CHA Stem Cell Institute

Seoul, South Korea

CHA Stem Cell Institute

Seoul, South Korea
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Kim W.-K.,CHA Medical University | Kim W.-K.,CHA Stem Cell Institute | Song S.-Y.,CHA Medical University | Oh W.K.,Chosun University | And 7 more authors.
European Journal of Pharmacology | Year: 2013

Panax ginseng is considered as one of the most valuable medicinal herbs in traditional medicine, and ginsenoside Rd is one of the main active ingredients in P. ginseng leaf. Although there is significant number of evidences implicated on the beneficial effects of the ginsenosides with diverse associated mechanisms, reports on the skin regeneration by the ginsenoside Rd are not sufficient. Therefore, we examined the mitogenic and protective effects of the ginsenoside Rd in the keratinocyte progenitor cells (KPCs) and human dermal fibroblasts (HDFs). Furthermore, the signaling pathways involved in the activation of KPCs and HDFs were investigated, and wound-healing effect is evaluated in vivo through animal wound models. We found that the ginsenoside Rd significantly increased the proliferation and migration level of KPCs and HDFs in a dose-dependent manner. Additionally, the cell survival was significantly increased in H2O2 treated KPCs. Moreover, the ginsenoside Rd effectively induced collagen type 1 and down-regulated matrix metalloprotinase-1 (MMP-1) in a dose-dependent manner. All of these beneficial effects are associated with an induction of intracellular cAMP levels and phosphorylated cAMP response element-binding protein expression in nucleus, which both attenuated by adenine 9-β-d-arabinofuranoside, an adenylate cyclase inhibitor. Application of the ginsenoside Rd to an excision wound in mice showed an effective healing process. As skin regeneration is mainly associated with the activation of HDFs and KPCs, P. ginseng leaf, an alternative source of the ginsenoside Rd, can be used as a natural source for skin regeneration. © 2013 Elsevier B.V.

Jeong Y.-M.,CHA Medical University | Jeong Y.-M.,CHA Stem Cell Institute | Sung Y.K.,Kyungpook National University | Kim W.-K.,CHA Medical University | And 8 more authors.
Stem Cells and Development | Year: 2013

Hypoxia induces the survival and regenerative potential of adipose-derived stem cells (ASCs), but there are tremendous needs to find alternative methods for ASC preconditioning. Therefore, this work investigated: (1) the ability of low-dose ultraviolet B (UVB) radiation to stimulate the survival, migration, and tube-forming activity of ASCs in vitro; (2) the ability of UVB preconditioning to enhance the hair growth-promoting capacity of ASCs in vivo; and (3) the mechanism of action for ASC stimulation by UVB. Although high-dose UVB decreased the proliferation of ASCs, low-dose (10 or 20mJ/cm2) treatment increased their survival, migration, and tube-forming activity. In addition, low-dose UVB upregulated the expression of ASC-derived growth factors, and a culture medium conditioned by UVB-irradiated ASCs increased the proliferation of dermal papilla and outer root sheet cells. Notably, injection of UVB-preconditioned ASCs into C3H/HeN mice significantly induced the telogen-to-anagen transition and increased new hair weight in vivo. UVB treatment significantly increased the generation of reactive oxygen species (ROS) in cultured ASCs, and inhibition of ROS generation by diphenyleneiodonium chloride (DPI) significantly attenuated UVB-induced ASC stimulation. Furthermore, NADPH oxidase 4 (Nox4) expression was induced in ASCs by UVB irradiation, and Nox4 silencing by small interfering RNA, like DPI, significantly reduced UVB-induced ROS generation. These results suggest that the primary involvement of ROS generation in UVB-mediated ASC stimulation occurs via the Nox4 enzyme. This is the first indication that a low dose of UVB radiation and/or the control of ROS generation could potentially be incorporated into a novel ASC preconditioning method for hair regeneration. © 2013, Mary Ann Liebert, Inc.

Lee H.J.,Samsung | Lee H.J.,Sungkyunkwan University | Yang H.-M.,Sungkyunkwan University | Choi Y.-S.,Samsung | And 5 more authors.
Annals of Surgery | Year: 2013

OBJECTIVE: To overcome the therapeutic limitations of malignant fibrous histiocytoma (MFH), we evaluated human adipose tissue-derived mesenchymal stromal cells (MSCs) that secrete tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on metastatic MFH. BACKGROUND: MFH is a highly malignant and metastatic type of sarcoma but surgical removal is the only effective method for treating MFH. MSCs are easily transduced to express a high level of transgene and can migrate toward cancer. For this reason, MSCs are a promising candidate for metastatic MFH therapies. METHODS: In vitro sustainability of MSC-TRAIL against MFH-ino was analyzed by apoptosis assay. For preclinical study, anti-MFH effects of MSC-TRAILs were validated in murine models for local tumorigenesis and metastasis. Furthermore, a time-interval metastasis model of MFH was applied to confirm antimetastatic ability of MSC-TRAIL for preestablished metastatic MFH. RESULTS: We found that MFH-ino is highly susceptible to recombinant TRAIL and MSC-TRAIL, which selectively induce apoptosis via caspase-8 activation in vitro. Moreover, not only MFH-ino but xenograft explants were also significantly inhibited by MSC-TRAIL in local tumorigenesis. In particular, the metastatic ability of MFH-ino was considerably reduced by MSC-TRAIL in metastasis murine model, particularly for preestablished metastatic MFH. CONCLUSIONS: These results suggest that MSC-TRAIL is sufficiently effective in inhibiting MFH-ino metastasis and the application using MSC-TRAIL could be extended to other sarcomas and recurrent metastatic cancers for cell-mediated cancer therapy. Copyright © 2013 by Lippincott Williams & Wilkins.

Kaewsuwan S.,CHA Medical University | Kaewsuwan S.,CHA Stem Cell Institute | Kaewsuwan S.,Prince of Songkla University | Song S.Y.,CHA Medical University | And 4 more authors.
Expert Opinion on Biological Therapy | Year: 2012

Introduction: A stem cell (SC) niche is defined as the microenvironment in which the adult SC resides and includes surrounding cells, low oxygen content and growth factor gradients. Crosstalk between SCs and their niche provides signals that keep SCs quiescent, or modulates their activation. Areas covered: This review discusses the characterization of niche conditions in the adipose-derived stem cell (ASC) in vivo environment, and introduces key signalling pathways and autocrine/paracrine regulators of ASCs. Expert opinion: Control of in vivo niche factors (such as low oxygen content, generation of reactive oxygen species and activation of platelet-derived growth factor receptor signalling) should increase ASC yields synergistically and reduce production costs. Additionally, the preconditioning of ASCs with these niche factors prior to transplantation might enhance their regenerative potential. ASC niche is complex, and there are components of the niche that we may not yet understand. Therefore, future research needs to focus on identifying the key regulatory factors of the ASC niche in vivo, and developing a novel method to mimic these niche factors for in vitro manipulation. © Informa UK, Ltd.

Kim J.H.,CHA Medical University | Kim J.H.,CHA Stem Cell Institute | Kim J.H.,CHA Bio and Diostech Co | Park S.-H.,CHA Medical University | And 6 more authors.
Stem Cells and Development | Year: 2011

Adipose-derived stem cells (ASCs) offer a potential alternative for tissue repair and regeneration. We have recently shown that hypoxia stimulates ASCs and enhances the regenerative potential of ASCs, which is beneficial for ASC therapy. In the present study, we further investigated a key mediator and a signal pathway involved in the stimulation of ASC during hypoxia. Culturing ASC in a hypoxic incubator (2% oxygen tension) increased the proliferation and migration, and this was mediated by Akt and ERK pathways. To determine the generation of reactive oxygen species (ROS), 2′,7′- dichlorofluorescin diacetate intensity was detected by fluorescence-activated cell sorting. Hypoxia significantly increased the dichlorofluorescin diacetate intensity, which was greatly reduced by N-acetyl-cysteine and diphenyleneiodonium treatment. Likewise, the hypoxia-induced proliferation and migration of ASCs were reversed by N-acetyl-cysteine and diphenyleneiodonium treatment, suggesting the involvement of ROS generation in ASC stimulation. Further, we examined the activation of receptor tyrosine kinases and observed that hypoxia stimulated the phosphorylation of platelet-derived growth factor receptor-β. In summary, the ROS produced by ASCs in response to hypoxia was mostly likely due to NADPH oxidase activity. The increased cellular ROS was accompanied by the phosphorylation of platelet-derived growth factor receptor-β as well as by the activation of ERK and Akt signal pathways. Our results suggest a pivotal role for ROS generation in the stimulation of ASCs by hypoxia. © Copyright 2011, Mary Ann Liebert, Inc.

Yang J.-A.,CHA Stem Cell Institute | Yang J.-A.,CHA Medical University | Chung H.-M.,CHA Stem Cell Institute | Chung H.-M.,CHA Medical University | And 3 more authors.
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Adipose tissue is one of the richest sources of mesenchymal stem cells. Even more interesting is the fact that adipose-derived stem cells (ASCs) show an outstanding ability to regenerate damaged skin. Thus, ASCs are a popular and feasible treatment in clinical dermatology. Areas covered in this review: This review discusses the potential applications of ASCs and conditioned medium of ASC (ASC-CM) to skin, and briefly touches on the mechanisms by which ASCs promote skin regeneration. What the reader will gain: Clinically, processed lipo-aspirated (PLA) cells are commonly used for treatment of aged skin; however, the use of PLA cells for cosmetic purposes is not convenient, because PLA cells are prepared from patients. Alternatively, cosmetics that contain ASC-CM can be pre-made from healthy volunteers such that they are immediately available for clinical treatment of aged skin. Cell-based therapies are adequate for improvement of wrinkles or for soft tissue augmentation, whereas ASC-CM has merit for amelioration of skin tone. When culturing ASCs for the production of cosmetic raw materials, hypoxic culture conditions and transduction of specific genes into ASCs may increase the regenerative protein content of the conditioned medium. Take home message: Application of ASCs and ASC-CM to dermatology shows promising results for skin regeneration. © 2010 Informa UK Ltd.

Kim J.H.,CHA Medical University | Kim J.H.,CHA Stem Cell Institute | Song S.-Y.,CHA Medical University | Park S.G.,CHA Medical University | And 4 more authors.
Stem Cells and Development | Year: 2012

We have previously demonstrated that hypoxia stimulates adipose-derived stem cells (ASCs) through the generation of reactive oxygen species (ROS). However, the precise mechanism involved in the ROS generation by ASCs is not well understood. We sought to investigate in this work: (1) which subtype of NADPH oxidase (Nox) is primarily expressed in ASCs; (2) where Nox4 is localized in ASCs; and (3) whether silencing of Nox4 attenuates hypoxia-enhanced function of ASC. We used 2′,7′-dichlorofluorescin diacetate (DCF-DA) as an indicator of ROS generation and found that the fluorescence intensity of DCF-DA was significantly increased after hypoxia exposure (2% oxygen). In addition, hypoxia enhanced the proliferation and migration of ASCs and upregulated the mRNA expression of Oct4 and Rex1. Quantitative analysis of mRNA expression of Nox family in ASCs demonstrated that Nox4 is primarily expressed in ASCs, while immunofluorescence assay showed that Nox4 is mainly localized in the perinuclear region and overlaps with Mitotracker, a mitochondria marker. Silencing of Nox4 by siRNA treatment downregulated the RNA and protein expression of Nox4, which significantly reduced the ROS generation under hypoxia. In addition, Nox4 silencing significantly reduced the proliferation and migration of ASCs and downregulated the mRNA expression of Oct4 and Rex1. Phosphorylation of platelet-derived growth factor receptor-β, AKT, and ERK1/2 also diminished following Nox4 silencing. In a nutshell, these results suggest that Nox4 is primarily expressed in ASCs and plays a pivotal role in the hypoxia-enhanced stimulation of ASCs. © 2012, Mary Ann Liebert, Inc.

Song S.-Y.,CHA Medical University | Chung H.-M.,CHA Stem Cell Institute | Chung H.-M.,CHA Medical University | Chung H.-M.,CHA Bio and Diostech Co. | And 3 more authors.
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Several lines of evidence suggest that VEGF is a key regulator of the paracrine effects of adipose-derived stem cells (ASCs), but the mechanism of action remains to be identified. Areas covered in this review: This brief review discusses the following research questions: i) Does VEGF increase the proliferation/migration and differentiation of ASCs?; ii) Does VEGF mediate the paracrine effects of ASCs?; and iii) How is VEGF synthesized, and which factors regulate VEGF secretion? What the reader will gain: External stimuli such as hypoxia may activate receptor tyrosine kinases in the membrane of ASCs, which, in turn, phosphorylate extracellular signal regulated kinase (ERK) and members of the Akt signaling pathway, stabilizing hypoxia inducible factor 1α (HIF-1α) that are primary regulators of VEGF expression. Secreted VEGF directly stimulates ASCs via VEGF receptors in an autocrine manner and regenerates damaged neighboring cells in a paracrine manner. Take home message: Most studies of stem cell regeneration have focused on differentiation of ASCs and their building block function; however, the paracrine effects of ASCs should also be the focus of attention. © 2010 Informa UK, Ltd.

Jang M.J.,CHA Stem Cell Institute | Kim H.-S.,CHA Stem Cell Institute | Lee H.-G.,CHA Stem Cell Institute | Kim G.J.,CHA Stem Cell Institute | And 7 more authors.
Acta Haematologica | Year: 2013

Background and Aims: Immunomodulatory properties of mesenchymal stem cells (MSCs) have been applied to reduce the incidence of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Among the various sources of MSCs that have immunomodulatory effects in vitro, only placenta-derived MSCs (PD-MSCs) have not been evaluated in an in vivo model of GVHD. In this study, we investigated the immunomodulatory properties of PD-MSCs in vitro and evaluated their clinical potential for controlling GVHD in an animal model. Methods: A GVHD animal model was established by transplanting C57BL/6 donor bone marrow cells and spleen cells into lethally irradiated BALB/c recipient mice. To control GVHD, human PD-MSCs were transplanted into recipient mice (5 × 105 or 1 × 106 cells). Results: PD-MSCs suppressed mitogen-stimulated T cell proliferation in vitro in a dose-dependent manner. Moreover, PD-MSCs inhibited cytokine secretion (interleukin-12, tumor necrosis factor-α and interferon-γ) of activated T cells. In vivo, the survival rate in the PD-MSC group (transplanted with 1 × 106 cells) was higher than that in the control group and histological scores were low in the PD-MSC group. Conclusion: We present the first evidence that human PD-MSCs can efficiently control GVHD in an HSCT in vivo model. © 2012 S. Karger AG, Basel.

Kim S.Y.,Dong - A University | Son W.S.,Korea University | Park M.C.,Seoul National University | Kim C.M.,Dong - A University | And 5 more authors.
Stem Cells and Development | Year: 2013

ARS-Interacting Multi-functional Protein 1 (AIMP1) is a cytokine that is involved in the regulation of angiogenesis, immune activation, and fibroblast proliferation. In this study, fibroblast growth factor receptor 2 (FGFR2) was isolated as a binding partner of AIMP peptide (amino acids 6-46) in affinity purification using human bone marrow-derived mesenchymal stem cells (BMMSCs). AIMP1 peptide induced the proliferation of adult BMMSCs by activating Akt, inhibiting glycogen synthase kinase-3β, and thereby increasing the level of β-catenin. In addition, AIMP1 peptide induced the translocation of β-catenin to the nucleus and increased the transcription of c-myc and cyclin D1 by activating the β-catenin/T-cell factor (TCF) complex. By contrast, transfection of dominant negative TCF abolished the effect of AIMP1. The inhibition of Akt, using LY294002, abolished the accumulation and nuclear translocation of β-catenin induced by AIMP1, leading to a decrease in c-myc and cyclin D1 expression, which decreased the proliferation of BMMSCs. An intraperitoneal injection of AIMP1 peptide into C57/BL6 mice increased the colony formation of fibroblast-like cells. Fluorescence activated cell sorting analysis showed that the colony-forming cells were CD29+/CD44 +/CD90+/CD105+/CD34-/CD45 -, which is characteristic of MSCs. In addition, the fibroblast-like cells differentiated into adipocytes, chondrocytes, and osteocytes. Taken together, these data suggest that AIMP1 peptide promotes the proliferation of BMMSCs by activating the β-catenin/TCF complex via FGFR2-mediated activation of Akt, which leads to an increase in MSCs in peripheral blood. © Mary Ann Liebert, Inc.

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