Publications by authors named "Yoon Sun Yang"

47 Publications

Cobalt Chloride Enhances the Anti-Inflammatory Potency of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells through the ERK-HIF-1-MicroRNA-146a-Mediated Signaling Pathway.

Stem Cells Int 2018 5;2018:4978763. Epub 2018 Sep 5.

Biomedical Research Institute, R&D Center, and MEDIPOST Co., Ltd., 21 Daewangpangyo-ro 644 Beon-gil, Bundang-gu, Seongnam-si, 13494 Gyeonggi-do, Republic of Korea.

Human mesenchymal stem cells (hMSCs), including human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs), which have high proliferation capacity and immunomodulatory properties, are considered to be a good candidate for cell-based therapies. hMSCs show enhanced therapeutic effects via paracrine secretion or cell-to-cell contact that modulates inflammatory or immune reactions. Here, treatment with cobalt chloride (CoCl) was more effective than naïve hUCB-MSCs in suppressing inflammatory responses in a coculture system with phytohemagglutinin- (PHA-) activated human peripheral blood mononuclear cells (hPBMCs). Furthermore, the effect of CoCl is exerted by promoting the expression of anti-inflammatory mediators (e.g., PGE) and inhibiting that of inflammatory cytokines (e.g., TNF- and IFN-). Treatment of hUCB-MSCs with CoCl leads to increased expression of microRNA- (miR-) 146a, which was reported to modulate anti-inflammatory responses. Hypoxia-inducible factor- (HIF-) 1 silencing and ERK inhibition abolished CoCl-induced miR-146a expression, suggesting that ERK and HIF-1 signals are required for CoCl-induced miR-146a expression in hUCB-MSCs. These data suggest that treatment with CoCl enhances the immunosuppressive capacity of hUCB-MSCs through the ERK-HIF-1-miR-146a-mediated signaling pathway. Furthermore, pretreatment of transplanted MSCs with CoCl can suppress lung inflammation more than naïve MSCs can in a mouse model of asthma. These findings suggest that CoCl may improve the therapeutic effects of hUCB-MSCs for the treatment of inflammatory diseases.
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http://dx.doi.org/10.1155/2018/4978763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145052PMC
September 2018

Effect of growth differentiation factor-15 secreted by human umbilical cord blood-derived mesenchymal stem cells on amyloid beta levels in in vitro and in vivo models of Alzheimer's disease.

Biochem Biophys Res Commun 2018 10 14;504(4):933-940. Epub 2018 Sep 14.

Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd, Gyeonggi-do, Republic of Korea. Electronic address:

Alzheimer's disease (AD), which is the most common progressive neurodegenerative disease, causes learning and memory impairment. The pathological progress of AD can derive from imbalanced homeostasis of amyloid beta (Aβ) in the brain. In such cases, microglia play important roles in regulating the brain Aβ levels. In the present study, we found that human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) can increase, through paracrine action, the ability of microglial cells to clear Aβ. In order to identify the associated paracrine factors, a secretome of hUCB-MSCs co-cultured with Aβ-treated BV2 microglial cells was analyzed using a human cytokine protein array. As a result, growth differentiation factor-15 (GDF-15) was identified as a predominant candidate, and its association with Aβ clearance by microglial cells was investigated in vitro and in a 5XFAD mouse model. When Aβ-treated BV2 cells were treated with exogenous recombinant GDF-15, the Aβ levels in the culture medium decreased. Moreover, GDF-15 injection in the brain parenchyma of 5XFAD mice also led to decrease in Aβ plaques. In contrast, co-culture of BV2 cells and hUCB-MSCs treated with GDF-15-specific siRNA did not influence the Aβ levels in the culture medium. To elucidate how these phenomena are related, we confirmed that GDF-15 specifically increases insulin-degrading enzyme (IDE) expression in microglial cells through TGFβ receptor type II (TGFβRII), both in vitro and in vivo. These findings suggest that hUCB-MSCs promote the Aβ clearance ability of microglial cells through regulation of GDF-15 secretion, thus elucidating a therapeutic mechanism for AD.
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http://dx.doi.org/10.1016/j.bbrc.2018.09.012DOI Listing
October 2018

Intracellular Calcium Determines the Adipogenic Differentiation Potential of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells via the Wnt5a/-Catenin Signaling Pathway.

Stem Cells Int 2018 11;2018:6545071. Epub 2018 Jul 11.

Biomedical Research Institute, MEDIPOST Co. Ltd., Seongnam 13494, Republic of Korea.

Mesenchymal stem cells- (MSCs-) based therapies show different degrees of efficacies for the treatment of various diseases, including lipogenesis. We evaluated the adipogenic differentiation ability of human umbilical cord blood-derived MSCs (hUCB-MSCs) from different donors and examined the contribution of the intracellular calcium (Ca) level to this diversity. hUCB-MSCs treated with Ca or the Ca chelator BAPTA-AM increased and decreased adipogenic differentiation, respectively. Canonical Wnt5a/-catenin expression decreased during adipogenic differentiation of hUCB-MSCs. Treatment with Wnt5a blocked the adipogenic differentiation of hUCB-MSCs and activated the Wnt pathway, with a decrease in the adipogenesis markers PPAR and leptin, and reduced lipid vacuole-associated Oil red O activity. In contrast, inhibition of the Wnt pathway with dickkopf-1 and -catenin small interfering RNA transfection promoted the adipogenic potential of hUCB-MSCs. Interestingly, the Ca-based system exhibited a synergic effect on adipogenic potential through the Wnt5a/-catenin pathway. Our data suggest that the variable adipogenic differentiation potential of hUCB-MSCs from different lots is due to variation in the intracellular Ca level, which can be used as a marker to predict hUCB-MSCs selection for lipogenesis therapy. Overall, these results demonstrate that exogenous calcium treatment enhanced the adipogenic differentiation of hUCB-MSCs via negatively regulating the Wnt5a/-catenin signaling pathway.
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http://dx.doi.org/10.1155/2018/6545071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079381PMC
July 2018

Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease.

Leukemia 2018 12 22;32(12):2672-2684. Epub 2018 May 22.

Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.

Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases due to their immunosuppressive capacity. Here, we show that Small MSCs primed with Hypoxia and Calcium ions (SHC-MSCs) exhibit enhanced stemness and immunomodulatory functions for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord blood-derived MSCs, SHC-MSCs were resistant to passage-dependent senescence mediated via the monocyte chemoattractant protein-1 and p53/p21 cascade and secreted large amounts of pro-angiogenic and immunomodulatory factors, resulting in suppression of T-cell proliferation. SHC-MSCs showed DNA demethylation in pluripotency, germline, and imprinted genes similarly to very small embryonic-like stem cells, suggesting a potential mutual relationship. Genome-wide DNA methylome and transcriptome analyses indicated that genes related to immune modulation, cell adhesion, and the cell cycle were up-regulated in SHC-MSCs. Particularly, polo-like kinase-1 (PLK1), zinc-finger protein-143, dehydrogenase/reductase-3, and friend-of-GATA2 play a key role in the beneficial effects of SHC-MSCs. Administration of SHC-MSCs or PLK1-overexpressing MSCs significantly ameliorated symptoms of graft-versus-host disease (GVHD) in a humanized mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.
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http://dx.doi.org/10.1038/s41375-018-0151-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286327PMC
December 2018

Thrombospondin-1 secreted by human umbilical cord blood-derived mesenchymal stem cells rescues neurons from synaptic dysfunction in Alzheimer's disease model.

Sci Rep 2018 01 10;8(1):354. Epub 2018 Jan 10.

Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd, Gyeonggi-do, Republic of Korea.

Alzheimer's disease (AD) is an incurable neurodegenerative disease characterised clinically by learning and memory impairments. Amyloid beta (Aβ) peptide-induced synaptic dysfunction is a pathological process associated with early-stage AD. Here, we show that paracrine action of human umbilical cord blood-derived-mesenchymal stem cells (hUCB-MSCs) protects the hippocampus from synaptic-density loss in in vitro and in vivo AD models. To identify paracrine factors underlying this rescue effect, we analysed hUCB-MSCs' secretome co-cultured with Aβ42-treated mouse hippocampal neurons. Thrombospondin-1 (TSP-1), a protein secreted by hUCB-MSCs in in vitro and 5XFAD AD mouse models, was selected for study. Treatment with exogenous recombinant TSP-1 or co-cultures with hUCB-MSCs significantly increased expression of synaptic-density markers, such as synaptophysin (SYP) and post-synaptic density protein-95 (PSD-95) in Aβ42-treated mouse hippocampal neurons. Knockdown of TSP-1 expression in hUCB-MSCs through small interfering RNA (siRNA) abolished the reversal of Aβ42-induced hippocampal synaptic-density loss. We demonstrate that the rescue effect of hUCB-MSC-secreted TSP-1 was mediated by neuroligin-1 (NLGN1) or α2δ-1 receptors. Interestingly, NLGN1 and α2δ-1 expression, which was reduced in Aβ42-treated hippocampal neurons, increased in co-cultures with hUCB-MSCs or exogenous TSP-1. Together, these findings suggest that hUCB-MSCs can attenuate Aβ42-induced synaptic dysfunction by regulating TSP-1 release, thus providing a potential alternative therapeutic option for early-stage AD.
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http://dx.doi.org/10.1038/s41598-017-18542-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762817PMC
January 2018

Optimization of culture conditions for rapid clinical-scale expansion of human umbilical cord blood-derived mesenchymal stem cells.

Clin Transl Med 2017 Oct 10;6(1):38. Epub 2017 Oct 10.

Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., 21 Daewangpangyo-ro 644beon-gil, Bundang-gu, Seongnam-Si, Gyeonggi-do, 13494, Republic of Korea.

Background: Mesenchymal stem cells (MSCs) have broad-spectrum therapeutic effects in various diseases, and thus have many clinical applications. However, it is difficult to produce sufficient numbers of MSCs for clinical use, and improved culture systems are required. Here, we report the effects of calcium (Ca) and hypoxia on the proliferation of human umbilical cord blood-derived MSCs (hUCB-MSCs). In addition, we determined the optimal conditions of these two factors for the large-scale culture of hUCB-MSCs.

Methods: hUCB-MSCs were maintained under hypoxic conditions (3% O) with 1.8 mM Ca during long-term culture, and their proliferation was evaluated. To characterize the underlying mechanisms, the effects on hypoxia-inducible factor (HIF)-1α and the extracellular signal-regulated kinase (ERK) signaling pathways were investigated. The therapeutic effects in a mouse emphysema model were analyzed and compared with those of naive MSCs.

Results: The proliferation of Ca/hypoxia-treated hUCB-MSCs was increased compared with that observed using either calcium or hypoxia culture alone, without loss of stem cell marker expression or differentiation ability. The enhancement of the proliferation capacity of hUCB-MSCs by the synergistic effects of Ca and hypoxia was dependent on the expression of HIF-1α and the ERK signaling pathway. The proliferation of Ca/hypoxia-treated hUCB-MSCs resulted in a delayed senescence phenotype and increased the expression levels of stemness genes such as Oct4 and Nanog compared to those observed in conventional culture conditions. In addition, Ca/hypoxia-treated MSCs transplantation in the mouse emphysema model showed the same therapeutic effects as observed with naive MSCs.

Conclusions: These findings suggest that a Ca/hypoxia-based expansion system has applications for the large-scale production of MSCs for therapeutic purposes.
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http://dx.doi.org/10.1186/s40169-017-0168-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634990PMC
October 2017

Effect of Single and Double Administration of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Following Focal Cerebral Ischemia in Rats.

Exp Neurobiol 2017 Feb 23;26(1):55-65. Epub 2017 Feb 23.

Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, Korea.; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea.

Stem cell therapies are administered during the acute phase of stroke to preserve the penumbral tissues from ischemic injury. However, the effect of repeated cell therapy during the acute phase remains unclear. In this study, we investigated and compared the functional outcome of single (two days post-injury) and repeated (two and nine days post-injury) treatment with human umbilical cord derived mesenchymal stem cells (hUCB-MSCs) after middle cerebral artery occlusion (MCAO). The rotarod and limb placement tests were utilized to investigate functional outcomes, while infarct volume and tissue damage were measured by immunofluorescent staining for neovascularization, neurogenesis, apoptosis, and inflammation in the penumbral zones. We observed notable motor dysfunction and a significant decrease in infarcted brain volume, as well as increases in neurons and vessels in both single and repeated hUCB-MSC treatments compared to the control group. Interestingly, repeated administration of hUCB-MSCs was not found to elicit additional or synergistic improvements over monotherapy. This study suggests that a clearer understanding of the therapeutic window after stroke will facilitate the development of more efficient treatment protocols in the clinical application of stem cell therapy.
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http://dx.doi.org/10.5607/en.2017.26.1.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326715PMC
February 2017

Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.

Stem Cells Transl Med 2016 Apr 3;5(4):427-39. Epub 2016 Mar 3.

Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea

Unlabelled: Therapeutic applications of mesenchymal stem cells (MSCs) for treating various diseases have increased in recent years. To ensure that treatment is effective, an adequate MSC dosage should be determined before these cells are used for therapeutic purposes. To obtain a sufficient number of cells for therapeutic applications, MSCs must be expanded in long-term cell culture, which inevitably triggers cellular senescence. In this study, we investigated the surface markers of human umbilical cord blood-derived MSCs (hUCB-MSCs) associated with cellular senescence using fluorescence-activated cell sorting analysis and 242 cell surface-marker antibodies. Among these surface proteins, we selected the melanoma cell adhesion molecule (MCAM/CD146) for further study with the aim of validating observed expression differences and investigating the associated implications in hUCB-MSCs during cellular senescence. We observed that CD146 expression markedly decreased in hUCB-MSCs following prolonged in vitro expansion. Using preparative sorting, we found that hUCB-MSCs with high CD146 expression displayed high growth rates, multilineage differentiation, expression of stemness markers, and telomerase activity, as well as significantly lower expression of the senescence markers p16, p21, p53, and senescence-associated β-galactosidase, compared with that observed in hUCB-MSCs with low-level CD146 expression. In contrast, CD146 downregulation with small interfering RNAs enhanced the senescence phenotype. In addition, CD146 suppression in hUCB-MSCs caused downregulation of other cellular senescence regulators, including Bmi-1, Id1, and Twist1. Collectively, our results suggest that CD146 regulates cellular senescence; thus, it could be used as a therapeutic marker to identify senescent hUCB-MSCs.

Significance: One of the fundamental requirements for mesenchymal stem cell (MSC)-based therapies is the expansion of MSCs during long-term culture because a sufficient number of functional cells is required. However, long-term growth inevitably induces cellular senescence, which potentially causes poor clinical outcomes by inducing growth arrest and the loss of stem cell properties. Thus, the identification of markers for evaluating the status of MSC senescence during long-term culture may enhance the success of MSC-based therapy. This study provides strong evidence that CD146 is a novel and useful marker for predicting senescence in human umbilical cord blood-derived MSCs (hUCB-MSCs), and CD146 can potentially be applied in quality-control assessments of hUCB-MSC-based therapy.
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http://dx.doi.org/10.5966/sctm.2015-0109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798732PMC
April 2016

The Effect of Donor-Dependent Administration of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells following Focal Cerebral Ischemia in Rats.

Exp Neurobiol 2015 Dec 6;24(4):358-65. Epub 2015 Nov 6.

Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03082, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03082, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03082, Korea.

Stroke is an ischemic disease caused by clotted vessel-induced cell damage. It is characterized by high morbidity and mortality and is typically treated with a tissue plasminogen activator (tPA). However, this therapy is limited by temporal constraints. Recently, several studies have focused on cell therapy as an alternative treatment. Most researches have used fixed donor cell administration, and hence, the effect of donor-dependent cell administration is unknown. In this study, we administered 3 types of donor-derived human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in the ischemic boundary zone of the ischemic stroke rat model. We then performed functional and pathological characterization using rotarod, the limb placement test, and immunofluorescent staining. We observed a significant decrease in neuron number, and notable stroke-like motor dysfunction, as assessed by the rotarod test (~40% decrease in time) and the limb placement test (4.5 point increase) in control rats with ischemic stroke. The neurobehavioral performance of the rats with ischemic stroke that were treated with hUCB-MSCs was significantly better than that of rats in the vehicle-injected control group. Regardless of which donor cells were used, hUCB-MSC transplantation resulted in an accumulation of neuronal progenitor cells, and angiogenic and tissue repair factors in the ischemic boundary zone. The neurogenic and angiogenic profiles of the 3 types of hUCB-MSCs were very similar. Our results suggest that intraparenchymal administration of hUCB-MSCs results in significant therapeutic effects in the ischemic brain regardless of the type of donor.
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http://dx.doi.org/10.5607/en.2015.24.4.358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688335PMC
December 2015

Human umbilical cord blood-derived mesenchymal stem cells improve functional recovery through thrombospondin1, pantraxin3, and vascular endothelial growth factor in the ischemic rat brain.

J Neurosci Res 2015 Dec 2;93(12):1814-25. Epub 2015 Sep 2.

Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.

Cell therapy is a potential therapeutic method for cerebral ischemia, which remains a serious problem. In the search for more effective therapeutic methods, many kinds of stem cells from various tissues have been developed and tested as candidate therapeutic agents. Among them, human umbilical cord blood (hUCB)-derived mesenchymal stem cells (MSCs) are widely used for cell therapy because of their genetic flexibility. To confirm that they are effective and understand how they affect ischemic neural cells, hUCB-MSCs were directly administered ipsilaterally into an ischemic zone induced by middle cerebral artery occlusion (MCAO). We found that the neurobehavioral performance of the hUCB-MSC group was significantly improved compared with that of the vehicle-injected control group. The infarct was also remarkably smaller in the hUCB-MSC group. Additionally, hUCB-MSC transplantation resulted in a greater number of newly generated cells and angiogenic and tissue repair factors and a lower number of inflammatory events in the penumbra zone. To determine why these events occurred, hUCB-MSCs were assayed under hypoxic and normoxic conditions in vitro. The results showed that hUCB-MSCs exhibit higher expression levels of thrombospondin1, pantraxin3, and vascular endothelial growth factor under hypoxic conditions than under normoxic conditions. These results were found to be correlated with our in vivo immunofluorescent staining results. On the basis of these findings, we suggest that hUCB-MSCs may have a beneficial effect on cerebral ischemia, especially through angiogenesis, neurogenesis, and anti-inflammatory effects, and thus could be used as a therapeutic agent to treat neurological disorders such as cerebral ischemia.
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http://dx.doi.org/10.1002/jnr.23616DOI Listing
December 2015

Autocrine Action of Thrombospondin-2 Determines the Chondrogenic Differentiation Potential and Suppresses Hypertrophic Maturation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.

Stem Cells 2015 Nov 25;33(11):3291-303. Epub 2015 Aug 25.

Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea.

Previous studies have shown that mesenchymal stem cell (MSC)-based therapies have varying efficacies for the treatment of various diseases, including cartilage defects. In this study, we demonstrated that the chondrogenic differentiation potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) obtained from different individual donors varies, and we investigated the molecular basis for this variation. Microarray gene expression analysis identified thrombospondin-2 (TSP2) as a candidate gene underlying the interindividual variation in the chondrogenic differentiation potential of hUCB-MSCs. To assess the association between TSP-2 and the differentiation potential, we evaluated chondrogenic differentiation of hUCB-MSCs treated with TSP2 siRNA. In addition, we studied the effect of supplementing exogenous recombinant TSP-2 on TSP2 siRNA-treated hUCB-MSCs. We found that TSP-2 autocrinally promoted chondrogenic differentiation of hUCB-MSCs via the Notch signaling pathway, which was confirmed in MSCs from other sources such as bone marrow and adipose tissue. Interestingly, we observed that TSP-2 attenuated hypertrophy, which inevitably occurs during chondrogenic differentiation of hUCB-MSCs. Our findings indicated that the variable chondrogenic differentiation potential of MSCs obtained from different donors is influenced by the TSP-2 level in the differentiating cells. Thus, the TSP-2 level can be used as a marker to select MSCs with superior chondrogenic differentiation potential for use in cartilage regeneration therapy.
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http://dx.doi.org/10.1002/stem.2120DOI Listing
November 2015

The Effect of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a Collagenase-Induced Intracerebral Hemorrhage Rat Model.

Exp Neurobiol 2015 Jun 17;24(2):146-55. Epub 2015 Jun 17.

Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.

Intracerebral hemorrhage (ICH) is one of the devastating types of stroke. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have potential benefits in recovery from brain damage following ICH. This study aimed to identify the beneficial effects of hUCB-MSCs and investigate whether they have anti-inflammatory effects on the ICH brain via neurotrophic factors or cytokines. hUCB-MSCs were transplanted into a collagenase-induced ICH rat model. At 2, 9, 16, and 30 days after ICH, rotarod and limb placement tests were performed to measure behavioral outcomes. ICH rats were sacrificed to evaluate the volume of lesion using H&E staining. Immunostaining was performed to investigate neurogenesis, angiogenesis, and anti-apoptosis at 4 weeks after transplantation. Inflammatory factors (TNF-α, COX-2, microglia, and neutrophils) were analyzed by immunofluorescence staining, RT-PCR, and Western blot at 3 days after transplantation. hUCB-MSCs were associated with neurological benefits and reduction in lesion volume. The hUCB-MSCs-treated group tended to reveal high levels of neurogenesis, angiogenesis, and anti-apoptosis (significant for angiogenesis). The expression levels of inflammatory factors tended to be reduced in the hUCB-MSCs-treated group compared with the controls. Our study suggests that hUCB-MSCs may improve neurological outcomes and modulate inflammation-associated immune cells and cytokines in ICH-induced inflammatory responses.
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http://dx.doi.org/10.5607/en.2015.24.2.146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479811PMC
June 2015

Conditioned Media from Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibits Melanogenesis by Promoting Proteasomal Degradation of MITF.

PLoS One 2015 29;10(5):e0128078. Epub 2015 May 29.

Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si, Gyeonggi-do, Republic of Korea.

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) secrete various beneficial molecules, which have anti-apoptotic activity and cell proliferation. However, the effect of hUCB-MSCs in melanogenesis is largely unclear. In this study, we show that conditioned media (CM) derived from hUCB-MSCs inhibit melanogenesis by regulating microphthalmia-associated transcription factor (MITF) expression via the ERK signalling pathway. Treatment of hUCB-MSC-CM strongly inhibited the alpha-melanocyte stimulating hormone-induced hyperpigmentation in melanoma cells as well as melanocytes. Treatment of hUCB-MSC-CM induced ERK1/2 activation in melanocytes. In addition, inhibition of ERK1/2 suppressed the anti-pigmentation activity of the hUCB-MSC-CM in melanocytes and in vitro artificial skin models. We also found that the expression of MITF was appreciably diminished while expression of phosphorylated MITF, which leads to its proteasomal degradation, was increased in cells treated with hUCB-MSC-CM. These results suggested that hUCB-MSC-CM significantly suppresses melanin synthesis via MITF degradation by the ERK pathway activation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449211PMC
April 2016

The Effect of Umbilical Cord Blood Derived Mesenchymal Stem Cells in Monocrotaline-induced Pulmonary Artery Hypertension Rats.

J Korean Med Sci 2015 May 15;30(5):576-85. Epub 2015 Apr 15.

Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.

Pulmonary arterial hypertension (PAH) causes right ventricular failure due to a gradual increase in pulmonary vascular resistance. The purposes of this study were to confirm the engraftment of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) placed in the correct place in the lung and research on changes of hemodynamics, pulmonary pathology, immunomodulation and several gene expressions in monocrotaline (MCT)-induced PAH rat models after hUCB-MSCs transfusion. The rats were grouped as follows: the control (C) group; the M group (MCT 60 mg/kg); the U group (hUCB-MSCs transfusion). They received transfusions via the external jugular vein a week after MCT injection. The mean right ventricular pressure (RVP) was significantly reduced in the U group after the 2 week. The indicators of RV hypertrophy were significantly reduced in the U group at week 4. Reduced medial wall thickness in the pulmonary arteriole was noted in the U group at week 4. Reduced number of intra-acinar muscular pulmonary arteries was observed in the U group after 2 week. Protein expressions such as endothelin (ET)-1, endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 significantly decreased at week 4. The decreased levels of ERA, eNOS and MMP-2 immunoreactivity were noted by immnohistochemical staining. After hUCB-MSCs were administered, there were the improvement of RVH and mean RVP. Reductions in several protein expressions and immunomodulation were also detected. It is suggested that hUCB-MSCs may be a promising therapeutic option for PAH.
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http://dx.doi.org/10.3346/jkms.2015.30.5.576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414641PMC
May 2015

Microarray analysis after umbilical cord blood derived mesenchymal stem cells injection in monocrotaline-induced pulmonary artery hypertension rats.

Anat Cell Biol 2014 Dec 23;47(4):217-26. Epub 2014 Dec 23.

Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.

Pulmonary arterial hypertension (PAH) is associated with structural alterations of lung vasculature. PAH is still a devastating disease needing an aggressive therapeutic approach. Despite the therapeutic potential of human umbilical cord mesenchymal stem cells (MSCs), the molecular parameters to define the stemness remain largely unknown. Using high-density oligonucleotide microarrays, the differential gene expression profiles between a fraction of mononuclear cells of human umbilical cord blood (UCB) and its MSC subpopulation were obtained. Of particular interest was a subset of 46 genes preferentially expressed at 7-fold or higher in the group treated with human UCB-MSCs. This subset contained numerous genes involved in the inflammatory response, immune response, lipid metabolism, cell adhesion, cell migration, cell differentiation, apoptosis, cell growth, transport, cell proliferation, transcription, and signal transduction. Our results provide a foundation for a more reproducible and reliable quality control using genotypic analysis for the definition of human UCB-MSCs. Therefore, our results will provide a basis for studies on molecular mechanisms controlling the core properties of human MSCs.
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http://dx.doi.org/10.5115/acb.2014.47.4.217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276895PMC
December 2014

Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo.

Biochem Biophys Res Commun 2014 Apr 20;446(4):983-9. Epub 2014 Mar 20.

Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 137-874, Republic of Korea. Electronic address:

Evaluation of the immunogenicity of human mesenchymal stem cells (MSCs) in an allogeneic setting during therapy has been hampered by lack of suitable models due to technical and ethical limitations. Here, we show that allogeneic human umbilical cord blood derived-MSCs (hUCB-MSCs) maintained low immunogenicity even after immune challenge in vitro. To confirm these properties in vivo, a humanized mouse model was established by injecting isolated hUCB-derived CD34+ cells intravenously into immunocompromised NOD/SCID IL2γnull (NSG) mice. After repeated intravenous injection of human peripheral blood mononuclear cells (hPBMCs) or MRC5 cells into these mice, immunological alterations including T cell proliferation and increased IFN-γ, TNF-α, and human IgG levels, were observed. In contrast, hUCB-MSC injection did not elicit these responses. While lymphocyte infiltration in the lung and small intestine and reduced survival rates were observed after hPBMC or MRC5 transplantation, no adverse events were observed following hUCB-MSC introduction. In conclusion, our data suggest that allogeneic hUCB-MSCs have low immunogenicity in vitro and in vivo, and are therefore "immunologically safe" for use in allogeneic clinical applications.
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http://dx.doi.org/10.1016/j.bbrc.2014.03.051DOI Listing
April 2014

Optimization of the therapeutic efficacy of human umbilical cord blood-mesenchymal stromal cells in an NSG mouse xenograft model of graft-versus-host disease.

Cytotherapy 2014 Mar 11;16(3):298-308. Epub 2014 Jan 11.

Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul, Korea. Electronic address:

Background Aims: Although in vitro studies have demonstrated the immunosuppressive capacity of mesenchymal stromal cells (MSCs), most in vivo studies on graft-versus-host disease (GVHD) have focused on prevention, and the therapeutic effect of MSCs is controversial. Moreover, optimal time intervals for infusing MSCs have not been established.

Methods: We attempted to evaluate whether human umbilical cord blood-MSCs (hUCB-MSCs) could either prevent or treat GVHD in an NSG mouse xenograft model by injection of MSCs before or after in vivo clearance. Mice were infused with either a single dose or multiple doses of 5 × 10(5) hUCB-MSCs (3- or 7-day intervals) before or after GVHD onset.

Results: Before onset, hUCB-MSCs significantly improved the survival rate only when repeatedly injected at 3-day intervals. In contrast, single or repeated injections after GVHD onset significantly increased the survival rate and effectively attenuated tissue damage and inflammation. Furthermore, the levels of prostaglandin E2 and transforming growth factor-β1 increased significantly, whereas the level of interferon-γ decreased significantly in all MSC treatment groups.

Conclusions: These data establish the optimal time intervals for preventing GVHD and show that hUCB-MSCs effectively attenuated symptoms and improved survival rate when administered after the onset of GVDH.
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http://dx.doi.org/10.1016/j.jcyt.2013.10.012DOI Listing
March 2014

Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy.

Int J Mol Sci 2013 Sep 3;14(9):17986-8001. Epub 2013 Sep 3.

Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea.

Various source-derived mesenchymal stem cells (MSCs) have been considered for cell therapeutics in incurable diseases. To characterize MSCs from different sources, we compared human bone marrow (BM), adipose tissue (AT), and umbilical cord blood-derived MSCs (UCB-MSCs) for surface antigen expression, differentiation ability, proliferation capacity, clonality, tolerance for aging, and paracrine activity. Although MSCs from different tissues have similar levels of surface antigen expression, immunosuppressive activity, and differentiation ability, UCB-MSCs had the highest rate of cell proliferation and clonality, and significantly lower expression of p53, p21, and p16, well known markers of senescence. Since paracrine action is the main action of MSCs, we examined the anti-inflammatory activity of each MSC under lipopolysaccharide (LPS)-induced inflammation. Co-culture of UCB-MSCs with LPS-treated rat alveolar macrophage, reduced expression of inflammatory cytokines including interleukin-1α (IL-1α), IL-6, and IL-8 via angiopoietin-1 (Ang-1). Using recombinant Ang-1 as potential soluble paracrine factor or its small interference RNA (siRNA), we found that Ang-1 secretion was responsible for this beneficial effect in part by preventing inflammation. Our results demonstrate that primitive UCB-MSCs have biological advantages in comparison to adult sources, making UCB-MSCs a useful model for clinical applications of cell therapy.
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http://dx.doi.org/10.3390/ijms140917986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794764PMC
September 2013

Thrombospondin-2 secreted by human umbilical cord blood-derived mesenchymal stem cells promotes chondrogenic differentiation.

Stem Cells 2013 Oct;31(10):2136-48

Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Seoul, Republic of Korea; Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Gyeonggi-Do, Republic of Korea.

Increasing evidence indicates that the secretome of mesenchymal stem cells (MSCs) has therapeutic potential for the treatment of various diseases, including cartilage disorders. However, the paracrine mechanisms underlying cartilage repair by MSCs are poorly understood. Here, we show that human umbilical cord blood-derived MSCs (hUCB-MSCs) promoted differentiation of chondroprogenitor cells by paracrine action. This paracrine effect of hUCB-MSCs on chondroprogenitor cells was increased by treatment with synovial fluid (SF) obtained from osteoarthritis (OA) patients but was decreased by SF of fracture patients, compared to that of an untreated group. To identify paracrine factors underlying the chondrogenic effect of hUCB-MSCs, the secretomes of hUCB-MSCs stimulated by OA SF or fracture SF were analyzed using a biotin label-based antibody array. Among the proteins increased in response to these two kinds of SF, thrombospondin-2 (TSP-2) was specifically increased in only OA SF-treated hUCB-MSCs. In order to determine the role of TSP-2, exogenous TSP-2 was added to a micromass culture of chondroprogenitor cells. We found that TSP-2 had chondrogenic effects on chondroprogenitor cells via PKCα, ERK, p38/MAPK, and Notch signaling pathways. Knockdown of TSP-2 expression on hUCB-MSCs using small interfering RNA abolished the chondrogenic effects of hUCB-MSCs on chondroprogenitor cells. In parallel with in vitro analysis, the cartilage regenerating effect of hUCB-MSCs and TSP-2 was also demonstrated using a rabbit full-thickness osteochondral-defect model. Our findings suggested that hUCB-MSCs can stimulate the differentiation of locally presented endogenous chondroprogenitor cells by TSP-2, which finally leads to cartilage regeneration.
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http://dx.doi.org/10.1002/stem.1471DOI Listing
October 2013

A strategy for enhancing the engraftment of human hematopoietic stem cells in NOD/SCID mice.

Ann Hematol 2013 Dec 9;92(12):1595-602. Epub 2013 Jul 9.

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

To overcome the limitations of allogeneic hematopoietic stem cell transplantation (HSCT), we conducted a study to identify a strategy for enhancing hematopoietic stem cell (HSC) engraftment during HSCT. Co-transplantation experiments with mesenchymal stem cells (MSCs) derived from adult human tissues including bone marrow (BM), adipose tissue (AT), and umbilical cord blood (CB) were conducted. We showed that AT-MSCs and CB-MSCs enhanced the engraftment of HSCs as effectively as BM-MSCs in NOD/SCID mice, suggesting that AT-MSCs and CB-MSCs can be used as alternative stem cell sources for enhancing the engraftment and homing of HSCs. CB-MSCs derived from different donors showed different degrees of efficacy in enhancing the engraftment of HSCs. The most effective CB-MSCs showed higher proliferation rates and secreted more MCP-1, RANTES, EGF, and VEGF. Our results suggest that AT-MSCs and CB-MSCs could be alternative stem cell sources for co-transplantation in HSCT. Furthermore, in terms of MSCs' heterogeneity, characteristics of each population of MSCs are considerable factors for selecting MSCs suitable for co-transplantation with HSC.
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http://dx.doi.org/10.1007/s00277-013-1830-1DOI Listing
December 2013

Charting microbial phenotypes in multiplex nanoliter batch bioreactors.

Anal Chem 2013 Jun 24;85(12):5892-9. Epub 2013 May 24.

Materials Research and Education Center, Department of Mechanical Engineering, Auburn University, Auburn, Alabama 36849, USA.

High-throughput growth phenotyping is receiving great attention for establishing the genotype-phenotype map of sequenced organisms owing to the ready availability of complete genome sequences. To date, microbial growth phenotypes have been investigated mostly by the conventional method of batch cultivation using test tubes, Erlenmeyer flasks, or the recently available microwell plates. However, the current batch cultivation methods are time- and labor-intensive and often fail to consider sophisticated environmental changes. The implementation of batch cultures at the nanoliter scale has been difficult because of the quick evaporation of the culture medium inside the reactors. Here, we report a microfluidic system that allows independent cell cultures in evaporation-free multiplex nanoliter reactors under different culture conditions to assess the behavior of cells. The design allows three experimental replicates for each of eight culture environments in a single run. We demonstrate the versatility of the device by performing growth curve experiments with Escherichia coli and microbiological assays of antibiotics against the opportunistic pathogen Pseudomonas aeruginosa. Our study highlights that the microfluidic system can effectively replace the traditional batch culture methods with nanoliter volumes of bacterial cultivations, and it may be therefore promising for high-throughput growth phenotyping as well as for single-cell analyses.
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http://dx.doi.org/10.1021/ac400648zDOI Listing
June 2013

Umbilical cord blood mesenchymal stem cells protect amyloid-β42 neurotoxicity via paracrine.

World J Stem Cells 2012 Nov;4(11):110-6

Ju-Yeon Kim, Dong Hyun Kim, Ji Hyun Kim, Yoon Sun Yang, Wonil Oh, Jong Wook Chang, Biomedical Research Institute, R & D Center, MEDIPOST Co., Ltd. Seoul 137-874, South Korea.

Aim: To understand the neuroprotective mechanism of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) against amyloid-β42 (Aβ42) exposed rat primary neurons.

Methods: To evaluate the neuroprotective effect of hUCB-MSCs, the cells were co-cultured with Aβ42-exposed rat primary neuronal cells in a Transwell apparatus. To assess the involvement of soluble factors released from hUCB-MSCs in neuroprotection, an antibody-based array using co-cultured media was conducted. The neuroprotective roles of the identified hUCB-MSC proteins was assessed by treating recombinant proteins or specific small interfering RNAs (siRNAs) for each candidate protein in a co-culture system.

Results: The hUCB-MSCs secreted elevated levels of decorin and progranulin when co-cultured with rat primary neuronal cells exposed to Aβ42. Treatment with recombinant decorin and progranulin protected from Aβ42-neurotoxicity in vitro. In addition, siRNA-mediated knock-down of decorin and progranulin production in hUCB-MSCs reduced the anti-apoptotic effects of hUCB-MSC in the co-culture system.

Conclusion: Decorin and progranulin may be involved in anti-apoptotic activity of hUCB-MSCs exposed to Aβ42.
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http://dx.doi.org/10.4252/wjsc.v4.i11.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536832PMC
November 2012

Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy.

J Transl Med 2012 Mar 23;10:58. Epub 2012 Mar 23.

Department of Rehabilitation Medicine, Hanyang University Medical Center, Seoul, Korea.

Backgrounds: We conducted a pilot study of the infusion of intravenous autologous cord blood (CB) in children with cerebral palsy (CP) to assess the safety and feasibility of the procedure as well as its potential efficacy in countering neurological impairment.

Methods: Patients diagnosed with CP were enrolled in this study if their parents had elected to bank their CB at birth. Cryopreserved CB units were thawed and infused intravenously over 10~20 minutes. We assessed potential efficacy over 6 months by brain magnetic resonance imaging (MRI)-diffusion tensor imaging (DTI), brain perfusion single-photon emission computed tomography (SPECT), and various evaluation tools for motor and cognitive functions.

Results: Twenty patients received autologous CB infusion and were evaluated. The types of CP were as follows: 11 quadriplegics, 6 hemiplegics, and 3 diplegics. Infusion was generally well-tolerated, although 5 patients experienced temporary nausea, hemoglobinuria, or urticaria during intravenous infusion. Diverse neurological domains improved in 5 patients (25%) as assessed with developmental evaluation tools as well as by fractional anisotropy values in brain MRI-DTI. The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia.

Conclusions: Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP.
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http://dx.doi.org/10.1186/1479-5876-10-58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369209PMC
March 2012

Correlation between chemokines released from umbilical cord blood-derived mesenchymal stem cells and engraftment of hematopoietic stem cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice.

Pediatr Hematol Oncol 2011 Nov;28(8):682-90

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) enhance the engraftment of human hematopoietic stem cells (HSCs) when they are cotransplanted in animal and human studies. However, the type of MSCs that preferentially facilitate the engraftment and homing of HSCs is largely unknown. The authors categorized UCB-MSCs as the least-effective MSCs (A) or most-effective MSCs (B) at enhancing the engraftment of HSCs, and compared the gene expression profiles of various cytokines and growth factors in the UCB-MSC populations. The most-effective UCB-MSCs (B) secreted higher levels of several factors, including chemokine (C-X-C motif) ligand 12 (CXCL12), regulated upon activation, normal T cells expressed and secreted (RANTES), epithelial growth factor (EGF), and stem cell factor (SCF), which are required for the engraftment and homing of HSCs. By contrast, levels of growth-related oncogene (GRO), insulin-like growth factor-binding protein 1 (IGFBP1), and interleukin-8 (IL-8), which are associated with immune inflammation, were secreted at higher levels in UCB-MSCs (A). In addition, there were no differences between the transcripts of the 2 UCB-MSC populations after interferon-gamma (IFN-γ) stimulation, except for cyclooxygenase (COX)-1. Based on these findings, the authors propose that these chemokines may be useful for modulating these cells in a clinical setting and potentially for enhancing the effectiveness of the engraftment and homing of HSCs.
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http://dx.doi.org/10.3109/08880018.2011.599477DOI Listing
November 2011

Application of human umbilical cord blood-derived mesenchymal stem cells in disease models.

World J Stem Cells 2010 Apr;2(2):34-8

Ju-Yeon Kim, Hong Bae Jeon, Yoon Sun Yang, Wonil Oh, Jong Wook Chang, Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 137-874, South Korea.

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) are regarded as an alternative source of bone marrow-derived mesenchymal stem cells because collection of cord blood is less invasive than that of bone marrow. hUCB-MSCs have recently been studied for evaluation of their potential as a source of cell therapy. In this review, the general characteristics of hUCB-MSCs and their therapeutic effects on various diseases in vitro and in vivo will be discussed.
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http://dx.doi.org/10.4252/wjsc.v2.i2.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3097922PMC
April 2010

CXC chemokine receptor 1 enhances the ability of human umbilical cord blood-derived mesenchymal stem cells to migrate toward gliomas.

Biochem Biophys Res Commun 2011 Apr 31;407(4):741-6. Epub 2011 Mar 31.

Department of Neurosurgery, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.

In this study, we showed that knocking-down interleukin-8 (IL-8) in glioma cells, or its receptor, CXC chemokine receptor 1 (CXCR1) in hUCB-MSCs reduced hUCB-MSC migration toward glioma cells in a Transwell chamber. In contrast, CXCR1-transfected hUCB-MSCs (CXCR1-MSCs) showed a superior capacity to migrate toward glioma cells in a Transwell chamber compared to primary hUCB-MSCs. Furthermore, these transfected cells also demonstrated the same ability to migrate toward tumors in mice bearing intracranial human gliomas as shown by histological and in vivo imaging analysis. Our findings indicate that overexpression of CXCR1 could be a useful tool for MSC-based gene therapy to achieve a sufficient quantity of therapeutic MSCs that are localized within tumors.
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http://dx.doi.org/10.1016/j.bbrc.2011.03.093DOI Listing
April 2011

Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells dose-dependently attenuates hyperoxia-induced lung injury in neonatal rats.

Cell Transplant 2011 ;20(11-12):1843-54

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea.

Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this preclinical translation study was to optimize the dose of human UCB-derived MSCs in attenuating hyperoxia-induced lung injury in newborn rats. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (95% oxygen) or normoxia after birth for 14 days. Three different doses of human UCB-derived MSCs, 5 × 10(3) (HT1), 5 × 10(4) (HT2), and 5 × 10(5) (HT3), were delivered intratracheally at postnatal day (P) 5. At P14, lungs were harvested for analyses including morphometry for alveolarization, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, myeoloperoxidase activity, mRNA level of tumor necross factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and transforming growth factor-β (TGF-β), human glyceradehyde-3-phosphate dehydrogenase (GAPDH), and p47(phox), and collagen levels. Increases in TUNEL-positive cells were attenuated in all transplantation groups. However, hyperoxia-induced lung injuries, such as reduced alveolarization, as evidenced by increased mean linear intercept and mean alveolar volume, and increased collagen levels were significantly attenuated in both HT2 and HT3, but not in HT1, with better attenuation in HT3 than in HT2. Dose-dependent human GAPDH expression, indicative of the presence of human RNA in lung tissue, was observed only in the transplantation groups, with higher expression in HT3 than in HT2, and higher expression in HT2 than in HT1. Hyperoxia-induced inflammatory responses such as increased myeloperoxidase acitivity, mRNA levels of TNF-α, IL-1β, IL-6, and TGF-β of the lung tissue, and upregulation of both cytosolic and membrane p47(phox), indicative of oxidative stress, were significantly attenuated in both HT2 and HT3 but not in HT1. These results demonstrate that intratracheal transplantation of human UCB-derived MSCs with appropriate doses may attenuate hyperoxia-induced lung injury through active involvement of these cells in modulating host inflammatory responses and oxidative stress in neonatal rats.
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http://dx.doi.org/10.3727/096368911X565038DOI Listing
June 2013

Galectin-3 secreted by human umbilical cord blood-derived mesenchymal stem cells reduces amyloid-beta42 neurotoxicity in vitro.

FEBS Lett 2010 Aug 24;584(16):3601-8. Epub 2010 Jul 24.

Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Republic of Korea.

In this study, we found that expression and secretion of galectin-3 (GAL-3) were upregulated by amyloid-beta42 (Abeta42) exposure in human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) without cell death. Abeta42-exposed rat primary cortical neuronal cells co-treated with recombinant GAL-3 were protected from neuronal death in a dose-dependent manner. hUCB-MSCs were cocultured with Abeta42-exposed rat primary neuronal cells or the neuroblastoma cell line, SH-SY5Y in a Transwell chamber. Coculture of hUCB-MSCs reduced cell death of Abeta42-exposed neurons and SH-SY5Y cells. This neuroprotective effect of hUCB-MSCs was reduced significantly by GAL-3 siRNA. These data suggested that hUCB-MSC-derived GAL-3 is a survival factor against Abeta42 neurotoxicity.
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http://dx.doi.org/10.1016/j.febslet.2010.07.028DOI Listing
August 2010

Protein expression profiles during osteogenic differentiation of mesenchymal stem cells derived from human umbilical cord blood.

Tohoku J Exp Med 2010 Jun;221(2):141-50

Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.

Mesenchymal stem cells (MSCs) can potentially differentiate along multiple lineages and be expanded in vitro, making them highly attractive candidates for cell therapy and tissue engineering applications. This study sought to investigate the critical proteins involved in osteogenic differentiation of mesenchymal stem cells derived from umbilical cord blood (UCB-MSCs). MSCs, which were isolated from three different preparations of human UCB, were osteoinduced, and total proteins were extracted from the cells. Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) was performed on the day (d) of induction d0, and on d2, d7, and d21 of differentiation. The optical density (OD) of each spot was measured, and spots with a mean OD of three cell lines of MSCs that increased > 30 or decreased < 0.1 relative to a previous time point were selected. Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF/MS) was used to identify the proteins. Through database searches, the properties and functions of the proteins were investigated and then classified according to the Gene Ontology classification. Among the 308 spots observed in the 2-D gel, 16 proteins with a mean OD ratio > 30, and 20 proteins with a mean OD ratio < 0.1 were identified during the differentiation process. Additionally, the distribution of differentially expressed proteins according to cellular component and molecular function criteria differed depending on whether protein expression increased or decreased during differentiation. The results of this study will comprise an initial proteomic database for UCB-MSCs differentiation.
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http://dx.doi.org/10.1620/tjem.221.141DOI Listing
June 2010

Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation.

Neurobiol Aging 2012 Mar 14;33(3):588-602. Epub 2010 May 14.

Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, Korea.

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) have a potential therapeutic role in the treatment of neurological disorders, but their current clinical usage and mechanism of action has yet to be ascertained in Alzheimer's disease (AD). Here we report that hUCB-MSC transplantation into amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice significantly improved spatial learning and memory decline. Furthermore, amyloid-β peptide (Aβ) deposition, β-secretase 1 (BACE-1) levels, and tau hyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice. Interestingly, these effects were associated with reversal of disease-associated microglial neuroinflammation, as evidenced by decreased microglia-induced proinflammatory cytokines, elevated alternatively activated microglia, and increased anti-inflammatory cytokines. These findings lead us to suggest that hUCB-MSC produced their sustained neuroprotective effect by inducing a feed-forward loop involving alternative activation of microglial neuroinflammation, thereby ameliorating disease pathophysiology and reversing the cognitive decline associated with Aβ deposition in AD mice.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.03.024DOI Listing
March 2012
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