Publications by authors named "Byeong-Wook Song"

52 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

Corrigendum to "Non-invasively enhanced intracranial transplantation of mesenchymal stem cells using focused ultrasound mediated by overexpression of cell-adhesion molecules" [Stem Cell Res. 43 (2020) 101726].

Stem Cell Res 2021 Mar 16;51:102179. Epub 2021 Jan 16.

Brain Korea 21 PLUS Project for Medical Science & Brain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Neurosurgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.scr.2021.102179DOI Listing
March 2021

Isoliquiritigenin Enhances the Beige Adipocyte Potential of Adipose-Derived Stem Cells by JNK Inhibition.

Molecules 2020 Dec 1;25(23). Epub 2020 Dec 1.

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

Human adipose-derived stem cells (hASCs) can be isolated from fat tissue and have attracted interest for their potential therapeutic applications in metabolic disease. hASCs can be induced to undergo adipogenic differentiation in vitro by exposure to chemical agents or inductive growth factors. We investigated the effects and mechanism of differentiating hASC-derived white adipocytes into functional beige and brown adipocytes with isoliquiritigenin (ILG) treatment. Here, we showed that hASC-derived white adipocytes could promote brown adipogenesis by expressing both uncoupling protein 1 (UCP1) and PR/SET Domain 16 (PRDM16) following low-dose ILG treatments. ILG treatment of white adipocytes enhanced the expression of brown fat-specific markers, while the expression levels of c-Jun N-terminal kinase (JNK) signaling pathway proteins were downregulated. Furthermore, we showed that the inhibition of JNK phosphorylation contributed to white adipocyte differentiation into beige adipocytes, which was validated by the use of SP600125. We identified distinct regulatory effects of ILG dose responses and suggested that low-dose ILG induced the beige adipocyte potential of hASCs via JNK inhibition.
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http://dx.doi.org/10.3390/molecules25235660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730955PMC
December 2020

Regulation of alternative macrophage activation by MSCs derived hypoxic conditioned medium, via the TGF-β1/Smad3 pathway.

BMB Rep 2020 Nov;53(11):600-604

Department of Biology Education, College of Education, Pusan National University, Busan 46241, Korea.

Macrophages are re-educated and polarized in response to myocardial infarction (MI). The M2 anti-inflammatory phenotype is a known dominator of late stage MI. Mesenchymal stem cells (MSCs) represent a promising tool for cell therapy, particularly heart related diseases. In general, MSCs induce alteration of the macrophage subtype from M1 to M2, both in vitro and in vivo. We conjectured that hypoxic conditions can promote secretome productivity of MSCs. Hypoxia induces TGF-β1 expression, and TGF-β1 mediates M2 macrophage polarization for anti-inflammation and angiogenesis in infarcted areas. We hypothesized that macrophages undergo advanced M2 polarization after exposure to MSCs in hypoxia. Treatment of MSCs derived hypoxic conditioned medium (hypo-CM) promoted M2 phenotype and neovascularization through the TGF-β1/Smad3 pathway. In addition, hypo-CM derived from MSCs improved restoration of ischemic heart, such as attenuating cell apoptosis and fibrosis, and ameliorating microvessel density. Based on our results, we propose a new therapeutic method for effective MI treatment using regulation of macrophage polarization. [BMB Reports 2020; 53(11): 600-604].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704222PMC
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

A Combinational Therapy of Articular Cartilage Defects: Rapid and Effective Regeneration by Using Low-Intensity Focused Ultrasound After Adipose Tissue-Derived Stem Cell Transplantation.

Tissue Eng Regen Med 2020 06 9;17(3):313-322. Epub 2020 Apr 9.

International St. Mary's Hospital, Catholic Kwandong University, 25, Simgok-ro 100beon-gil, Seo-gu, Incheon, 22711, Republic of Korea.

Background: Although low-intensity pulsed ultrasound has been reported to be potential cartilage regeneration, there still unresolved treatment due to cartilage fibrosis and degeneration by a lack of rapid and high-efficiency treatment. The purpose of this study was to investigate the effect of a combination therapy of focused acoustic force and stem cells at site for fast and efficient healing on cartilage regeneration.

Methods: Using a rat articular cartilage defects model, one million adipose tissue-derived stem cells (ASCs) were injected into the defect site, and low-intensity focused ultrasound (LOFUS) in the range of 100-600 mV was used for 20 min/day for 2 weeks. All experimental groups were sacrificed after 4 weeks in total. The gross appearance score and hematoxylin and eosin (H&E), Alcian blue, and Safranin O staining were used for measuring the chondrogenic potential. The cartilage characteristics were observed, and type II collagen, Sox 9, aggrecan, and type X collagen were stained with immunofluorescence. The results of the comprehensive analysis were calculated using the Mankin scoring method.

Results: The gross appearance scores of regenerated cartilage and chondrocyte-like cells in H&E images were higher in LOFUS-treated groups compared to those in negative control or ASC-treated groups. Safranin O and Alcian blue staining demonstrated that the 100 and 300 mV LOFUS groups showed greater synthesis of glycosaminoglycan and proteoglycan. The ASC + LOFUS 300 mV group showed positive regulation of type II collagen, Sox 9 and aggrecan and negative regulation of type X collagen, which indicated the occurrence of cartilage regeneration based on the Mankin score result.

Conclusion: The combination therapy, which involved treatment with ASC and 300 mV LOFUS, quickly and effectively reduced articular cartilage defects.
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http://dx.doi.org/10.1007/s13770-020-00256-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260301PMC
June 2020

Non-invasively enhanced intracranial transplantation of mesenchymal stem cells using focused ultrasound mediated by overexpression of cell-adhesion molecules.

Stem Cell Res 2020 03 30;43:101726. Epub 2020 Jan 30.

Brain Korea 21 PLUS Project for Medical Science & Brain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Neurosurgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address:

Although there have been reports of promising results regarding the transplantation of mesenchymal stem cells (MSCs) for neurodegenerative diseases through the use of neuronal differentiation or control of the microenvironment, traditional surgical transplantation methods like parenchymal or intravenous injection have limitations such as secondary injuries in the brain, infection, and low survival rate of stem cells in the target site. Focused ultrasound (FUS) treatment is an emerging modality for the treatment of brain diseases, including neurodegenerative disorders. The various biological effects of FUS treatment have been investigated; therefore, the goal is now to improve the delivery efficiency and function of MSCs by capitalizing on the advantages of FUS. In this study, we demonstrated that FUS increases MSC transplantation into brain tissue by >2-fold, and that this finding might be related to the activation of intercellular adhesion molecule-1 in endothelial and subendothelial cells and vascular adhesion molecule-1 in endothelial cells.
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http://dx.doi.org/10.1016/j.scr.2020.101726DOI Listing
March 2020

Hypoxia Rapidly Induces the Expression of Cardiomyogenic Factors in Human Adipose-Derived Adherent Stromal Cells.

J Clin Med 2019 Aug 15;8(8). Epub 2019 Aug 15.

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

Background: The efficacy of interstitial vascular fraction (SVF) transplantation in the treatment of heart disease has been proven in a variety of in vivo studies. In a previous study, we found that bone marrow-derived mesenchymal stem cells (BM-MSCs) altered their expression of several cardiomyogenic factors under hypoxic conditions.

Methods: We hypothesized that hypoxia may also induce obtained adipose-derived adherent stromal cells (ADASs) from SVFs and adipose-derived stem cells (ASCs) to differentiate into cardiomyocytes and/or cells with comparable phenotypes. We examined the differentiation markers of cell lineages in ADASs and ASCs according to time by hypoxic stress and found that only ADASs expressed cardiomyogenic markers within 24 h under hypoxic conditions in association with the expression of hypoxia-inducible factor 1-α (HIF-1α).

Results: Differentially secreted proteins in a conditioned medium (CM) from ASCs and ADASs under normoxic or hypoxic conditions were detected using an antibody assay and may be associated with a dramatic increase in the expression of cardiomyogenic markers in only ADASs. Furthermore, the cardiomyogenic factors were expressed more rapidly in ADASs than in ASCs under hypoxic conditions in association with the expression of HIF-1α, and angiogenin, fibroblast growth factor-19 (FGF-19) and/or macrophage inhibitory factor (MIF) are related.

Conclusions: These results provide new insights into the applicability of ADASs preconditioned by hypoxic stress in cardiac diseases.
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http://dx.doi.org/10.3390/jcm8081231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723458PMC
August 2019

Curcumin Treatment in Combination with Glucose Restriction Inhibits Intracellular Alkalinization and Tumor Growth in Hepatoma Cells.

Int J Mol Sci 2019 May 14;20(10). Epub 2019 May 14.

Institute for Translational and Clinical Research, Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Korea.

Dysregulation of cellular energy metabolism is closely linked to cancer development and progression. Calorie or glucose restriction (CR or GR) inhibits energy-dependent pathways, including IGF-1/PI3K/Akt/mTOR, in cancer cells. However, alterations in proton dynamics and reversal of the pH gradient across the cell membrane, which results in intracellular alkalinization and extracellular acidification in cancer tissues, have emerged as important etiopathogenic factors. We measured glucose, lactate, and ATP production after GR, plant-derived CR-mimetic curcumin treatment, and curcumin plus GR in human hepatoma cells. Intracellular pH regulatory effects, in particular, protein-protein interactions within mTOR complex-1 and its structural change, were investigated. Curcumin treatment or GR mildly inhibited Na+/H+ exchanger-1 (NHE1). vATPase, monocarboxylate transporter (MCT)-1, and MCT4 level. Combination treatment with curcumin and GR further enhanced the inhibitory effects on these transporters and proton-extruding enzymes, with intracellular pH reduction. ATP and lactate production decreased according to pH change. Modeling of mTOR protein revealed structural changes upon treatments, and curcumin plus GR decreased binding of Raptor and GβL to mTOR, as well as of Rag A and Rag B to Raptor. Consequently, 4EBP1 phosphorylation was decreased and cell migration and proliferation were inhibited in a pH-dependent manner. Autophagy was increased by curcumin plus GR. In conclusion, curcumin treatment combined with GR may be a useful supportive approach for preventing intracellular alkalinization and cancer progression.
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http://dx.doi.org/10.3390/ijms20102375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566721PMC
May 2019

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

Combination Therapy Comprising a Static Magnetic Field with Contractility Improves Skin Wounds.

Tissue Eng Part A 2018 09 7;24(17-18):1354-1363. Epub 2018 Jun 7.

2 Department of Medical Science, College of Medicine, Catholic Kwandong University , Gangneung, Republic of Korea.

Cutaneous wounds can present significant clinical problems because of abnormal healing after deep dermal damage. Despite technical advances in wound care, there are still unmet needs that result from inefficient treatment. In this study, we aimed to improve skin wound healing using a contractibility band with static magnetic field (SMF), termed a magnetic band (Mb). To examine the effect of the Mb on wound healing, full-thickness 15 × 35 mm excision wounds were surgically created on the dorsum of rats. An elastic and contractile band (nontreatment), or one neodymium magnet (Nd-1) or two magnets with an elastic and contractile band (Nd-2) were topically applied to the wound daily and the wound size was measured from day 1 to 7 after surgery. Nd-2 showed a significant (95%) reduction in the wound size on day 3. Histological analysis showed that proinflammatory cytokine levels were diminished by Nd-2, and granulation tissue and microvessels were increased compared with those in the sham group. During Mb-induced wound healing, apoptosis was significantly reduced and matrix remodeling-related factors were initially regulated. The results suggest that combination therapy comprising an SMF and an elastic and contractile band could be a promising tool to heal cutaneous wounds rapidly.
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http://dx.doi.org/10.1089/ten.TEA.2017.0470DOI Listing
September 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

Preliminary study on Low Intensity Focused Ultrasound system For neuromodulation.

Annu Int Conf IEEE Eng Med Biol Soc 2017 Jul;2017:4545-4548

A Prototype Low Intensity Focused Ultrasound for brain targeting in a rat model was developed and tested. Accordingly, were evaluated low intensity focused ultrasound accuracy and performance. By utilizing the Rat Brain, no death or necrosis of cells, it was confirmed that the energy is gathered at that targeted.
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http://dx.doi.org/10.1109/EMBC.2017.8037867DOI Listing
July 2017

In Vivo Assessment of Stem Cells for Treating Neurodegenerative Disease: Current Approaches and Future Prospects.

Authors:
Byeong-Wook Song

Stem Cells Int 2017 23;2017:9751583. Epub 2017 Feb 23.

EIT/LOFUS R&D Center, Institute for Integrative Medicine, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 25601, Republic of Korea; Catholic Kwandong University International St. Mary's Hospital, 25 Simgok-Ro, 100 Beon-Gil, Seo-Gu, Incheon 22711, Republic of Korea.

In recent years, stem cell-related therapies have been widely applied for treating neurodegenerative disease. Despite their potential, stem cell tracking and imaging techniques for the evaluation of in vivo proof-of-concept (PoC) therapies have not been sufficiently represented in the research area. This review summarizes the recent approaches that have been used for tracking and imaging engrafted stem cells in vivo. Furthermore, we introduce tissue clearing technology that can be applied to develop three-dimensional in vivo experiments. Monitoring stem cell survival and migration and graft-host relationships is a useful strategy to evaluate the therapeutic efficacy of regenerative medicine approaches in neurodegenerative disease.
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http://dx.doi.org/10.1155/2017/9751583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343274PMC
February 2017

Potential therapeutic application of small molecule with sulfonamide for chondrogenic differentiation and articular cartilage repair.

Bioorg Med Chem Lett 2016 10 22;26(20):5098-5102. Epub 2016 Aug 22.

Catholic Kwandong University International St. Mary's Hospital, Seo-go, Incheon Metropolitan City 22711, Republic of Korea; Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 25601, Republic of Korea. Electronic address:

The restoration of damaged articular cartilage is a long-pursued goal in regenerative medicine. Chondrocyte-specific differentiation of mesenchymal stem cells (MSCs) may be an effective means of repairing damaged cartilage. We identified small molecule 6 with sulfonamide as an agent that promotes specific chondrogenic differentiation of human adipose-derived MSCs (hASCs). Unlike other chondrogenic differentiation media composed of various defined components, simply adding compound 6 into culture medium was sufficient to induce chondrogenesis in this study. In an animal osteoarthritis model, both the small molecule 6 and the 6-treated hASCs exhibited enhanced recovery of injured articular cartilage. This work provides new insight into MSC differentiation induced by small molecules and potential new therapeutic approaches for articular cartilage injury.
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http://dx.doi.org/10.1016/j.bmcl.2016.08.069DOI Listing
October 2016

The microRNA-dependent cell fate of multipotent stromal cells differentiating to endothelial cells.

Exp Cell Res 2016 Feb 8;341(2):139-46. Epub 2016 Feb 8.

Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Republic of Korea; Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do 25601, Republic of Korea. Electronic address:

In the endothelial recovery process, bone marrow-derived MSCs are a potential source of cells for both research and therapy, and their capacities to self-renew and to differentiate into all the cell types in the human body make them a promising therapeutic agent for remodeling cellular differentiation and a valuable resource for the treatment of many diseases. Based on the results provided in a miRNA database, we selected miRNAs with unique targets in cell fate-related signaling pathways. The tested miRNAs targeting GSK-3β (miR-26a), platelet-derived growth factor receptor, and CD133 (miR-26a and miR-29b) induced MSC differentiation into functional ECs, whereas miRNAs targeting VEGF receptor (miR-15, miR-144, miR-145, and miR-329) inhibited MSC differentiation into ECs through VEGF stimulation. In addition, the expression levels of these miRNAs were correlated with in vivo physiological endothelial recovery processes. These findings indicate that the miRNA expression profile is distinct for cells in different stages of differentiation from MSCs to ECs and that specific miRNAs can function as regulators of endothelialization.
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http://dx.doi.org/10.1016/j.yexcr.2016.02.005DOI Listing
February 2016

1H-pyrrole-2,5-dione-based small molecule-induced generation of mesenchymal stem cell-derived functional endothelial cells that facilitate rapid endothelialization after vascular injury.

Stem Cell Res Ther 2015 Sep 15;6:174. Epub 2015 Sep 15.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University Gangneung, Beomilro 579beongil 24, Gangwon-do, 210-701, Republic of Korea.

Introduction: Despite the success of interventional processes such as drug-eluting stents, complete prevention of restenosis is still hindered by impaired or delayed endothelialization or both. Here, we report that 1H-pyrrole-2,5-dione-based small molecule-generated mesenchymal stem cell-derived functional endothelial cells (MDFECs) facilitated rapid transmural coverage of injured blood vessels.

Methods: Small molecules that induced CD31 expression were screened by principal component analysis (PCA). Rat mesenchymal stem cells (MSCs) were treated with selected small molecules for up to 16 days, and the expression levels of CD90 and CD31 were examined by immunocytochemistry. In vitro functional assays of MDFECs, including tube formation assays and nitric oxide production assays, were performed. After MDFECs (intravenous, 3×10(6) cells per animal) were injected into balloon-injured rats, neointima formation was monitored for up to 21 days. The endothelial coverage of denuded blood vessels was evaluated by Evans Blue staining. The functionality of repaired blood vessels was evaluated by measuring vasorelaxation and hemodynamic changes. Additionally, derivatives of the selected small molecules were examined for their ability to induce endothelial markers.

Results: PCA indicated that 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione effectively induced MDFECs. MDFECs inhibited the neointima formation of denuded blood vessels by facilitating more rapid endothelialization. Further examination indicated that derivatives with a 1H-pyrrole-2,5-dione moiety are important for initiating the endothelial cell differentiation of MSCs.

Conclusions: Small molecules with 1H-pyrrole-2,5-dione as a core structure have great potential to improve the efficacy of MSC-based cell therapy for vascular diseases, such as atherosclerosis and restenosis.
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http://dx.doi.org/10.1186/s13287-015-0170-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572653PMC
September 2015

Combination of a peroxisome proliferator-activated receptor-gamma agonist and an angiotensin II receptor blocker attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats.

J Diabetes Investig 2014 Jul 7;5(4):362-71. Epub 2013 Nov 7.

Cardiology Division Severance Cardiovascular Hospital Yonsei University College of Medicine Seoul South Korea ; Cardiovascular Research Institute Yonsei University College of Medicine Seoul South Korea.

Aims/introduction: We aimed to examine the effect of an angiotensin II receptor blocker (ARB), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, and their combination on myocardial fibrosis and function in type 2 diabetic rats.

Materials And Methods: Five male Long-Evans Tokushima Otsuka (LETO) rats and 20 male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used. OLETF rats were assigned to four groups (n = 5 per group) at 28 weeks-of-age: untreated, losartan-treated, rosiglitazone-treated and combination-treated. The ARB, losartan, was administered at a dose of 5 mg/kg/day, and the PPAR-gamma agonist, rosiglitazone, was administered at a dose of 3 mg/kg/day by oral gavage for 12 weeks. Urine and blood samples were collected, and two-dimensional echocardiograms and strain rate imaging were obtained at 28 and 40 weeks. Cytokines were evaluated by reverse transcriptase polymerase chain reaction, and histological analysis was carried out at 40 weeks.

Results: At 40 weeks, the global radial strains of the losartan-treated (55.7 ± 4.5%, P = 0.021) and combination-treated groups (59.3 ± 6.7%, P = 0.001) were significantly higher compared with the untreated OLETFs (44.3 ± 10.5%). No difference was observed when compared with LETO rats. Although the rosiglitazone-treated group showed a better metabolic profile than the untreated OLETF group, there was no difference in the global radial strain (49.8 ± 6.0 vs 44.3 ± 10.5, P = 0.402). The expression of pro-inflammatory cytokines, and collagen type I and III were consistently attenuated in the losartan-treated and combination-treated OLETF groups, but not in the rosiglitazone-treated group.

Conclusions: A combination of rosiglitazone and losartan attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats.
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http://dx.doi.org/10.1111/jdi.12153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210065PMC
July 2014

MicroRNA-29b inhibits migration and proliferation of vascular smooth muscle cells in neointimal formation.

J Cell Biochem 2015 Apr;116(4):598-608

Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, 120-752, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, Republic of Korea.

The proliferation and migration of smooth muscle cells (SMCs) are considered to be key steps in the progression of atherosclerosis and restenosis. Certain stimuli, such as, interleukin-3 (IL-3) are known to stimulate proliferation and migration in vascular diseases. Meanwhile, microRNAs (miRs) have been revealed as critical modulators of various diseases in which miR-29b is known to regulate cell growth by targeting Mcl-1 and MMP2. However, roles of miR-29b in vascular smooth muscle cells remain almost unknown. We hypothesized that miR-29b may control the proliferation and migration processes induced by IL-3 stimulation by inhibiting its own specific targets in SMCs. MiR-29b significantly suppressed the proliferation and migration of SMCs through the inhibition of the signaling pathway related to Mcl-1 and MMP2. We also found that miR-29b expression levels significantly declined in balloon-injured rat carotid arteries and that the overexpression of miR-29b by local oligonucleotide delivery can inhibit neointimal formation. Consistent with the critical role of miR-29b in vitro, we observed down-regulated expression levels of Mcl-1 and MMP2 from the neointimal region. These results indicate that miR-29b suppressed the proliferation and migration of SMCs, possibly through the inhibition of Mcl-1 and MMP2, and suggest that miR-29b may serve as a useful therapeutic tool to treat cardiovascular diseases such as, atherosclerosis and restenosis.
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http://dx.doi.org/10.1002/jcb.25011DOI Listing
April 2015

Flt3 ligand induces monocyte proliferation and enhances the function of monocyte-derived dendritic cells in vitro.

J Cell Physiol 2015 Aug;230(8):1740-9

Institute for Bio-Medical Convergence, College of medicine, Catholic Kwandong University, Incheon, Korea; Innovative Cell & Gene Therapy Center, International St. Mary's Hospital, Incheon, Korea.

Flt3 ligand (FL), a potent hematopoietic cytokine, plays an important role in development and activation of dendritic cells (DCs) and natural killer cells (NK). Although some post-receptor signaling events of FL have been characterized, the role of FL on Flt3 expressing human peripheral blood monocyte is unclear. In the current study, we examined the role of FL on cell survival and growth of peripheral blood monocytes and function of monocyte-derived DCs. FL promoted monocyte proliferation in a dose-dependent manner and prevented spontaneous apoptosis. FL induced ERK phosphorylation and a specific ERK inhibitor completely abrogated FL-mediated cellular growth, while p38 MAPK, JNK, and AKT were relatively unaffected. Addition of FL to GM-CSF and IL-4 during DCs generation from monocytes increased the yield of DCs through induction of cell proliferation. DCs generated in the presence of FL expressed more costimulatory molecules on their surfaces and stimulated allogeneic T cell proliferation in MLR to a higher magnitude. Furthermore, FL partially antagonized IL-10-mediated inhibition on DCs function. Further characterization of FL actions may provide new and important information for immunotherapeutic approaches utilizing DCs.
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http://dx.doi.org/10.1002/jcp.24824DOI Listing
August 2015

Upregulation of miR-23b enhances the autologous therapeutic potential for degenerative arthritis by targeting PRKACB in synovial fluid-derived mesenchymal stem cells from patients.

Mol Cells 2014 Jun 11;37(6):449-56. Epub 2014 Jun 11.

Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea ; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.

The use of synovial fluid-derived mesenchymal stem cells (SFMSCs) obtained from patients with degenerative arthropathy may serve as an alternative therapeutic strategy in osteoarthritis (OA) and rheumatoid arthritis (RA). For treatment of OA and RA patients, autologous transplantation of differentiated MSCs has several beneficial effects for cartilage regeneration including immunomodulatory activity. In this study, we induced chondrogenic differentiation of SFMSCs by inhibiting protein kinase A (PKA) with a small molecule and microRNA (miRNA). Chondrogenic differentiation was confirmed by PCR and immunocytochemistry using probes specific for aggrecan, the major cartilaginous proteoglycan gene. Absorbance of alcian blue stain to detect chondrogenic differentiation was increased in H-89 and/or miRNA-23btransfected cells. Furthermore, expression of matrix metalloproteinase (MMP)-9 and MMP-2 was decreased in treated cells. Therefore, differentiation of SFMSCs into chondrocytes through inhibition of PKA signaling may be a therapeutic option for OA or RA patients.
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http://dx.doi.org/10.14348/molcells.2014.0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086338PMC
June 2014

Modulation of Fas-Fas Ligand Interaction Rehabilitates Hypoxia-Induced Apoptosis of Mesenchymal Stem Cells in Ischemic Myocardium Niche.

Cell Transplant 2015 12;24(7):1329-41. Epub 2014 May 12.

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

Mesenchymal stem cells (MSCs) have the potential to repair and regenerate ischemic heart tissue; however, the poor viability of transplanted MSCs in the ischemic region is a major obstacle to their therapeutic use. This cell death is caused by Fas and Fas ligand (FasL) interactions under harsh conditions. To investigate improving the survival and therapeutic effects of MSCs, we focused our research on Fas-FasL-mediated cell death. In this study, we found that the poor viability of transplanted MSCs was caused by Fas-FasL interactions between host ischemic myocardial cells and implanted MSCs. In addition, we found that increased Fas expression and the corresponding decrease of cell survival were in close relation to hypoxic MSCs treated with FasL and H2O2. When MSCs were treated with a recombinant Fas/Fc chimera (Fas/Fc) inhibiting Fas-FasL interactions, the expressions of proapoptotic proteins including caspase-8, caspase-3, Bax, and cytochrome-c were attenuated, and the survival of MSCs was recovered. In ischemia-reperfusion injury models, the interaction between FasL in ischemic heart and Fas in implanted MSCs caused a loss of transplanted MSCs, whereas the inhibition of this interaction by Fas/Fc treatment improved cell survival and restored heart function. Thus, our study suggests that Fas-FasL interactions are responsible for activating cell death signaling in implanted stem cells and could be a potential target for improving therapeutic efficacy of stem cells in treating ischemic heart diseases.
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http://dx.doi.org/10.3727/096368914X681748DOI Listing
April 2016

PLCδ1 protein rescues ischemia-reperfused heart by the regulation of calcium homeostasis.

Mol Ther 2014 Jun 18;22(6):1110-1121. Epub 2014 Mar 18.

Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Myocardial Ca(2+) overload induced by ischemia/reperfusion (I/R) is a major element of myocardial dysfunction in heart failure. Phospholipase C (PLC) plays important roles in the regulation of the phosphoinositol pathway and Ca(2+) homeostasis in various types of cells. Here, we investigated the protective role of PLCδ1 against myocardial I/R injury through the regulation of Ca(2+) homeostasis. To investigate its role, PLCδ1 was fused to Hph1, a cell-permeable protein transduction domain (PTD), and treated into rat neonatal cardiomyocytes and rat hearts under respective hypoxia-reoxygenation (H/R) and ischemia-reperfusion conditions. Treatment with Hph1-PLCδ1 significantly inhibited intracellular Ca(2+) overload, reactive oxygen species generation, mitochondrial permeability transition pore opening, and mitochondrial membrane potential elevation in H/R neonatal cardiomyocytes, resulting in the inhibition of apoptosis. Intravenous injections of Hph1-PLCδ1 in rats with I/R-injured myocardium caused significant reductions in infarct size and apoptosis and also improved systolic and diastolic cardiac functioning. Furthermore, a small ions profile obtained using time-of-flight secondary ion mass spectrometry showed that treatment with Hph1-PLCδ1 leads to significant recovery of calcium-related ions toward normal levels in I/R-injured myocardium. These results suggest that Hph1-PLCδ1 may manifest as a promising cardioprotective drug due to its inhibition of the mitochondrial apoptotic pathway in cells suffering from I/R injury.
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http://dx.doi.org/10.1038/mt.2014.46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048898PMC
June 2014

Effect of hypoxic paracrine media on calcium-regulatory proteins in infarcted rat myocardium.

Korean Circ J 2014 Jan 14;44(1):16-21. Epub 2014 Jan 14.

Division of Cardiology, Severance Cardiovascular Research Center, Yonsei University College of Medicine, Seoul, Korea.

Background And Objectives: An increase in intracellular calcium concentration due to loss of Ca(2+) homeostasis triggers arrhythmia or cardiac cell death in the heart. Paracrine factors released from stem cells have beneficial cardioprotective effects. However, the mechanism of modulation of Ca(2+) homeostasis by paracrine factors in ischemic myocardium remains unclear.

Materials And Methods: We isolated rat bone marrow-derived mesenchymal stem cells (MSCs), and prepared paracrine media (PM) from MSCs under hypoxic or normoxic conditions (hypoxic PM and normoxic PM). We induced rat myocardial infarction by left anterior descending ligation for 1 hour, and treated PM into the border region of infarcted myocardium (n=6/group) to identify the alteration in calcium-regulated proteins. We isolated and stained the heart tissue with specific calcium-related antibodies after 11 days.

Results: The hypoxic PM treatment increased Ca(2+)-related proteins such as L-type Ca(2+) channel, sarcoplasmic reticulum Ca(2+) ATPase, Na(+)/K(+) ATPase, and calmodulin, whereas the normoxic PM treatment increased those proteins only slightly. The sodium-calcium exchanger was significantly reduced by hypoxic PM treatment, compared to moderate suppression by the normoxic PM treatment.

Conclusion: Our results suggest that hypoxic PM was significantly associated with the positive regulation of Ca(2+) homeostasis in infarcted myocardium.
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http://dx.doi.org/10.4070/kcj.2014.44.1.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905111PMC
January 2014

Anti-death strategies against oxidative stress in grafted mesenchymal stem cells.

Histol Histopathol 2013 12 13;28(12):1529-36. Epub 2013 Jun 13.

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

Mesenchymal stem cells (MSCs) possess the potential for use in cell-based therapy for repair of myocardial injury. The therapeutic potential of MSCs is based on the capacity of MSCs to differentiate into cardiac tissue and release paracrine factors. However, a major problem in the clinical application of MSC-based therapy is the poor viability of transplanted MSCs at the site of graft due to harsh microenvironment conditions, such as ischemia and/or anoikis. Ischemia after myocardial infarction (MI) and interaction of MSCs with their niche is associated with increased production of reactive oxygen species (ROS). ROS hinder cell adhesion and induce detachment of cells, which induces anoikis signals in implanted MSCs. Therefore, strategies to regulate oxidative stress following the implantation of MSCs are therapeutically attractive. In this review, we first describe ROS as a major obstacle in MSC-based therapy and focus on manipulation of implanted MSCs to reduce ROS-mediated anoikis.
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http://dx.doi.org/10.14670/HH-28.1529DOI Listing
December 2013

MicroRNA-145 suppresses ROS-induced Ca2+ overload of cardiomyocytes by targeting CaMKIIδ.

Biochem Biophys Res Commun 2013 Jun 20;435(4):720-6. Epub 2013 May 20.

Cardiovascular Research Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodamun-gu, Seoul 120-752, Republic of Korea.

A change in intracellular free calcium (Ca(2+)) is a common signaling mechanism of reperfusion-induced cardiomyocyte death. Calcium/calmodulin dependent protein kinase II (CaMKII) is a critical regulator of Ca(2+) signaling and mediates signaling pathways responsible for functions in the heart including hypertrophy, apoptosis, arrhythmia, and heart disease. MicroRNAs (miRNA) are involved in the regulation of cell response, including survival, proliferation, apoptosis, and development. However, the roles of miRNAs in Ca(2+)-mediated apoptosis of cardiomyocytes are uncertain. Here, we determined the potential role of miRNA in the regulation of CaMKII dependent apoptosis and explored its underlying mechanism. To determine the potential roles of miRNAs in H2O2-mediated Ca(2+) overload, we selected and tested 6 putative miRNAs that targeted CaMKIIδ, and showed that miR-145 represses CaMKIIδ protein expression and Ca(2+) overload. We confirmed CaMKIIδ as a direct downstream target of miR-145. Furthermore, miR-145 regulates Ca(2+)-related signals and ameliorates apoptosis. This study demonstrates that miR-145 regulates reactive oxygen species (ROS)-induced Ca(2+) overload in cardiomyocytes. Thus, miR-145 affects ROS-mediated gene regulation and cellular injury responses.
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http://dx.doi.org/10.1016/j.bbrc.2013.05.050DOI Listing
June 2013

Alpha B-crystallin prevents the arrhythmogenic effects of particulate matter isolated from ambient air by attenuating oxidative stress.

Toxicol Appl Pharmacol 2013 Jan 12;266(2):267-75. Epub 2012 Nov 12.

The Division of Cardiology, Yonsei University College of Medicine, Seoul, Republic of Korea.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated by particulate matter (PM) isolated from ambient air and linked to prolonged repolarization and cardiac arrhythmia. We evaluated whether alpha B-crystallin (CryAB), a heat shock protein, could prevent the arrhythmogenic effects of PM by preventing CaMKII activation. CryAB was delivered into cardiac cells using a TAT-protein transduction domain (TAT-CryAB). ECGs were measured before and after tracheal exposure of diesel exhaust particles (DEP) and each intervention in adult Sprague-Dawley rats. After endotracheal exposure of DEP (200 μg/mL for 30 minutes, n=11), QT intervals were prolonged from 115±14 ms to 144±20 ms (p=0.03), and premature ventricular contractions were observed more frequently (0% vs. 44%) than control (n=5) and TAT-Cry (n=5). However, DEP-induced arrhythmia was not observed in TAT-CryAB (1 mg/kg) pretreated rats (n=5). In optical mapping of Langendorff-perfused rat heats, compared with baseline, DEP infusion of 12.5 μg/mL (n=12) increased apicobasal action potential duration (APD) differences from 2±6 ms to 36±15 ms (p<0.001), APD restitution slope from 0.26±0.07 to 1.19±0.11 (p<0.001) and ventricular tachycardia (VT) from 0% to 75% (p<0.001). DEP infusion easily induced spatially discordant alternans. However, the effects of DEP were prevented by TAT-CryAB (1mg/kg, n=9). In rat myocytes, while DEP increased reactive oxygen species (ROS) generation and phosphated CaMKII, TAT-CryAB prevented these effects. In conclusion, CryAB, a small heat shock protein, might prevent the arrhythmogenic effects of PM by attenuating ROS generation and CaMKII activation.
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http://dx.doi.org/10.1016/j.taap.2012.10.013DOI Listing
January 2013

The promotion of cardiogenic differentiation of hMSCs by targeting epidermal growth factor receptor using microRNA-133a.

Biomaterials 2013 Jan 13;34(1):92-9. Epub 2012 Oct 13.

Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.

Human bone marrow-derived mesenchymal stem cells (hMSCs) are an attractive candidate for cell therapy in heart disease. Low survival and incomplete electromechanical integration between resident cardiomyocytes and transplanted hMSCs remain unsolved. In order for an infarcted heart to tolerate transplantation, differentiation capacity in stem cells must be reinforced. In this study, we found that compound 56, an epidermal growth factor receptor (EGFR) inhibitor, promotes cardiogenic differentiation of hMSCs and the transplantation of hMSCs treated with compound 56 resulted in enhancement of heart functions. Furthermore, hMSCs transfected with microRNA-133a (miR-133a), which targets EGFR, were observed to express cardiac-specific markers. We also discovered that luciferase activity is exclusively decreased by targeting EGFR in hMSCs transfected with miR-133a mimic. These results suggest that EGFR plays a key role in the regulation of cardiogenic differentiation in hMSCs.
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http://dx.doi.org/10.1016/j.biomaterials.2012.09.069DOI Listing
January 2013

Protein kinase C activation stimulates mesenchymal stem cell adhesion through activation of focal adhesion kinase.

Cell Transplant 2013 ;22(5):797-809

Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.

Emerging evidence suggests that cell therapy with mesenchymal stem cells (MSCs) has beneficial effects on the injured heart. However, the decreased survival and/or adhesion of MSCs under ischemic conditions limits the application of cell transplantation as a therapeutic modality. We investigated a potential method of increasing the adhesion ability of MSCs to improve their efficacy in the ischemic heart. Treatment of MSCs with PKC activator, phorbol 12-myristate 13-acetate (PMA), increased cell adhesion and spreading in a dose-dependent method and significantly decreased detachment. When MSCs were treated with PKC inhibitor, that is, rottlerin, adhesion of MSCs was slightly diminished, and detachment was also decreased compared to the treatment with PMA. MSCs treated with both PMA and rottlerin behaved similarly to normal controls. In 3D matrix cardio gel, treatment with PMA increased the number of MSCs compared to the control group and MSCs treated with rottlerin. Expressions of focal adhesion kinase, cytoskeleton-associated proteins, and integrin subunits were clearly demonstrated in PMA-treated MSCs by immunoblotting and/or immunocytochemistry. The effect of PKC activator treatment on MSCs was validated in vivo. Following injection into rat hearts, the PMA-treated MSCs exhibited significantly higher retention in infarcted myocardium compared to the MSC group. Infarct size, fibrosis area, and apoptotic cells were reduced, and cardiac function was improved in rat hearts injected with PMA-treated MSCs compared to sham and/or MSC-implanted group. These results indicate that PKC activator is a potential target for niche manipulation to enhance adhesion of MSCs for cardiac regeneration.
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http://dx.doi.org/10.3727/096368912X656126DOI Listing
December 2013

Antiarrhythmic potential of mesenchymal stem cell is modulated by hypoxic environment.

J Am Coll Cardiol 2012 Oct 19;60(17):1698-706. Epub 2012 Sep 19.

Cardiology Division, Yonsei University College of Medicine, Seoul, Republic of Korea.

Objectives: The purpose of this study was to evaluate the antiarrhythmic potential of mesenchymal stem cells (MSC) under a different environment.

Background: Little is known about how environmental status affects antiarrhythmic potential of MSCs.

Methods: To investigate the effect of paracrine factors secreted from MSCs under different circumstances on arrhythmogenicity in rats with myocardial infarction, we injected paracrine media (PM) secreted under hypoxic, normoxic conditions (hypoxic PM and normoxic PM), and MSC into the border zone of infarcted myocardium in rats.

Results: We found that the injection of hypoxic PM, but not normoxic PM, markedly restored conduction velocities, suppressed focal activity, and prevented sudden arrhythmic deaths in rats. Underlying this electrophysiological alteration was a decrease in fibrosis, restoration of connexin 43, alleviation of Ca(2+) overload, and recovery of Ca(2+)-regulatory ion channels and proteins, all of which is supported by proteomic data showing that several paracrine factors including basic fibroblast growth factor, insulinlike growth factor 1, hepatocyte growth factor, and EF-hand domain-containing 2 are potential mediators. When compared with PM, MSC injection did not reduce or prevent arrhythmogenicity, suggesting that the antiarrhythmic or proarrhythmic potential of MSC is mainly dependent on paracrine factors.

Conclusions: A hypoxic or normoxic environment surrounding MSC affects the type and properties of the growth factors or cytokines, and these secreted molecules determine the characteristics of the electro-anatomical substrate of the surrounding myocardium.
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http://dx.doi.org/10.1016/j.jacc.2012.04.056DOI Listing
October 2012