Publications by authors named "Hye Jin Jin"

38 Publications

PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model.

Cells 2021 Sep 14;10(9). Epub 2021 Sep 14.

Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea.

Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, mRNA silencing was applied to confirm PTX-3 function. silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.
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http://dx.doi.org/10.3390/cells10092420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466059PMC
September 2021

A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke.

Nat Biomed Eng 2021 08 12;5(8):847-863. Epub 2021 Aug 12.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.

The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood-brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies. We observed that each type of stem cell showed unique neurorestorative effects, primarily by supporting endogenous recovery rather than through direct cell replacement, and that the recovery of synaptic activities is correlated with the recovery of the structural and functional integrity of the neurovascular unit rather than with the regeneration of neurons.
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http://dx.doi.org/10.1038/s41551-021-00744-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524779PMC
August 2021

Ambipolar Channel p-TMD/n-Ga O Junction Field Effect Transistors and High Speed Photo-sensing in TMD Channel.

Adv Mater 2021 Sep 2;33(38):e2103079. Epub 2021 Aug 2.

Van der Waals Materials Research Center, Department of Physics, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Highly crystalline 2D/3D-mixed p-transition metal dichalcogenide (TMD)/n-Ga O heterojunction devices are fabricated by mechanical exfoliation of each p- and n-type material. N-type β-Ga O and p-type TMD separately play as a channel for junction field effect transistors (JFETs) with each type of carriers as well as materials for a heterojunction PN diode. The work thus mainly focuses on such ambipolar channel transistors with two different types of channel in a single device architecture. For more extended applications, the transparency of high energy band gap β-Ga O (E  ≈ 4.8 eV) is taken advantage of, firstly to measure the electrical energy gap of p-TMDs receiving visible or near infrared (NIR) photons through the β-Ga O . Next, the p-TMD/n-Ga O JFETs are put to high speed photo-sensing which is achieved from the p-TMD channel under reverse bias voltages on n-Ga O . The photo-switching cutoff frequency appears to be ≈16 and 29 kHz for visible red and NIR illuminations, respectively, on the basis of -3 dB photoelectric power loss. Such a high switching speed of the JFET is attributed to the fast transport of photo-carriers in TMD channels. The 2D/3D-mixed ambipolar channel JFETs and their photo-sensing applications are regarded novel, promising, and practically easy to achieve.
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http://dx.doi.org/10.1002/adma.202103079DOI Listing
September 2021

Positively Correlated CD47 Activation and Autophagy in Umbilical Cord Blood-Derived Mesenchymal Stem Cells during Senescence.

Stem Cells Int 2021 15;2021:5582792. Epub 2021 Apr 15.

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

Autophagy plays a critical role in stem cell maintenance and is related to cell growth and cellular senescence. It is important to find a quality-control marker for predicting senescent cells. This study verified that CD47 could be a candidate to select efficient mesenchymal stem cells (MSCs) to enhance the therapeutic effects of stem cell therapy by analyzing the antibody surface array. CD47 expression was significantly decreased during the expansion of MSCs in vitro ( < 0.01), with decreased CD47 expression correlated with accelerated senescence phenotype, which affected cell growth. UCB-MSCs transfected with CD47 siRNA significantly triggered the downregulation of pRB and upregulation of pp38, which are senescence-related markers. Additionally, autophagy-related markers, ATG5, ATG12, Beclin1, and LC3B, revealed significant downregulation with CD47 siRNA transfection. Furthermore, autophagy flux following treatment with an autophagy inducer, rapamycin, has shown that CD47 is a key player in autophagy and senescence to maintain and regulate the growth of MSCs, suggesting that CD47 may be a critical key marker for the selection of effective stem cells in cell therapy.
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http://dx.doi.org/10.1155/2021/5582792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062176PMC
April 2021

Reduced extrinsic recombination process in anatase and rutile TiO epitaxial thin films for efficient electron transport layers.

Sci Rep 2021 Mar 24;11(1):6810. Epub 2021 Mar 24.

Department of Physics and New and Renewable Energy Research Center (NREC), Ewha Womans University, Seoul, 03760, Korea.

TiO is the most widely used material for the electron transport layers (ETLs) because it is characterized by proper band alignment with light absorbers, adequate optical transmittance, and high electron mobility. There are two thermodynamically stable crystal phases of TiO: anatase and rutile. However, understanding which phase is more effective as the ETL is still required. In this paper, we demonstrate the different effects of using epitaxial anatase TiO and epitaxial rutile TiO (both grown using pulsed laser deposition) as the ETL material on the electrical and optical properties. Epitaxial Nb-doped TiO layers were used as the common electrode material for the both epitaxial ETLs for which the crystalline structural analysis revealed high crystalline qualities and good coherency for both phases. By analyzing the recombination kinetics, the anatase phase shows a preferable performance in comparison with the rutile phase, although both epitaxial phases show remarkably reduced extrinsic recombination properties, such as trap-assisted recombination. This study demonstrates not only a better electron transporting performance of anatase phase but also reduced extrinsic recombination through epitaxy growth.
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http://dx.doi.org/10.1038/s41598-021-86422-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990940PMC
March 2021

Prospects for the therapeutic development of umbilical cord blood-derived mesenchymal stem cells.

World J Stem Cells 2020 Dec;12(12):1511-1528

Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea.

Umbilical cord blood (UCB) is a primitive and abundant source of mesenchymal stem cells (MSCs). UCB-derived MSCs have a broad and efficient therapeutic capacity to treat various diseases and disorders. Despite the high latent self-renewal and differentiation capacity of these cells, the safety, efficacy, and yield of MSCs expanded for clinical applications remains a concern. However, immunomodulatory effects have emerged in various disease models, exhibiting specific mechanisms of action, such as cell migration and homing, angiogenesis, anti-apoptosis, proliferation, anti-cancer, anti-fibrosis, anti-inflammation and tissue regeneration. Herein, we review the current literature pertaining to the UCB-derived MSC application as potential treatment strategies, and discuss the concerns regarding the safety and mass production issues in future applications.
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http://dx.doi.org/10.4252/wjsc.v12.i12.1511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789129PMC
December 2020

High Integrity and Fidelity of Long-Term Cryopreserved Umbilical Cord Blood for Transplantation.

J Clin Med 2021 Jan 14;10(2). Epub 2021 Jan 14.

Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si, Gyeonggi-do 13494, Korea.

Umbilical cord blood (UCB) is used as a source of donor cells for hematopoietic stem cell (HSC) transplantation. The success of transplantation is dependent on the quality of cord blood (CB) units for maximizing the chance of engraftment. Improved outcomes following transplantation are associated with certain factors of cryopreserved CB units: total volume and total nucleated cell (TNC) count, mononuclear cell (MNC) count, and CD34+ cell count. The role of the storage period of CB units in determining the viability and counts of cells is less clear and is related to the quality of cryopreserved CB units. Herein, we demonstrate the recovery of viable TNCs and CD34+ cells, as well as the MNC viability in 20-year-old cryopreserved CB units in a CB bank (MEDIPOST Co., Ltd., Seongnam-si, Gyeonggi-do, Korea). In addition, cell populations in CB units were evaluated for future clinical applications. The stable recovery rate of the viability of cryopreserved CB that had been stored for up to 20 years suggested the possibility of uses of the long-term cryopreservation of CB units. Similar relationships were observed in the recovery of TNCs and CD34+ cells in units of cryopreserved and fresh CB. The high-viability recovery of long-term cryopreserved CB suggests that successful hematopoietic stem cell (HSC) transplantation and other clinical applications, which are suitable for treating incurable diseases, may be performed regardless of long-term storage.
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http://dx.doi.org/10.3390/jcm10020293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830419PMC
January 2021

Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling.

Cells 2021 01 3;10(1). Epub 2021 Jan 3.

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

In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.
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http://dx.doi.org/10.3390/cells10010063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824096PMC
January 2021

Nonvolatile and Neuromorphic Memory Devices Using Interfacial Traps in Two-Dimensional WSe/MoTe Stack Channel.

ACS Nano 2020 Sep 25;14(9):12064-12071. Epub 2020 Aug 25.

Van der Waals Materials Research Center, Department of Physics, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.

Very recently, stacked two-dimensional materials have been studied, focusing on the van der Waals interaction at their stack junction interface. Here, we report field effect transistors (FETs) with stacked transition metal dichalcogenide (TMD) channels, where the heterojunction interface between two TMDs appears useful for nonvolatile or neuromorphic memory FETs. A few nanometer-thin WSe and MoTe flakes are vertically stacked on the gate dielectric, and bottom MoTe performs as a channel for hole transport. Interestingly, the WSe/MoTe stack interface functions as a hole trapping site where traps behave in a nonvolatile manner, although trapping/detrapping can be controlled by gate voltage (). Memory retention after high pulse appears longer than 10000 s, and the Program/Erase ratio in a drain current is higher than 200. Moreover, the traps are delicately controllable even with small , which indicates that a neuromorphic memory is also possible with our heterojunction stack FETs. Our stack channel FET demonstrates neuromorphic memory behavior of ∼94% recognition accuracy.
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http://dx.doi.org/10.1021/acsnano.0c05393DOI Listing
September 2020

Migration Inhibitory Factor in Conditioned Medium from Human Umbilical Cord Blood-Derived Mesenchymal Stromal Cells Stimulates Hair Growth.

Cells 2020 05 28;9(6). Epub 2020 May 28.

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

Conventional therapeutic applications of mesenchymal stromal cells (MSCs) focus on cell replacement and differentiation; however, increasing evidence suggests that most of their therapeutic effects are carried out by their various secretions. This study investigated the application of conditioned medium (CM) from human umbilical cord blood-derived MSCs (hUCB-MSCs) to improve hair growth and developed a method to reliably produce this optimized CM. Primed MSC-derived CM (P-CM) with combinations of TGF-β1 and LiCl was optimized by comparing its effects on the cell viability of dermal papilla cells (DPCs). P-CM significantly increased the viability of DPCs compared to CM. The secretion of vascular endothelial growth factor (VEGF) in DPCs was regulated by the macrophage migration inhibitory factor (MIF) in the P-CM secreted by MSCs. These findings suggest that P-CM can improve the efficacy in hair growth via a paracrine mechanism and that MIF in P-CM exerts hair growth-promoting effects via a VEGF-related β-catenin and p-GSK-3β [SER9] signaling pathway. Furthermore, clinical trials have shown that 5% P-CM improved androgenetic alopecia through producing an increased hair density, thickness, and growth rate, suggesting that this topical agent may be a novel and effective treatment option for patients with androgenetic alopecia.
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http://dx.doi.org/10.3390/cells9061344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349163PMC
May 2020

A Small-Sized Population of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Shows High Stemness Properties and Therapeutic Benefit.

Stem Cells Int 2020 28;2020:5924983. Epub 2020 Apr 28.

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

Mesenchymal stem cells (MSCs) represent a promising means to promote tissue regeneration. However, the heterogeneity of MSCs impedes their use for regenerative medicine. Further investigation of this phenotype is required to develop cell therapies with improved clinical efficacy. Here, a small-sized population of human umbilical cord blood-derived MSCs (UCB-MSCs) was isolated using a filter and centrifuge system to analyze its stem cell characteristics. Consequently, this population showed higher cell growth and lower senescence. Additionally, it exhibited diverse stem cell properties including differentiation, stemness, and adhesion, as compared to those of the population before isolation. Using cell surface protein array or sorting analysis, both EGFR and CD49f were identified as markers associated with the small-sized population. Accordingly, suppression of these surface proteins abolished the superior characteristics of this population. Moreover, compared to that with large or nonisolated populations, the small-sized population showed greater therapeutic efficacy by promoting the engraftment potential of infused cells and reducing lung damage in an emphysema mouse model. Therefore, the isolation of this small-sized population of UCB-MSCs could be a simple and effective way to enhance the efficacy of cell therapy.
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http://dx.doi.org/10.1155/2020/5924983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204153PMC
April 2020

Soluble PTX3 of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Attenuates Hyperoxic Lung Injury by Activating Macrophage Polarization in Neonatal Rat Model.

Stem Cells Int 2020 23;2020:1802976. Epub 2020 Jan 23.

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

Therapeutic treatment of various inflammation-related diseases using mesenchymal stem cells (MSCs) has increased in recent years because of the paracrine action of these cells but shows several limitations. First, MSC-based therapies exhibit varying efficacies; thus, biomarkers should be determined to identify who may benefit from these candidate therapeutic agents. Second, the mechanism underlying the therapeutic effects is poorly understood. To evaluate the effects of human umbilical cord blood-derived MSCs (UCB-MSCs) on macrophages, the macrophage cell line NR8383 stimulated with lipopolysaccharide (LPS) was cocultured by UCB-MSCs. We found that UCB-MSCs mediated changes in macrophage polarization towards M2 from M1 macrophages. To identify the paracrine action underlying the anti-inflammation effect of UCB-MSCs, the secretion of UCB-MSCs exposed to LPS-stimulated NR8383 cells was tested using a biotin label-based 507 antibody array. Among the secreted proteins, we selected pentraxin-related protein PTX3/tumor necrosis factor-inducible gene 14 protein (PTX3) to investigate its association with UCB-MSCs in macrophage polarization. We found that human PTX3 was secreted from UCB-MSCs under inflammation condition and reinforced the M2 macrophage marker via the Dectin-1 receptor by activating MSK1/2 phosphorylation signaling in NR8383 cells. Accordingly, knockdown of PTX3 in UCB-MSCs significantly attenuated their therapeutic effects in a neonatal hyperoxic lung injury resulting in reduced survival, lung alveolarization, M2 marker expression, Dectin-1 levels, anti-inflammatory cytokines, and improved M1 marker expression and inflammatory cytokines compared to control MSC-injected rats. UCB-MSCs show therapeutic potential by controlling macrophage polarization. Interestingly, higher PTX3 levels in UCB-MSCs induced greater improvement in the therapeutic effects than lower PTX3 levels. Collectively, PTX3 is a potential marker with critical paracrine effects for predicting the therapeutic potential of MSC therapy in inflammatory diseases; quality control assessments using PTX3 may be useful for improving the therapeutic effects of UCB-MSCs.
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http://dx.doi.org/10.1155/2020/1802976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204119PMC
January 2020

Primary Cilia Mediate Wnt5a/β-catenin Signaling to Regulate Adipogenic Differentiation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Following Calcium Induction.

Tissue Eng Regen Med 2020 04 1;17(2):193-202. Epub 2020 Feb 1.

Biomedical Research Institute, MEDIPOST Co. Ltd, 21, Daewangpangyo-ro 644-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13494, Korea.

Background: Regeneration of soft tissue defects is essential for adipose tissue pathologies and disease, trauma, or injury-induced damage. Here, we show that umbilical cord blood-derived mesenchymal stem cells could potentially be tailored and used for the reconstruction of specific damaged sites. Adipogenesis can be exploited in soft tissue reconstruction. Also, primary cilia play a role in the control of adipogenesis.

Methods: The adipogenic differentiation capacity of mesenchymal stem cells (MSCs) was shown to influence ciliogenesis. MSCs transfected with intraflagellar transport 88 (IFT88) small interfering RNA (siRNA), which blocks the assembly and maintenance of cilia, were examined to confirm the relationship between adipogenesis and ciliogenesis. Also, 1,2-Bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM), calcium chelator, inhibited the ciliogenesis of MSCs in adipogenic differentiation.

Results: IFT88-knockdown led to decreased cilia formation and limitation of cilia elongation in adipogenesis. Additionally, intracellular calcium triggered cilia formation in MSCs adipogenesis. Interestingly, intracellular calcium cannot overcome the inhibition of adipogenesis caused by low numbers of cilia in MSCs.

Conclusion: Our data suggested that ciliogenesis was negatively regulated by Wnt5a/β-catenin signaling during adipogenesis. Thus, we suggest that calcium induction triggers adipogenesis and ciliogenesis.
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http://dx.doi.org/10.1007/s13770-019-00237-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105559PMC
April 2020

Up-Regulation of Superoxide Dismutase 2 in 3D Spheroid Formation Promotes Therapeutic Potency of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.

Antioxidants (Basel) 2020 Jan 11;9(1). Epub 2020 Jan 11.

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

Umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are accessible, available in abundance, and have been shown to be a promising source that can regenerate cartilage in patients with osteoarthritis or other orthopedic diseases. Recently, a three-dimensional (3D) cell culture system was developed to mimic the naive tissue microenvironment. However, the efficacy of cells generated from the 3D spheroid culture system has not yet been elucidated. In the present study, we demonstrate the changes in superoxide dismutase 2 (SOD2) gene expression, an indicator of oxidative stress, on 3D spheroid MSCs. Moreover, siRNA transfection and neutralizing antibody investigations were performed to confirm the function of SOD2 and E-cadherin. Overall, we found that SOD2 siRNA transfection in the spheroid form of MSCs increases the expression of apoptotic genes and decreases the clearance of mitochondrial reactive oxygen species (ROS). As a result, we confirm that 3D spheroid formation increases E-cadherin and SOD2 expression, ultimately regulating the phosphoinositide 3-kinase (PI3K/pAkt/pNrf2 and pERK/pNrf2 signaling pathway. Additionally, we show that SOD2 expression on 3D spheroid MSCs affects the regeneration rates of destructive cartilage in an osteoarthritic model. We postulate that the impact of SOD2 expression on 3D spheroid MSCs reduces oxidative stress and apoptosis, and also promotes cartilage regeneration.
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http://dx.doi.org/10.3390/antiox9010066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023074PMC
January 2020

Reconfigurable Dipole-Induced Resistive Switching of MoS Thin Layers on Nb:SrTiO.

ACS Appl Mater Interfaces 2019 Dec 25;11(49):46344-46349. Epub 2019 Nov 25.

Department of Physics , Ewha Womans University , Seoul 03760 , Republic of Korea.

The controllable band gap and charge-trapping capability of MoS render it suitable for use in the fabrication of various electrical devices with high- dielectric oxides. In this study, we investigated reconfigurable resistance states in a MoS/Nb:SrTiO heterostructure by using conductive atomic force microscopy. Low-resistance and high-resistance states were observed in all MoS because of barrier height modification resulting from redistribution of charge and oxygen vacancies in the vicinity of interfaces. In a thin layer of the MoS film, the carrier density was high, and layer-dependent transport properties appeared because of the charge separation in MoS. The hysteresis and switching voltage of the MoS/Nb:SrTiO heterostructure could be varied by controlling the number of layers of MoS.
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http://dx.doi.org/10.1021/acsami.9b15097DOI Listing
December 2019

Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury.

Int J Mol Sci 2019 Sep 27;20(19). Epub 2019 Sep 27.

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

Bronchopulmonary dysplasia (BPD), caused by hyperoxia in newborns and infants, results in lung damage and abnormal pulmonary function. However, the current treatments for BPD are steroidal and pharmacological therapies, which cause neurodevelopmental impairment. Treatment with umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) is an efficient alternative approach. To prevent pulmonary inflammation in BPD, this study investigated the hypothesis that a key regulator was secreted by MSCs to polarize inflammatory macrophages into anti-inflammatory macrophages at inflammation sites. Lipopolysaccharide-induced macrophages co-cultured with MSCs secreted low levels of the inflammatory cytokines, IL-8 and IL-6, but high levels of the anti-inflammatory cytokine, IL-10. Silencing decorin in MSCs suppressed the expression of CD44, which mediates anti-inflammatory activity in macrophages. The effects of MSCs were examined in a rat model of hyperoxic lung damage. Macrophage polarization differed depending on the levels of decorin secreted by MSCs. Moreover, intratracheal injection of decorin-silenced MSCs or MSCs secreting low levels of decorin confirmed impaired alveolarization of damaged lung tissues by down-regulation of decorin. In tissues, a decrease in the anti-inflammatory macrophage marker, CD163, was observed via CD44. Thus, we identified decorin as a key paracrine factor, inducing macrophage polarization via CD44, a master immunoregulator in mesenchymal stem cells.
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http://dx.doi.org/10.3390/ijms20194815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801980PMC
September 2019

The Upregulation of Toll-Like Receptor 3 via Autocrine IFN-β Signaling Drives the Senescence of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Through JAK1.

Front Immunol 2019 23;10:1659. Epub 2019 Jul 23.

Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Although mesenchymal stromal cells (MSCs) are among the most promising cell sources for cell-based therapies and regenerative medicine, the decline in their function with age due to cellular senescence limits their therapeutic applications. Unveiling the underlying mechanism of MSC senescence is therefore of substantial interest with regard to advancing MSC-based cell therapies. We here show that the induction of human umbilical cord blood-derived MSC (UCB-MSC) senescence causes the predominant upregulation of Toll-like receptor 3 (TLR3). Subsequent TLR3 activation by polyinosinic-polycytidylic acid triggers the prominent features of senescence. Using a clustered regularly interspaced short palindromic repeats/Cas9 library screening system, we identified Janus kinase 1 (JAK1) as the candidate regulatory factor for TLR3-mediated MSC senescence. A JAK1 deficiency blocked the MSC senescence phenotype upon TLR3 activation and TLR3 induction. Targeting the JAK1 pathway using chemical JAK1 inhibitors also significantly suppressed TLR3-mediated MSC senescence. Importantly, we further observed that UCB-MSC senescence is driven by a senescence-associated secretory phenotype (SASP) and that interferon-β (IFN-β) is a component of TLR3-dependent SASP, whereby its autocrine actions upregulate TLR3 and suppress cell proliferation. A JAK1 depletion significantly interrupted these effects of IFN-β, indicating that JAK1 is a signaling mediator linking IFN-β activity to TLR3 expression and the process of MSC senescence. Collectively, our findings provide new mechanistic insights into UCB-MSC senescence by revealing the role of an autocrine regulatory loop of SASP evoked by TLR3 activation.
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http://dx.doi.org/10.3389/fimmu.2019.01659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6665952PMC
November 2020

Mesenchymal stem cells prevent the progression of diabetic nephropathy by improving mitochondrial function in tubular epithelial cells.

Exp Mol Med 2019 07 9;51(7):1-14. Epub 2019 Jul 9.

Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea.

The administration of mesenchymal stem cells (MSCs) was shown to attenuate overt as well as early diabetic nephropathy in rodents, but the underlying mechanism of this beneficial effect is largely unknown. Inflammation and mitochondrial dysfunction are major pathogenic factors in diabetic nephropathy. In this study, we found that the repeated administration of MSCs prevents albuminuria and injury to tubular epithelial cells (TECs), an important element in the progression of diabetic nephropathy, by improving mitochondrial function. The expression of M1 macrophage markers was significantly increased in diabetic kidneys compared with that in control kidneys. Interestingly, the expression of arginase-1 (Arg1), an important M2 macrophage marker, was reduced in diabetic kidneys and increased by MSC treatment. In cultured TECs, conditioned media from lipopolysaccharide-activated macrophages reduced peroxisomal proliferator-activated receptor gamma coactivator 1α (Pgc1a) expression and impaired mitochondrial function. The coculture of macrophages with MSCs increased and decreased the expression of Arg1 and M1 markers, respectively. Treatment with conditioned media from cocultured macrophages prevented activated macrophage-induced mitochondrial dysfunction in TECs. In the absence of MSC coculture, Arg1 overexpression in macrophages reversed Pgc1a suppression in TECs. These observations suggest that MSCs prevent the progression of diabetic nephropathy by reversing mitochondrial dysfunction in TECs via the induction of Arg1 in macrophages.
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http://dx.doi.org/10.1038/s12276-019-0268-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802630PMC
July 2019

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

Virtual Out-of-Plane Piezoelectric Response in MoS Layers Controlled by Ferroelectric Polarization.

ACS Appl Mater Interfaces 2018 Jan 19;10(1):1334-1339. Epub 2017 Dec 19.

Department of Physics and New and Renewable Energy Research Center (NREC), Ewha Womans University , Seoul 03760, Republic of Korea.

The MoS carrier distribution can be controlled with the use of a dielectric environment substrate. Ferroelectric thin films are used to investigate the electrical responses at the MoS layer. The MoS/(111)-PbTiO vertical heterostructure is investigated, and the electrical responses, including piezoelectricity, are obtained using piezoresponse force microscopy. The piezoelectric response modifications obtained at the MoS layer on the ferroelectric thin films are a result of the depolarizing effect. In particular, the piezoelectricity enhancement is observed at the 19-layer MoS because of an induced dipole effect. By considering the polarization effects of ferroelectric thin films, the electrical responses at the MoS layers can be controlled, and the interfacial carrier distribution at the interface results in different electrical performances at the MoS.
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http://dx.doi.org/10.1021/acsami.7b14001DOI Listing
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

Preoperative serum levels of insulin-like growth factor-binding protein 2 predict prognosis of gastric cancer patients.

Oncotarget 2017 Feb;8(7):10994-11003

Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea.

It has been reported that serum insulin-like growth factor-binding protein 2 (IGFBP2) levels are elevated in various types of cancers. However, the clinicopathologic and prognostic implications of circulating IGFBP2 have never been investigated in gastric cancer. We tested IGFBP2 levels in the sera of 118 gastric cancer patients and 34 healthy controls using enzyme-linked immunosorbent assay (ELISA). The mean serum IGFBP2 level was significantly elevated in the gastric cancer patients compared to controls (805.23 ± 590.56 ng/ml vs. 459.61 ± 277.01 ng/ml; P < 0.001). Serum IGFBP2 levels were significantly higher in larger (> 6 cm) tumors (956.8 ± 734.0 ng/ml vs. 548.6 ± 364.0 ng/ml; P = 0.007) and in higher (T3/4) T stages (854.8 ± 621.4 ng/ml vs. 546.5 ± 315.1 ng/ml; P = 0.037). Multivariate Cox analysis showed that higher serum IGFBP2 level (> 400.01 ng/ml) was an independent prognostic factor predicting worse overall survival in patients with gastric cancer (hazard ratio (HR): 3.749, P = 0.034). When we divided patients into four groups based on blood IGFBP2 levels, survival was stratified. The HRs for death in the 3rd and 4th quartiles of serum IGFBP2 levels in comparison to that in the 1st quartile were 2.527 (P = 0.043) and 3.092 (P = 0.012). In conclusion, circulating IGFBP2 has potential as a biomarker predicting prognosis for gastric cancer patients.
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http://dx.doi.org/10.18632/oncotarget.14202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355240PMC
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

Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells.

Antioxid Redox Signal 2016 Mar 27;24(9):471-85. Epub 2016 Jan 27.

1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.

Aims: Cellular senescence and its secretory phenotype (senescence-associated secretory phenotype [SASP]) develop after long-term expansion of mesenchymal stromal cells (MSCs). Further investigation of this phenotype is required to improve the therapeutic efficacy of MSC-based cell therapies. In this study, we show that positive feedback between SASP and inherent senescence processes plays a crucial role in the senescence of umbilical cord blood-derived MSCs (UCB-MSCs).

Results: We found that monocyte chemoattractant protein-1 (MCP-1) was secreted as a dominant component of the SASP during expansion of UCB-MSCs and reinforced senescence via its cognate receptor chemokine (c-c motif) receptor 2 (CCR2) by activating the ROS-p38-MAPK-p53/p21 signaling cascade in both an autocrine and paracrine manner. The activated p53 in turn increased MCP-1 secretion, completing a feed-forward loop that triggered the senescence program in UCB-MSCs. Accordingly, knockdown of CCR2 in UCB-MSCs significantly improved their therapeutic ability to alleviate airway inflammation in an experimental allergic asthma model. Moreover, BMI1, a polycomb protein, repressed the expression of MCP-1 by binding to its regulatory elements. The reduction in BMI1 levels during UCB-MSC senescence altered the epigenetic status of MCP-1, including the loss of H2AK119Ub, and resulted in derepression of MCP-1.

Innovation: Our results provide the first evidence supporting the existence of the SASP as a causative contributor to UCB-MSC senescence and reveal a so far unappreciated link between epigenetic regulation and SASP for maintaining a stable senescent phenotype.

Conclusion: Senescence of UCB-MSCs is orchestrated by MCP-1, which is secreted as a major component of the SASP and is epigenetically regulated by BMI1.
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http://dx.doi.org/10.1089/ars.2015.6359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800271PMC
March 2016

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

A decline in Wnt3a signaling is necessary for mesenchymal stem cells to proceed to replicative senescence.

Stem Cells Dev 2015 Apr 8;24(8):973-82. Epub 2015 Jan 8.

1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.

Umbilical cord blood-derived mesenchymal stem cells are a promising source of cells for regeneration therapy due to their multipotency, high proliferative capacity, relatively noninvasive collection, and ready availability. However, extended cell culture inevitably triggers cellular senescence-the irreversible arrest of cell division-thereby limiting the proliferative lifespan of adult stem cells. Wnt/β-catenin signaling plays a functional role as a key regulator of self-renewal and differentiation in mesenchymal stem cells (MSCs), and thus Wnt/β-catenin signaling and cellular senescence might be closely connected. Here, we show that the expression levels of canonical Wnt families decrease as MSCs age during subculture. Activation of the Wnt pathway by treatment with Wnt3a-conditioned medium or glycogen synthase kinase 3β inhibitors, such as SB-216763 and 6-bromoindirubin-3'-oxime, delays the progression of cellular senescence as shown by the decrease in the senescence effectors p53 and pRb, lowered senescence-associated β-galactosidase activity, and increased telomerase activity. In contrast, suppression of the Wnt pathway by treatment with dickkopf-1 (an antagonist of the Wnt coreceptor) and β-catenin siRNA transfection promotes senescence in MSCs. Interestingly, the magnitude of the response to enhanced Wnt3a/β-catenin signaling appears to depend on the senescent state during extended culture, particularly after multiple passages. These results suggest that Wnt3a signaling might be a predominant factor that could be used to overcome senescence in long-term cultured MSCs by directly intervening in the proliferative capacity and MSC senescence. The functional role of Wnt3a/β-catenin signaling in hedging cellular senescence may allow the development of new approaches for stem cell-based therapies.
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http://dx.doi.org/10.1089/scd.2014.0273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389919PMC
April 2015

Effect of preemptive treatment with human umbilical cord blood-derived mesenchymal stem cells on the development of renal ischemia-reperfusion injury in mice.

Am J Physiol Renal Physiol 2014 Nov 20;307(10):F1149-61. Epub 2014 Aug 20.

Nephrology Division, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea;

Human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) have been studied in several models of immune-mediated disease because of their unique immunomodulatory properties. We hypothesized that HUCB-MSCs could suppress the inflammatory response in postischemic kidneys and attenuate early renal injury. In 8- to 10-wk-old male C57BL/6 mice, bilateral ischemia-reperfusion injury (IRI) surgery was performed, and 1 × 10(6) HUCB-MSCs were injected intraperitoneally 24 h before surgery and during reperfusion. Renal functional and histological changes, HUCB-MSC trafficking, leukocyte infiltration, and cytokine expression were analyzed. Renal functional decline and tubular injury after IRI were attenuated by HUCB-MSC treatment. PKH-26-labeled HUCB-MSCs trafficked into the postischemic kidney. Although numbers of CD45-positive leukocytes in the postischemic kidney were comparable between groups, the expression of interferon-γ in the postischemic kidney was suppressed by HUCB-MSC treatment. The rapid decrease in intrarenal VEGF after IRI was markedly mitigated by HUCB-MSC treatment. In inflammatory conditions simulated in a cell culture experiment, VEGF secretion from HUCB-MSCs was substantially enhanced. VEGF inhibitor abolished the renoprotective effect of HUCB-MSCs after IRI. Flow cytometry analysis revealed the decreased infiltration of natural killer T cells and increased number of regulatory T cells in postischemic kidneys. In addition, these effects of HUCB-MSCs on kidney infiltrating mononuclear cells after IRI were attenuated by VEGF inhibitor. HUCB-MSCs attenuated renal injury in mice in the early injury phase after IRI, mainly by humoral effects and secretion of VEGF. Our results suggest a promising role for HUCB-MSCs in the treatment of renal IRI.
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http://dx.doi.org/10.1152/ajprenal.00555.2013DOI Listing
November 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

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
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