4. Our results demonstrate the protective role of Pterosin B in cardiomyocyte hypertrophy, suggesting it is a potential therapeutic candidate.
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http://dx.doi.org/10.3390/molecules25225279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697794PMC
November 2020

Differentiation of adipose-derived stem cells into functional chondrocytes by a small molecule that induces Sox9.

Exp Mol Med 2020 04 21;52(4):672-681. Epub 2020 Apr 21.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Republic of Korea.

Osteoarthritis (OA) is a common joint disease that results from the disintegration of joint cartilage and the underlying bone. Because cartilage and chondrocytes lack the ability to self-regenerate, efforts have been made to utilize stem cells to treat OA. Although various methods have been used to differentiate stem cells into functional chondrocytes, the currently available methods cannot induce stem cells to undergo differentiation into chondrocyte-like cells without inducing characteristics of hypertrophic chondrocytes, which finally lead to cartilage disintegration and calcification. Therefore, an optimized method to differentiate stem cells into chondrocytes that do not display undesired phenotypes is needed. This study focused on differentiating adipose-derived stem cells (ASCs) into functional chondrocytes using a small molecule that regulated the expression of Sox9 as a key factor in cartilage development and then explored its ability to treat OA. We selected ellipticine (ELPC), which induces chondrocyte differentiation of ASCs, using a GFP-Sox9 promoter vector screening system. An in vivo study was performed to confirm the recovery rate of cartilage regeneration with ASC differentiation into chondrocytes by ELPC in a collagenase-induced animal model of OA. Taken together, these data indicate that ellipticine induces ASCs to differentiate into mature chondrocytes without hypertrophic chondrocytes in vitro and in vivo, thus overcoming a problem encountered in previous studies. These results indicate that ELPC is a novel chondrocyte differentiation-inducing drug that shows potential as a cell therapy for OA.
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http://dx.doi.org/10.1038/s12276-020-0424-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210883PMC
April 2020

Simultaneous Suppression of Multiple Programmed Cell Death Pathways by miRNA-105 in Cardiac Ischemic Injury.

Mol Ther Nucleic Acids 2019 Mar 10;14:438-449. Epub 2019 Jan 10.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Republic of Korea; Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City 404-834, Republic of Korea. Electronic address:

Recent studies have shown that several upstream signaling elements of apoptosis and necroptosis are closely associated with acute injury in the heart. In our study, we observed that miR-105 was notably dysregulated in rat hearts with myocardial infarction (MI). Thus, the purpose of this study was to test the hypothesis that miR-105 participates in the regulation of RIP3/p-MLKL- and BNIP3-dependent necroptosis/apoptosis in H9c2 cells and MI rat hearts. Our results show that the RIP3/p-MLKL necroptotic pathway and BNIP3-dependent apoptosis signaling are enhanced in H9c2 cells under hypoxic conditions, whereas, compared with these pathways in the controls, those in miR-105-treated H9c2 cells are suppressed. Mechanistically, we identified miR-105 as the miRNA directly suppressing the expression of RIP3 and BNIP3, two important mediators involved in cell necroptosis and apoptosis. Furthermore, MI rat hearts injected with miR-105 had decreased infarct sizes, indicating that miR-105 is among three miRNAs that function simultaneously to suppress necroptotic/apoptotic cell death pathways and to inhibit MI-induced cardiomyocyte cell death at multiple levels. Taken together, miR-105 may constitute a new therapeutic strategy for cardioprotection in ischemic heart disease.
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http://dx.doi.org/10.1016/j.omtn.2018.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369328PMC
March 2019

TAK733 attenuates adrenergic receptor-mediated cardiomyocyte hypertrophy via inhibiting ErkThr188 phosphorylation.

Clin Hemorheol Microcirc 2019 ;72(2):179-187

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Republic of Korea.

Background: Cardiac hypertrophy is an important risk factor for heart failure. The MEK-ERK axis has been reported as a major regulator in controlling cardiac hypertrophy. TAK733 is a potent and selective MEK inhibitor that suppresses cell growth in a broad range of cell lines.

Objective: Therefore, we aimed to investigate the anti-hypertrophic effect of TAK733 in cardiomyocytes.

Methods: Cardiomyocyte hypertrophy was induced with norepinephrine (NE) or phenylepinephrine (PE) using H9c2 cells. To confirm the cardiomyocyte hypertrophy, cell size and protein synthesis were measured and hypertrophy-related gene expression was estimated by reverse transcription polymerase chain reaction. To identify the signaling pathway involved, immunoblot analysis were performed.

Results: We observed that NE activated MEK-ERK signaling and increased ANP and BNP expression, resulting in cardiomyocyte hypertrophy. TAK733 significantly reduced cardiomyocyte hypertrophy by regulating NE-induced ERK1/2 and ERKThr188 activation, hypertrophy marker expression, and cardiomyocyte hypertrophy through depression of MEK activity. In addition, we examined that PE-induced cardiomyocyte hypertrophy was also attenuated by TAK733.

Conclusions: Here, we report that TAK733 suppressed NE- or PE-induced cardiomyocyte hypertrophy by repressing a crucial component of cardiac hypertrophy-related pathways. These results suggest that TAK733 may be a useful therapeutics for cardiac hypertrophy and warrants further in vivo studies.
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http://dx.doi.org/10.3233/CH-180476DOI Listing
November 2019

Multiple Combination of Angelica gigas Extract and Mesenchymal Stem Cells Enhances Therapeutic Effect.

Biol Pharm Bull 2018 ;41(12):1748-1756

Department of Biology Education, College of Education, Pusan National University.

Alternative medicines attract attention because stroke is rarely expected to make a full recovery with the most advanced medical technology. Angelica gigas (AG) is a well-known herbal medicine as a neuroprotective agent. The present study introduced mesenchymal stem cells (MSCs) to identify for the advanced treatment of the cerebrovascular disease. The objective of this research is validation of the enhanced effects of multiple combined treatment of AG extract with MSCs on stroke through angiogenesis. Our results confirmed that AG extract with MSCs improved the neovascularization increasing expression of angiogenesis-regulated molecules. The changes of brain and the behavioral ability showed the increased effects of AG extract with MSCs. As a result, AG extract and MSCs may synergistically increase the therapeutic potential by enhancing neovascularization. This mixed approach provides a new experimental protocol of herbal medicine therapy for the treatment of a variety of diseases including stroke, trauma, and spinal cord injury.
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http://dx.doi.org/10.1248/bpb.b18-00193DOI Listing
March 2019

Priming stem cells with protein kinase C activator enhances early stem cell-chondrocyte interaction by increasing adhesion molecules.

Biol Res 2018 Nov 1;51(1):41. Epub 2018 Nov 1.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, South Korea.

Background: Osteoarthritis (OA) can be defined as degradation of articular cartilage of the joint, and is the most common degenerative disease. To regenerate the damaged cartilage, different experimental approaches including stem cell therapy have been tried. One of the major limitations of stem cell therapy is the poor post-transplantation survival of the stem cells. Anoikis, where insufficient matrix support and adhesion to extracellular matrix causes apoptotic cell death, is one of the main causes of the low post-transplantation survival rate of stem cells. Therefore, enhancing the initial interaction of the transplanted stem cells with chondrocytes could improve the therapeutic efficacy of stem cell therapy for OA. Previously, protein kinase C activator phorbol 12-myristate 13-acetate (PMA)-induced increase of mesenchymal stem cell adhesion via activation of focal adhesion kinase (FAK) has been reported. In the present study, we examine the effect PMA on the adipose-derived stem cells (ADSCs) adhesion and spreading to culture substrates, and further on the initial interaction between ADSC and chondrocytes.

Results: PMA treatment increased the initial adhesion of ADSC to culture substrate and cellular spreading with increased expression of adhesion molecules, such as FAK, vinculin, talin, and paxillin, at both RNA and protein level. Priming of ADSC with PMA increased the number of ADSCs attached to confluent layer of cultured chondrocytes compared to that of untreated ADSCs at early time point (4 h after seeding).

Conclusion: Taken together, the results of this study suggest that priming ADSCs with PMA can increase the initial interaction with chondrocytes, and this proof of concept can be used to develop a non-invasive therapeutic approach for treating OA. It may also accelerate the regeneration process so that it can relieve the accompanied pain faster in OA patients. Further in vivo studies examining the therapeutic effect of PMA pretreatment of ADSCs for articular cartilage damage are required.
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http://dx.doi.org/10.1186/s40659-018-0191-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211543PMC
November 2018

Multipoint targeting of TGF-β/Wnt transactivation circuit with microRNA 384-5p for cardiac fibrosis.

Cell Death Differ 2019 06 11;26(6):1107-1123. Epub 2018 Sep 11.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Republic of Korea.

Cardiac fibrosis is a common precursor to ventricular dysfunction and eventual heart failure, and cardiac fibrosis begins with cardiac fibroblast activation. Here we have demonstrated that the TGF-β signaling pathway and Wnt signaling pathway formed a transactivation circuit during cardiac fibroblast activation and that miR-384-5p is a key regulator of the transactivation circuit. The results of in vitro study indicated that TGF-β activated an auto-positive feedback loop by increasing Wnt production in cardiac fibroblasts, and Wnt neutralizing antibodies disrupted the feedback loop. Also, we demonstrated that miR-384-5p simultaneously targeted the key receptors of the TGF-β/Wnt transactivation circuit and significantly attenuated both TGF-β-induced cardiac fibroblast activation and ischemia-reperfusion-induced cardiac fibrosis. In addition, small molecule that prevented pro-fibrogenic stimulus-induced downregulation of endogenous miR-384-5p significantly suppressed cardiac fibroblast activation and cardiac fibrosis. In conclusion, modulating a key endogenous miRNA targeting multiple components of the TGF-β/Wnt transactivation circuit can be an effective means to control cardiac fibrosis and has great therapeutic potential.
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http://dx.doi.org/10.1038/s41418-018-0187-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748152PMC
June 2019

Salvia miltiorrhiza enhances the survival of mesenchymal stem cells under ischemic conditions.

J Pharm Pharmacol 2018 Sep 25;70(9):1228-1241. Epub 2018 Jun 25.

Department of Biology Education, College of Education, Pusan National University, Busan, Korea.

Objectives: To validate the enhanced therapeutic effect of Salvia miltiorrhiza Bunge (SM) for brain ischemic stroke through the anti-apoptotic and survival ability of mesenchymal stem cells (MSCs).

Methods: The viability and the expression level of cell apoptotic and survival-related proteins in MSCs by treatment of SM were assessed in vitro. In addition, the infarcted brain region and the behavioural changes after treatment of MSCs with SM were confirmed in rat middle cerebral artery occlusion (MCAo) models.

Key Findings: We demonstrated that SM attenuates apoptosis and improves the cell viability of MSCs. In the rat MCAo model, the recovery of the infarcted region and positive changes of behaviour are observed after treatment of MSCs with SM.

Conclusions: The therapy using SM enhances the therapeutic effect for brain ischemic stroke by promoting the survival of MSCs. This synergetic effect thereby proposes a new experimental approach of traditional Chinese medicine and stem cell-based therapies for patients suffering from a variety of diseases.
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http://dx.doi.org/10.1111/jphp.12950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099286PMC
September 2018

TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo.

Exp Mol Med 2018 04 20;50(4):1-12. Epub 2018 Apr 20.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 25601, Korea.

As a potent and selective allosteric inhibitor of MEK, TAK-733 has been shown to exert anti-cancer effects for a wide range of cancers both in vitro and in vivo. However, its effects on inhibiting growth have never been investigated in the cardiovascular system, where regulation of abnormal vascular smooth muscle cell growth in neointimal hyperplasia is an important area of focus. Angiotensin II was used to mimic inflammatory neointimal hyperplasia in an in vitro environment, and balloon catheter-induced injury with an infusion of angiotensin II was used to generate an in vivo rat restenosis model under inflammatory conditions. TAK-733 exerted anti-proliferative and anti-migratory effects on human vascular smooth muscle cells. These multiple effects of TAK-733 were evaluated using various assays, such as cell cycle analysis and wound healing. Interestingly, TAK-733 did not induce apoptosis in smooth muscle cells but only reduced the proliferation rate; additionally, it did not affect EC viability. TAK-733 also exhibited anti-inflammatory activity, as observed by attenuated monocyte adhesion to smooth muscle cells via inhibition of ICAM1 and VCAM1 overexpression. The in vivo study demonstrated that neointimal hyperplasia after balloon injury and angiotensin II stimulation was suppressed by TAK-733, and downregulation of the inflammatory signal and enhanced re-endothelialization were observed. TAK-733 may have therapeutic potential for treating neointimal hyperplasia by attenuating smooth muscle cell proliferation, migration, and inflammation. Thus, TAK-733 could be a promising drug candidate for treating patients with restenosis.
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http://dx.doi.org/10.1038/s12276-018-0052-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938062PMC
April 2018

Extract of Oxytropis pseudoglandulosa inhibits vascular smooth muscle cell proliferation and migration via suppression of ERK1/2 and Akt signaling pathways1.

Clin Hemorheol Microcirc 2018 ;69(1-2):277-287

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Korea.

Excessive vascular smooth muscle cell (VSMC) proliferation and migration accelerate the development of occlusive vascular disease. Therefore, finding a means to control the aberrant proliferation and migration of VSMCs has own clinical significance. In the present study, we examined the feasibility of using extract from medicinal plant Oxytropis pseudoglandulosa (OG) to control pathologic proliferation and migration of VSMCs, which never have been tested. Our data indicate that the extract of OG significantly suppressed proliferation and migration of VSMCs without cytotoxic effect, suggesting the OG extract may be an alternative agent to effectively control the aberrant VSMC proliferation and migration without any serious adverse effect. These data suggest that the extract of OG may be a potent therapeutic agent for the treatment of occlusive vascular disease and warrant further studies to identify the major acting ingredient and to validate in vivo efficacy.
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http://dx.doi.org/10.3233/CH-189126DOI Listing
June 2018

Protective effects of kenpaullone on cardiomyocytes following HO-induced oxidative stress are attributed to inhibition of connexin 43 degradation by SGSM3.

Biochem Biophys Res Commun 2018 05 26;499(2):368-373. Epub 2018 Mar 26.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, 210-701, Republic of Korea; Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea. Electronic address:

A previous study showed that small G protein signaling modulator 3 (SGSM3) was highly correlated with Cx43 in heart functions and that high levels of SGSM3 may induce Cx43 turnover through lysosomal degradation in infarcted rat hearts. Here, we investigated the protective effects of kenpaullone on cardiomyocytes following HO-induced oxidative stress mediated by the interaction of SGSM3 with Cx43. We found that the gap junction protein Cx43 was significantly down-regulated in an HO concentration-dependent manner, whereas expression of SGSM3 was up-regulated upon HO exposure in H9c2 cells. The effect of kenpaullone pretreatment on HO-induced cytotoxicity was evaluated in H9c2 cells. HO markedly increased the release of lactate dehydrogenase (LDH), while kenpaullone pretreatment suppressed LDH release in H9c2 cells. Moreover, kenpaullone pretreatment significantly reduced ROS fluorescence intensity and significantly down-regulated the level of apoptosis-activating genes (cleaved caspase-3, cleaved caspase-9 and cytochrome C), autophagy markers (LC3A/B), and the Cx43-interacting partner SGSM3. These results suggest that kenpaullone plays a role in protecting cardiomyocytes from oxidative stress and that the turnover of Cx43 through SGSM3-induced lysosomal degradation underlies the anti-apoptotic effect of kenpaullone.
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http://dx.doi.org/10.1016/j.bbrc.2018.03.166DOI Listing
May 2018

Small molecule-mediated induction of miR-9 suppressed vascular smooth muscle cell proliferation and neointima formation after balloon injury.

Oncotarget 2017 Nov 28;8(55):93360-93372. Epub 2017 Sep 28.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Incheon, Republic of Korea.

Pathologic proliferation and migration of vascular smooth muscle cells (VSMCs) exacerbate cardiovascular disease. MicroRNAs (miRNAs), as endogenous inhibitors of protein synthesis, are expected to modulate pathologic proliferation of VSMCs. Here we report that both platelet-derived growth factor receptor (PDGFR) targeting miR-9 and a small molecule that increases miR-9 can inhibit the serum-induced proliferation of VSMCs. First, based on miRNA-target prediction databases and empirical data, we have selected miR-9 as a potent anti-proliferative miRNA in VSMCs. Further examination indicated that miR-9 directly targets PDGFR disrupting downstream signaling cascades, and this resulted in inhibition of VSMC proliferation and migration. Exogenous delivery of miR-9 inhibited VSMC proliferation and a small molecule that increased miR-9 expression also inhibited neointima formation following balloon injury . We provide evidence of miRNA-mediated modulation of VSMC proliferation and further demonstrate that small molecule-mediated regulation of miRNA targeting a key regulator of VSMC proliferation is a viable therapeutic strategy for treating vascular disease involving pathologic VSMC proliferation such as restenosis.
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http://dx.doi.org/10.18632/oncotarget.21382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706801PMC
November 2017

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

Cell Physiol Biochem 2017 3;44(1):53-65. Epub 2017 Nov 3.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Republic of Korea.

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.
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http://dx.doi.org/10.1159/000484582DOI Listing
March 2018

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

J Int Med Res 2018 Mar 6;46(3):951-964. Epub 2017 Oct 6.

1 395886 Catholic Kwandong University, International St. Mary's Hospital , Incheon Metropolitan City, Republic of Korea.

Objective 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. Methods 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. Results 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. Conclusion Protein expression profiles were unchanged in HUVECs induced by isolated ADASs from donors of different ages under oxidative stress conditions.
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http://dx.doi.org/10.1177/0300060517731684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972239PMC
March 2018

Human Long Noncoding RNA Regulation of Stem Cell Potency and Differentiation.

Stem Cells Int 2017 30;2017:6374504. Epub 2017 Aug 30.

Institute for Biomedical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea.

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.
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http://dx.doi.org/10.1155/2017/6374504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603141PMC
August 2017

Adipose-derived stem cell-released osteoprotegerin protects cardiomyocytes from reactive oxygen species-induced cell death.

Stem Cell Res Ther 2017 09 19;8(1):195. Epub 2017 Sep 19.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Korea.

Background: The paracrine effect is likely the major mechanism of the adipose-derived stem cell (ASC)-mediated cardioprotective effect. However, the exact composition and nature of ASC-released paracrine factors remain elusive. In the present study, we examined the effect of osteoprotegerin (OPG), a stem cell-released decoy receptor for death ligand, on the survival of cardiomyocytes exposed to oxidative stress.

Methods: The production of OPG from ASCs under oxidative stress was determined by ELISA and immunohistochemistry. The effects of OPG and the OPG-containing conditioned media of ASCs on the survival of cardiomyocytes were determined using a cell viability assay.

Results: Hydrogen peroxide (HO) significantly increased OPG production from ASCs in vitro, and OPG production from the ASCs transplanted into the ischemia-reperfusion-injured heart was also observed. OPG significantly attenuated cardiomyocyte death in vitro. OPG-containing conditioned media of ASCs also significantly protected cardiomyocytes. Delivery of siRNA specific to OPG significantly decreased the OPG production of ASCs, and also offset the protective effect of the conditioned media of ASCs.

Conclusions: Our study strongly suggests that OPG is one of the prosurvival factors released from ASCs that may contribute to the ASC-mediated cardioprotection and calls for further studies to elucidate detailed underlying mechanisms.
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http://dx.doi.org/10.1186/s13287-017-0647-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606035PMC
September 2017

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

Mol Cell Biochem 2018 Feb 9;439(1-2):105-115. Epub 2017 Aug 9.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Republic of Korea.

During the past decade, microRNAs have continuously been suggested as a promising therapeutic tool due to their beneficial effects, such as their multi-targets and multi-functions in pathologic conditions. As a pathologic phenotype is generally regulated by multiple signaling pathways, in this study we identified a microRNA regulating multiple target genes within cardiac hypertrophic signaling pathways. microRNA-133a is known to play a crucial role in cardiac hypertrophy. However, the role of microRNA-133a, which may regulate several signaling pathways in norepinephrine-induced cardiac hypertrophy via multi-targeting, has not been investigated. In the current study, we showed that microRNA-133a can protect cardiomyocyte hypertrophy against norepinephrine stimulation in neonatal rat ventricular cardiomyocytes via new targets, PKCδ and Gq, all of which are related to downstream signaling pathways of the α-adrenergic receptor. Taken together, these results suggest the advantages of the therapeutic use of microRNAs as an effective potential drug regulating multiple signaling pathways under pathologic conditions.
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http://dx.doi.org/10.1007/s11010-017-3140-8DOI Listing
February 2018

Interaction of small G protein signaling modulator 3 with connexin 43 contributes to myocardial infarction in rat hearts.

Biochem Biophys Res Commun 2017 09 14;491(2):429-435. Epub 2017 Jul 14.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Republic of Korea; Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea. Electronic address:

Connexin 43 (Cx43), a ubiquitous connexin expressed in the heart and skin, is associated with a variety of hereditary conditions. Therefore, the characterization of Cx43-interacting proteins and their dynamics is important to understand not only the molecular mechanisms underlying pathological malfunction of gap junction-mediated intercellular communication but also to identify novel and unanticipated biological functions of Cx43. In the present study, we observed potential targets of Cx43 to determine new molecular functions in cardio-protection. MALDI-TOF mass spectrometry analysis of Cx43 co-immunoprecipitated proteins showed that Cx43 interacts with several proteins related to metabolism. In GeneMANIA network analysis, SGSM3, which has not been previously associated with Cx43, was highly correlated with Cx43 in heart functions, and high levels of SGSM3 appeared to induce the turnover of Cx43 through lysosomal degradation in myocardial infarcted rat hearts. Moreover, we confirmed that lysosomal degradation of Cx43 is dependent upon the interaction between SGSM3 and Cx43 in H9c2 cardiomyocytes. The functional importance of the interaction between SGSM3 and Cx43 was confirmed by results showing that Cx43 expression was enhanced by SGSM3 siRNA knockdown in H9c2 cells. In summary, the results of this study elucidate the molecular mechanisms in which Cx43 with SGSM3 is degraded in myocardial infarcted rat hearts, which may contribute to the establishment of new therapeutic targets to modulate cardiac function in physiological and pathological conditions.
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http://dx.doi.org/10.1016/j.bbrc.2017.07.081DOI Listing
September 2017

Exogenous miRNA-146a Enhances the Therapeutic Efficacy of Human Mesenchymal Stem Cells by Increasing Vascular Endothelial Growth Factor Secretion in the Ischemia/Reperfusion-Injured Heart.

J Vasc Res 2017 14;54(2):100-108. Epub 2017 Apr 14.

Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.

Adult stem cells have been studied as a promising therapeutic modality for the functional restoration of the damaged heart. In the present study, a strategy for enhancing the angiogenic efficacy of human mesenchymal stem cells (hMSCs) using micro-RNA was examined. We investigated whether micro-RNA-146a (miR-146a) influences the secretion of vascular endothelial growth factor (VEGF) and angiogenesis of MSCs. Our data indicated that miR-146a-transfected hMSCs (hMSCmiR-146a) decreased the expression of neurofibromin 2, an inhibitor of p21-activated kinase-1 (PAK1). miR-146a also increased the expression of Ras-related C3 botulinum toxin substrate 1 and PAK1, which are known to induce VEGF expression, and the formation of vascular branches was increased in hMSCmiR-146a compared to hMSCs treated with VEGF. VEGF and p-Akt were increased in hMSCmiR-146a. Furthermore, injection of hMSCmiR-146a after ischemia/reperfusion (I/R) injury led to a reduction of fibrosis area and increased VEGF expression, confirming the regenerative capacity such as reparative angiogenesis in the infarcted area. Cardiac functions in I/R injury were improved following injection of hMSCmiR-146a compared to the I/R group. Taken together, these data suggest that miR-146 is a novel microRNA that regulates VEGF expression, and its use may be an effective strategy for enhancing the therapeutic efficacy of hMSC transplantation into the I/R-injured heart.
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http://dx.doi.org/10.1159/000461596DOI Listing
June 2017

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.

Eur J Pharmacol 2017 Mar 6;798:35-42. Epub 2017 Feb 6.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Korea. Electronic address:

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-cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-ylamine, a lymphocyte-specific protein tyrosine kinase (Lck) inhibitor, significantly inhibited both VSMC proliferation and migration. 7-cyclopentyl-5-(4-phenoxyphenyl)-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 D1 and, the phosphorylation of retinoblastoma protein (pRb). Additionally, 7-cyclopentyl-5-(4-phenoxyphenyl)-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-cyclopentyl-5-(4-phenoxyphenyl)-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.
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http://dx.doi.org/10.1016/j.ejphar.2017.02.004DOI Listing
March 2017

A spleen tyrosine kinase inhibitor attenuates the proliferation and migration of vascular smooth muscle cells.

Biol Res 2017 Jan 18;50(1). Epub 2017 Jan 18.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, South Korea.

Background: Pathologic vascular smooth muscle cell (VSMC) proliferation and migration after vascular injury promotes the development of occlusive vascular disease. Therefore, an effective chemical agent to suppress aberrant proliferation and migration of VSMCs can be a potential therapeutic modality for occlusive vascular disease such as atherosclerosis and restenosis. To find an anti-proliferative chemical agent for VSMCs, we screened an in-house small molecule library, and the selected small molecule was further validated for its anti-proliferative effect on VSMCs using multiple approaches, such as cell proliferation assays, wound healing assays, transwell migration assays, and ex vivo aortic ring assay.

Results: Among 43 initially screened small molecule inhibitors of kinases that have no known anti-proliferative effect on VSMCs, a spleen tyrosine kinase (Syk) inhibitor (BAY61-3606) showed significant anti-proliferative effect on VSMCs. Further experiments indicated that BAY61 attenuated the VSMC proliferation in both concentration- and time-dependent manner, and it also significantly suppressed the migration of VSMCs as assessed by both wound healing assays and transwell assays. Additionally, BAY61 suppressed the sprouting of VSMCs from endothelium-removed aortic rings.

Conclusion: The present study identified a Syk kinase inhibitor as a potent VSMC proliferation and migration inhibitor and warrants further studies to elucidate its underlying molecular mechanisms, such as its primary target, and to validate its in vivo efficacy as a therapeutic agent for restenosis and atherosclerosis.
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http://dx.doi.org/10.1186/s40659-016-0106-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244549PMC
January 2017

Alternative new mesenchymal stem cell source exerts tumor tropism through ALCAM and N-cadherin via regulation of microRNA-192 and -218.

Mol Cell Biochem 2017 Mar 30;427(1-2):177-185. Epub 2016 Dec 30.

Department of Biology Education, College of Education, Pusan National University, Pusan, 609-735, South Korea.

Gliomas are the most common type of malignant primary brain tumors. Some treatments of gliomas exist, but they are rarely curative. Mesenchymal stem cells (MSCs) are emerging as potential modes of targeted cancer therapy owing to their capacity for homing toward tumor sites. It has been proposed that MSCs derived from various sources, such as bone marrow, adipose tissue and umbilical cord blood, can be used as cell-based therapy for brain tumors. Here, MSCs obtained from the synovial fluid of osteoarthritis or rheumatoid arthritis patients were investigated as therapeutic candidates. Specifically, we compared migratory and adhesive abilities, as well as expression levels of related genes and microRNA in bone marrow derived-MSCs (BMMSCs), adipose derived-MSCs (ADMSCs), and synovial fluid derived-MSCs (SFMSCs) after treatment with conditioned medium from gliomas. Migration and adhesion of SFMSCs increased through upregulation of the activated lymphocyte cell adhesion molecule (ALCAM) and N-cadherin by microRNA-192 and -218 downregulation, similar to BMMSCs and ADMSCs. Migratory capacities of all types of MSCs were evaluated in vivo, and SFMSCs migrated intensively toward gliomas. These results suggest that SFMSCs have potential for use in cell-based antitumor therapies.
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http://dx.doi.org/10.1007/s11010-016-2909-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306073PMC
March 2017

Proteomic Analysis and Identification of Paracrine Factors in Mesenchymal Stem Cell-Conditioned Media under Hypoxia.

Cell Physiol Biochem 2016 21;40(1-2):400-410. Epub 2016 Nov 21.

Department of Cardiovascular Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

Background/aims: We previously showed that a hypoxic environment modulates the antiarrhythmic potential of mesenchymal stem cells.

Methods: To investigate the mechanism by which secreted proteins contribute to the pathogenesis of antiarrhythmic potential in mesenchymal stem cells, we used two-dimensional electrophoresis combined with MALDI-TOF-MS to perform a proteomic analysis to compare the paracrine media produced by normoxic and hypoxic cells.

Results: The proteomic analysis revealed that 66 protein spots out of a total of 231 matched spots indicated differential expression between the normoxic and hypoxic conditioned media of mesenchymal stem cells. Interestingly, two tropomyosin isoforms were dramatically increased in the hypoxic conditioned medium of mesenchymal stem cells. An increase in tropomyosin was confirmed using Western blot to analyze the conditioned media between normoxic and hypoxic cells. In a network analysis based on gene ontology (GO) Molecular Function by GeneMANIA analysis, most of the identified proteins were found to be involved in the regulation of heart processes.

Conclusion: Our results show that hypoxia up-regulates tropomyosin and other secreted proteins which suggests that tropomyosin may be involved in regulating proarrhythmic and antiarrhythmic functions.
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http://dx.doi.org/10.1159/000452555DOI Listing
February 2017

Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases.

Stem Cells Int 2016 18;2016:4285938. Epub 2016 Oct 18.

Department of Biology Education, College of Education, Pusan National University, Busan 609-735, Republic of Korea.

Despite development of medicine, cardiovascular diseases (CVDs) are still the leading cause of mortality and morbidity worldwide. Over the past 10 years, various stem cells have been utilized in therapeutic strategies for the treatment of CVDs. CVDs are characterized by a broad range of pathological reactions including inflammation, necrosis, hyperplasia, and hypertrophy. However, the causes of CVDs are still unclear. While there is a limit to the currently available target-dependent treatments, the therapeutic potential of stem cells is very attractive for the treatment of CVDs because of their paracrine effects, anti-inflammatory activity, and immunomodulatory capacity. Various studies have recently reported increased therapeutic potential of transplantation of microRNA- (miRNA-) overexpressing stem cells or small-molecule-treated cells. In addition to treatment with drugs or overexpressed miRNA in stem cells, stem cell-derived extracellular vesicles also have therapeutic potential because they can deliver the stem cell-specific RNA and protein into the host cell, thereby improving cell viability. Here, we reported the state of stem cell-based therapy for the treatment of CVDs and the potential for cell-free based therapy.
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http://dx.doi.org/10.1155/2016/4285938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088322PMC
October 2016

MicroRNA-Mediated Down-Regulation of Apoptosis Signal-Regulating Kinase 1 (ASK1) Attenuates the Apoptosis of Human Mesenchymal Stem Cells (MSCs) Transplanted into Infarcted Heart.

Int J Mol Sci 2016 Oct 20;17(10). Epub 2016 Oct 20.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, 25601 Gangwon-do, Korea.

Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs) has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic effect of stem cells. In the damaged heart, oxidative stress due to reactive oxygen species (ROS) production can cause the death of transplanted MSCs. Apoptosis signal-regulating kinase 1 (ASK1) has been implicated in the development of oxidative stress-related pathologic conditions. Thus, we hypothesized that down-regulation of ASK1 in human MSCs (hMSCs) might attenuate the post-transplantation death of MSCs. To test this hypothesis, we screened microRNAs (miRNAs) based on a miRNA-target prediction database and empirical data and investigated the anti-apoptotic effect of selected miRNAs on human adipose-derived stem cells (hASCs) and on rat myocardial infarction (MI) models. Our data indicated that miRNA-301a most significantly suppressed ASK1 expression in hASCs. Apoptosis-related genes were significantly down-regulated in miRNA-301a-enriched hASCs exposed to hypoxic conditions. Taken together, these data show that miRNA-mediated down-regulation of ASK1 protects MSCs during post-transplantation, leading to an increase in the efficacy of MSC-based cell therapy.
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http://dx.doi.org/10.3390/ijms17101752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085777PMC
October 2016

Alterations in Cardiomyocyte Differentiation-Related Proteins in Rat Mesenchymal Stem Cells Exposed to Hypoxia.

Cell Physiol Biochem 2016 15;39(4):1595-607. Epub 2016 Sep 15.

Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City, Republic of Korea.

Background/aims: It is known that mesenchymal stem cells (MSCs) can have variable responses to hypoxic conditions and that hypoxia may specifically stimulate differentiation into osteogenic, chondrogenic, or adipogenic cells. Based on our previous study, we hypothesized that hypoxia may also induce MSC differentiation into cardiomyocytes and/or cells with comparable phenotypes.

Methods: The differences in the proteomes were specifically investigated in bone marrow-derived rat MSCs (BM-rMSCs) under normoxic and hypoxic conditions using 2-DE combined with a MALDI-TOF-MS analysis and western blot analysis. In addition, genetic and/or proteomic interactions were assessed using a String network analysis.

Results: Among the 35 markedly changed spots from a total of 393 matched spots, 24 were highly up-regulated and 11 were significantly down-regulated in hypoxic rMSCs based on a proteomic analysis. Although hypoxia failed to induce the direct differentiation of rMSCs into cardiomyocytes, several cardiomyocyte differentiation-related genes and proteins were significantly increased by hypoxic stress.

Conclusion: We found that BM-rMSCs alter their expression of several cardiomyocyte differentiation-related genes and proteins under hypoxic conditions, and we examined the interactions between these genes and/or proteins, providing new insights for the applicability of MSCs preconditioned by hypoxic stimulation for use in cardiac diseases.
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http://dx.doi.org/10.1159/000447861DOI Listing
January 2017

The role of nuclear factor of activated T cells during phorbol myristate acetate-induced cardiac differentiation of mesenchymal stem cells.

Stem Cell Res Ther 2016 Jul 12;7(1):90. Epub 2016 Jul 12.

Institute for Bio-medical Convergence, Catholic Kwandong University, Incheon, South Korea.

Background: We previously reported that phorbol 12-myristate 13-acetate (PMA) treatment can induce the cardiac differentiation of mesenchymal stem cells (MSCs). In the present study, we investigated how PMA induces cardiac differentiation of MSCs, focusing on its effect on the transcription factors responsible for increased cardiac marker gene expression.

Methods: Human MSCs (hMSCs) were treated with 1 μM PMA for 9 days. The expression of MSC markers and cardiac markers in the PMA-treated hMSC, as well as the nuclear translocation of transcription factors, nuclear factor of activated T cells (NFAT), and myogenic differentiation 1 (MyoD), was examined. Transcriptional activity of NFAT was examined by utilizing a green fluorescent protein (GFP) vector containing NFAT motif of human interleukin-2 promoter. The effect of PMA on the expression of key cell cycle regulators was examined.

Results: PMA induces the transcriptional activity of NFAT and MyoD, which have been associated with increased expression of cardiac troponin T (cTnT) and myosin heavy chain (MHC), respectively. Our data suggested that protein kinase C (PKC) mediates the effect of PMA on NFAT activation. Furthermore, PMA treatment increased cell-cycle regulator p27(kip1) expression, suggesting that PMA triggers the cardiac differentiation program in MSCs by regulating key transcription factors and cell cycle regulators.

Conclusions: The results of this study demonstrate the importance of NFAT activation during PMA-induced MSC differentiation and help us to better understand the underlying mechanisms of small molecule-mediated MSC differentiation so that we can develop a strategy for synthesizing novel and improved differentiation-inducing small molecules.
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http://dx.doi.org/10.1186/s13287-016-0348-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942985PMC
July 2016