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( Sung Hyun Choi ),( Seok Yun Jung ),( Takayuki Asahara ),( Wonhee Suh ),( Sang Mo Kwon ),( Sang Hong Baek ) 한국조직공학·재생의학회 2012 조직공학과 재생의학 Vol.9 No.6
Cardiac stem/progenitor cells can be differentiated into cardiomyocytes in vitro using several differentiation methodologies. However, the methodology of cardiomyogenic induction in human c-kit positive progenitor cells (hCPCsc-kit+) was not fully demonstrated. Thus, the purpose of our study was to directly evaluate each cardiomyocyte induction system using hCPCsc-kit+. In this study, cardiomyocyte induction methodologies were divided into the following three groups; treatment with dexamethasone, 5-azacytidine, and co-treatment with 5-azacytidine and Transforming Growth Factor Beta 1 (TGF-β1), using different serum concentrations [2% or 10% fetal bovine serum (FBS)]. GATA4 and Nkx2-5, cardiac-specific transcription factors, were expressed in our hCPCsckit+. However, the GATA4 and Nkx2-5 expressions were significantly decreased in 10% FBS/cardiomyogenic induction system (p < 0.01), whereas the GATA4 and Nkx2-5 expressions were preserved in 2% FBS/cardiomyogenic induction system (p > 0.05). GATA4 and Nkx2-5 is crucial roles in cardiac development, thus we considered the low serum conditions more affected in our cardiomyogenic induction system. In addition, c-kit expression decreased significantly during cardiomyogenic differentiation. Importantly, we demonstrated that co-treated with 5-azacytidine and TGF-β1 led to an earlier expression pattern of alpha-sarcomeric actin (α-SA), implying that this cardiomyocyte induction system facilitates early cardiomyocyte differentiation of hCPCsc-kit+. Thus, the present study provides a pivotal cardiomyogenic differentiation methodology using hCPCsc-kit+ for basic or clinical research.
Effect of Ionizing Radiation Induced Damage of Endothelial Progenitor Cells in Vascular Regeneration
Lee, Mi-Ok,Song, Seung-Hyun,Jung, Seokyun,Hur, Seulgi,Asahara, Takayuki,Kim, Hyongbum,Kwon, Sang-Mo,Cha, Hyuk-Jin Ovid Technologies Wolters Kluwer -American Heart A 2012 Arteriosclerosis, thrombosis, and vascular biology Vol.32 No.2
<P>A number of studies have revealed that stress signaling and subsequent stress responses in stem/progenitor cells are responsible for attenuated regeneration or degenerative disease. Because ionizing radiation (IR), which sensitizes diverse types of stem cells, reportedly induces cardio-circulatory diseases, we hypothesized that IR-induced vascular abnormalities are associated with defects in endothelial progenitor cells (EPCs) that are responsible for vascular homeostasis.</P>
Jung, Seok Yun,Choi, Jin Hwa,Kwon, Sang‐,Mo,Masuda, Haruchika,Asahara, Takayuki,Lee, You‐,Mie Wiley Subscription Services, Inc., A Wiley Company 2012 Journal of cellular biochemistry Vol.113 No.5
<P><B>Abstract</B></P><P>Endothelial progenitor cells (EPCs) contribute to the tumor vasculature during tumor progression. Decursin isolated from the herb <I>Angelica gigas</I> is known to possess potent anti‐inflammatory activities. Recently, we reported that decursin is a novel candidate for an angiogenesis inhibitor [Jung et al., 2009]. In this study, we investigated whether decursin regulates EPC differentiation and function to inhibit tumor vasculogenesis. We isolated AC133+ cells from human cord blood and decursin significantly decreased the number of EPC colony forming units of human cord blood‐derived AC133+ cells that produce functional EPC progenies. Decursin dose‐dependently decreased the cell number of EPC committing cells as demonstrated by EPC expansion studies. Decursin inhibited EPC differentiation from progenitor cells into spindle‐shaped EPC colonies. Additionally, decursin inhibited proliferation and migration of early EPCs isolated from mouse bone marrow. Furthermore, decursin suppressed expression of angiopoietin‐2, angiopoietin receptor Tie‐2, Flk‐1 (vascular endothelial growth factor receptor‐2), and endothelial nitric oxide synthase in mouse BM derived EPCs in a dose‐dependent manner. Decursin suppressed tube formation ability of EPCs in collaboration with HUVEC. Decursin (4 mg/kg) inhibited tumor‐induced mobilization of circulating EPCs (CD34 + /VEGFR‐2+ cells) from bone marrow and early incorporation of Dil‐Ac‐LDL‐labeled or green fluorescent protein (GFP)+ EPCs into neovessels of xenograft Lewis lung carcinoma tumors in wild‐type‐ or bone‐marrow‐transplanted mice. Accordingly, decursin attenuated EPC‐derived endothelial cells in neovessels of Lewis lung carcinoma tumor masses grown in mice. Together, decursin likely affects EPC differentiation and function, thereby inhibiting tumor vasculogenesis in early tumorigenesis. J. Cell. Biochem. 113: 1478–1487, 2012. © 2012 Wiley Periodicals, Inc.</P>
Lee, Jun Hee,Lee, Sang Hun,Yoo, So Young,Asahara, Takayuki,Kwon, Sang Mo American Heart Association, Inc. 2013 Arteriosclerosis, thrombosis, and vascular biology Vol.33 No.7
<P><B>Objective—</B></P><P>Although endothelial progenitor cells (EPCs) have been reported to promote neovessel formation during vascular injury, the function of supporting cells of EPCs and their interaction with EPCs during EPC isolation remain unclear.</P><P><B>Approach and Results—</B></P><P>We investigated the functional properties of 2 types of EPCs, also known as endothelial colony-forming cells (ECFCs), CD34<SUP>−</SUP>/CD34<SUP>+</SUP> cell–derived ECFCs (hybrid-dECFCs) and CD34<SUP>+</SUP> cell–derived ECFCs (stem-dECFCs), isolated using different methods, to elucidate the role of CD34<SUP>−</SUP> cell populations as cell-supporting niches. Using EPC colony-forming and insert coculture assays, we found that CD34<SUP>−</SUP> accessory cells dynamically modulate hematopoietic stem cell–derived endothelial cell progenitor commitment via angiogenic cytokines secreted by CD34<SUP>−</SUP>/CD11b<SUP>+</SUP> macrophages. On the basis of these findings, we isolated 2 types of ECFCs and investigated their bioactivities. We found that stem-dECFCs showed remarkably retarded cell growth, enhanced senescence, and decreased characteristics of ECFCs, whereas hybrid-dECFCs showed greater proliferative properties but delayed senescence. In a murine hind-limb ischemia model, hybrid-dECFCs showed significantly enhanced blood perfusion, capillary density, transplanted cell survival and proliferation, and angiogenic cytokine secretion compared with stem-dECFCs. In particular, the migratory capacity of hybrid-dECFCs was significantly enhanced, in part mediated via an augmented phosphorylation cascade of focal adhesion kinase and Src, resulting in a highly increased incorporation capacity of hybrid-dECFCs compared with stem-dECFCs. CD34<SUP>−</SUP> accessory cells of hybrid-dECFCs might be niche-supporting cells that facilitate cell survival, increase the secretion of angiogenic cytokines, and increase incorporation.</P><P><B>Conclusions—</B></P><P>This study provided important insight into blood vessel formation and repair in ischemic diseases for ECFC-based cell therapy.</P>
Lee, Jun Hee,Lee, Sang Hun,Choi, Sung Hyun,Asahara, Takayuki,Kwon, Sang-Mo AlphaMed Press 2015 Stem Cells Vol.33 No.6
<P>The efficacy of cell therapy using endothelial colony-forming cells (ECFCs) in the treatment of ischemia is limited by the replicative senescence of isolated ECFCs in vitro. Such senescence must therefore be overcome in order for such cell therapies to be clinically applicable. This study aimed to investigate the potential of sulfated polysaccharide fucoidan to rescue ECFCs from cellular senescence and to improve in vivo vascular repair by ECFCs. Fucoidan-preconditioning of senescent ECFCs was shown by flow cytometry to restore the expression of functional ECFC surface markers (CD34, c-Kit, VEGFR2, and CXCR4) and stimulate the in vitro tube formation capacity of ECFCs. Fucoidan also promoted the expression of cell cycle-associated proteins (cyclin E, Cdk2, cyclin D1, and Cdk4) in senescent ECFCs, significantly reversed cellular senescence, and increased the proliferation of ECFCs via the FAK, Akt, and ERK signaling pathways. Fucoidan was found to enhance the survival, proliferation, incorporation, and endothelial differentiation of senescent ECFCs transplanted in ischemic tissues in a murine hind limb ischemia model. Moreover, ECFC-induced functional recovery and limb salvage were markedly improved by fucoidan pretreatment of ECFCs. To our knowledge, the findings of our study are the first to demonstrate that fucoidan enhances the neovasculogenic potential of ECFCs by rescuing them from replicative cellular senescence. Pretreatment of ECFCs with fucoidan may thus provide a novel strategy for the application of senescent stem cells to therapeutic neovascularization.</P>