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1.
J Korean Med Sci ; 37(31): e244, 2022 Aug 08.
Article in English | MEDLINE | ID: mdl-35942557

ABSTRACT

BACKGROUND: To deliver therapeutics into the brain, it is imperative to overcome the issue of the blood-brain-barrier (BBB). One of the ways to circumvent the BBB is to administer therapeutics directly into the brain parenchyma. To enhance the treatment efficacy for chronic neurodegenerative disorders, repeated administration to the target location is required. However, this increases the number of operations that must be performed. In this study, we developed the IntraBrain Injector (IBI), a new implantable device to repeatedly deliver therapeutics into the brain parenchyma. METHODS: We designed and fabricated IBI with medical grade materials, and evaluated the efficacy and safety of IBI in 9 beagles. The trajectory of IBI to the hippocampus was simulated prior to surgery and the device was implanted using 3D-printed adaptor and surgical guides. Ferumoxytol-labeled mesenchymal stem cells (MSCs) were injected into the hippocampus via IBI, and magnetic resonance images were taken before and after the administration to analyze the accuracy of repeated injection. RESULTS: We compared the planned vs. insertion trajectory of IBI to the hippocampus. With a similarity of 0.990 Ā± 0.001 (mean Ā± standard deviation), precise targeting of IBI was confirmed by comparing planned vs. insertion trajectories of IBI. Multiple administrations of ferumoxytol-labeled MSCs into the hippocampus using IBI were both feasible and successful (success rate of 76.7%). Safety of initial IBI implantation, repeated administration of therapeutics, and long-term implantation have all been evaluated in this study. CONCLUSION: Precise and repeated delivery of therapeutics into the brain parenchyma can be done without performing additional surgeries via IBI implantation.


Subject(s)
Ferrosoferric Oxide , Mesenchymal Stem Cells , Animals , Brain/diagnostic imaging , Brain/surgery , Dogs , Humans , Imaging, Three-Dimensional , Magnetic Resonance Imaging/methods
2.
Int J Mol Sci ; 20(19)2019 Sep 27.
Article in English | MEDLINE | ID: mdl-31569732

ABSTRACT

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.


Subject(s)
Decorin/biosynthesis , Fetal Blood/cytology , Hyaluronan Receptors/blood , Macrophage Activation/immunology , Macrophages/immunology , Macrophages/metabolism , Mesenchymal Stem Cells/metabolism , Animals , Biomarkers , Disease Models, Animal , Fluorescent Antibody Technique , Gene Knockdown Techniques , Humans , Hyperoxia/complications , Lung Injury/diagnosis , Lung Injury/etiology , Lung Injury/metabolism , Lung Injury/therapy , Rats
3.
Biochem Biophys Res Commun ; 504(4): 933-940, 2018 10 12.
Article in English | MEDLINE | ID: mdl-30224067

ABSTRACT

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 (AƟ) in the brain. In such cases, microglia play important roles in regulating the brain AƟ 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 AƟ. In order to identify the associated paracrine factors, a secretome of hUCB-MSCs co-cultured with AƟ-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 AƟ clearance by microglial cells was investigated inĀ vitro and in a 5XFAD mouse model. When AƟ-treated BV2 cells were treated with exogenous recombinant GDF-15, the AƟ levels in the culture medium decreased. Moreover, GDF-15 injection in the brain parenchyma of 5XFAD mice also led to decrease in AƟ plaques. In contrast, co-culture of BV2 cells and hUCB-MSCs treated with GDF-15-specific siRNA did not influence the AƟ 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 TGFƟ receptor type II (TGFƟRII), both inĀ vitro and inĀ vivo. These findings suggest that hUCB-MSCs promote the AƟ clearance ability of microglial cells through regulation of GDF-15 secretion, thus elucidating a therapeutic mechanism for AD.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Growth Differentiation Factor 15/metabolism , Mesenchymal Stem Cells/metabolism , Alzheimer Disease/pathology , Animals , Coculture Techniques , Disease Models, Animal , Fetal Blood/cytology , Growth Differentiation Factor 15/genetics , Growth Differentiation Factor 15/pharmacology , Humans , Insulysin/metabolism , Mesenchymal Stem Cells/cytology , Mice, Mutant Strains , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Paracrine Communication , Peptide Fragments/metabolism , Receptor, Transforming Growth Factor-beta Type II/genetics , Receptor, Transforming Growth Factor-beta Type II/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/pharmacology
4.
Korean J Physiol Pharmacol ; 22(5): 555-566, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30181702

ABSTRACT

Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) are used in tissue repair and regeneration; however, the mechanisms involved are not well understood. We investigated the hair growth-promoting effects of hUCB-MSCs treatment to determine whether hUCB-MSCs enhance the promotion of hair growth. Furthermore, we attempted to identify the factors responsible for hair growth. The effects of hUCB-MSCs on hair growth were investigated in vivo, and hUCB-MSCs advanced anagen onset and hair follicle neogeneration. We found that hUCB-MSCs co-culture increased the viability and up-regulated hair induction-related proteins of human dermal papilla cells (hDPCs) in vitro. A growth factor antibody array revealed that secretory factors from hUCB-MSCs are related to hair growth. Insulin-like growth factor binding protein-1 (IGFBP-1) and vascular endothelial growth factor (VEGF) were increased in co-culture medium. Finally, we found that IGFBP-1, through the co-localization of an IGF-1 and IGFBP-1, had positive effects on cell viability; VEGF secretion; expression of alkaline phosphatase (ALP), CD133, and Ɵ-catenin; and formation of hDPCs 3D spheroids. Taken together, these data suggest that hUCB-MSCs promote hair growth via a paracrine mechanism.

5.
Am J Physiol Renal Physiol ; 313(4): F984-F996, 2017 Oct 01.
Article in English | MEDLINE | ID: mdl-28356286

ABSTRACT

Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUCB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3 Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1 and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2-fold higher than baseline levels) showed no renoprotective effects on day 6 Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AKI progression or alter the intrarenal inflammatory micromilieu.


Subject(s)
Acute Kidney Injury/prevention & control , Antineoplastic Agents/adverse effects , Cisplatin/adverse effects , Immunomodulation , Mesenchymal Stem Cell Transplantation , Acute Kidney Injury/immunology , Animals , Male , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/physiology
6.
Biochem Biophys Res Commun ; 493(1): 751-757, 2017 11 04.
Article in English | MEDLINE | ID: mdl-28859977

ABSTRACT

Due to their widely known therapeutic benefits, mesenchymal stem cells have been proposed as a novel treatment option for a wide range of diseases including Alzheimer's disease. To maximize these benefits, critical factors such as delivery route, cell viability, and cell migration must be accounted for. Out of the various delivery routes to the brain, the intracerebroventricular (ICV) route stands out due to the widespread distribution that can occur via cerebrospinal fluid flow. The major objective of this present study was to observe how altering cell concentration influences the migration and viability of human umbilical cord blood derived-mesenchymal stem cells (hUCB-MSCs), delivered via ICV injection, in the brains of wild-type (WT) mice. C3H/C57 WT mice were divided into three groups and were injected with 1Ā Ć—Ā 105 hUCB-MSCs suspended in varying volumes: high (3Ā Āµl), middle (5Ā Āµl), and low (7Ā Āµl) concentrations, respectively. Lowering the concentration increased the migratory capabilities and elevated the viability of hUCB-MSCs. These results suggest that cell concentration can affect the physiological state of hUCB-MSCs, and thus the extent of therapeutic efficacy that can be achieved.


Subject(s)
Cell Movement/physiology , Cell Survival/physiology , Cerebral Ventricles/cytology , Cerebral Ventricles/physiology , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/physiology , Animals , Cell Count , Cells, Cultured , Humans , Injections, Intraventricular/methods , Mice , Mice, Inbred C3H
7.
Stem Cells ; 33(11): 3291-303, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26235673

ABSTRACT

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.


Subject(s)
Autocrine Communication/physiology , Cell Differentiation/physiology , Chondrogenesis/physiology , Fetal Blood/metabolism , Mesenchymal Stem Cells/metabolism , Thrombospondins/metabolism , Cells, Cultured , Humans , Hypertrophy , Infant, Newborn
8.
J Neurosci Res ; 93(12): 1814-25, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26332684

ABSTRACT

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.


Subject(s)
C-Reactive Protein/metabolism , CD47 Antigen/metabolism , Infarction, Middle Cerebral Artery/therapy , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Recovery of Function/physiology , Serum Amyloid P-Component/metabolism , Vascular Endothelial Growth Factor A/metabolism , Analysis of Variance , Animals , Cells, Cultured , Disease Models, Animal , Humans , In Situ Nick-End Labeling , Nerve Tissue Proteins/metabolism , Rats , Time Factors
9.
J Korean Med Sci ; 30(5): 576-85, 2015 May.
Article in English | MEDLINE | ID: mdl-25931788

ABSTRACT

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.


Subject(s)
Fetal Blood/cytology , Hypertension, Pulmonary/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Animals , Cytokines/metabolism , Disease Models, Animal , Endothelin-1/metabolism , Gene Expression Regulation/drug effects , Hemodynamics , Humans , Hypertension, Pulmonary/chemically induced , Hypertrophy, Right Ventricular/physiopathology , Immunohistochemistry , Lung/metabolism , Lung/pathology , Male , Matrix Metalloproteinase 2/metabolism , Mesenchymal Stem Cells/metabolism , Monocrotaline/toxicity , Nitric Oxide Synthase Type III/metabolism , Pulmonary Artery/pathology , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A/metabolism
10.
Am J Physiol Renal Physiol ; 307(10): F1149-61, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25143451

ABSTRACT

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 Ɨ 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-ƎĀ³ 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.


Subject(s)
Acute Kidney Injury/prevention & control , Mesenchymal Stem Cell Transplantation , Reperfusion Injury/prevention & control , Acute Kidney Injury/immunology , Acute Kidney Injury/metabolism , Animals , Humans , Interferon-gamma/metabolism , Male , Mice, Inbred C57BL , Reperfusion Injury/immunology , Reperfusion Injury/metabolism , T-Lymphocytes/physiology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism
11.
Biochem Biophys Res Commun ; 446(4): 983-9, 2014 Apr 18.
Article in English | MEDLINE | ID: mdl-24657442

ABSTRACT

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 IL2ƎĀ³null (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-ƎĀ³, 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.


Subject(s)
Fetal Blood/cytology , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/immunology , Animals , Antigens, CD34/analysis , Cells, Cultured , Disease Models, Animal , Humans , Immunoglobulin G/immunology , Interferon-gamma/immunology , Lymphocyte Activation , Mice , Mice, SCID , Tumor Necrosis Factor-alpha/immunology
12.
Stem Cells ; 31(10): 2136-48, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23843355

ABSTRACT

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.


Subject(s)
Cell Differentiation , Mesenchymal Stem Cells/metabolism , Thrombospondins/metabolism , Adult , Aged , Animals , Cartilage, Articular/pathology , Cartilage, Articular/physiopathology , Cells, Cultured , Coculture Techniques , Female , Humans , MAP Kinase Signaling System , Male , Mice , Middle Aged , Osteoarthritis, Knee/drug therapy , Osteoarthritis, Knee/pathology , Rabbits , Regeneration , Regenerative Medicine , Synovial Fluid/physiology , Thrombospondins/physiology , Thrombospondins/therapeutic use
13.
Cytotherapy ; 16(3): 298-308, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24418403

ABSTRACT

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 Ɨ 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-Ɵ1 increased significantly, whereas the level of interferon-ƎĀ³ 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.


Subject(s)
Fetal Blood/cytology , Graft vs Host Disease/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Animals , Cells, Cultured , Dinoprostone/metabolism , Disease Models, Animal , Humans , Immunosuppression Therapy , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred Strains , Quality Improvement , Transforming Growth Factor beta1/metabolism , Transplantation, Heterologous
14.
Ann Hematol ; 92(12): 1595-602, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23835655

ABSTRACT

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.


Subject(s)
Graft Survival/physiology , Hematopoietic Stem Cell Transplantation/methods , Mesenchymal Stem Cells/physiology , Adipose Tissue/cytology , Adipose Tissue/physiology , Adipose Tissue/transplantation , Animals , Bone Marrow Cells/physiology , Cell Proliferation , Cells, Cultured , Fetal Blood/physiology , Fetal Blood/transplantation , Humans , Mice , Mice, Inbred NOD , Mice, SCID
15.
J Pediatr Hematol Oncol ; 35(6): e229-33, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23426002

ABSTRACT

Despite advantages of cord blood (CB) cells, such as their high capacity for proliferation and low immunogenicity, CB transplantation is also associated with delayed neutrophil and platelet recovery relative to bone marrow transplantation. These limitations arise from the reduced abundances of primitive hematopoietic stem cells expressing adhesion molecules in CB relative to bone marrow. To address this limitation, we evaluated whether human parathyroid hormone (hPTH) could increase the number of primitive hematopoietic stem cells with adhesion molecules in cryopreserved CB. When cryopreserved CB cells were cocultured with differentiated osteoblasts in the presence of hPTH, numbers of CD34CD38 cells increased 4-fold after 7 days. Exposure to hPTH promoted clonogenic cell expansion and significantly increased the expression of adhesion molecules, such as CD44 (a cell surface glycoprotein) and VLA-4 (α4 integrin) in CD34 cells. This result shows that short-term coculture of cryopreserved CB with differentiated osteoblasts in the presence of hPTH may improve the rate of engraftment of CD34 cells through increasing the abundances of primitive cells bearing adhesion molecules.


Subject(s)
Cell Adhesion Molecules/biosynthesis , Fetal Blood/cytology , Hematopoietic Stem Cells/metabolism , Osteoblasts/cytology , Parathyroid Hormone/metabolism , Cell Differentiation , Coculture Techniques , Cord Blood Stem Cell Transplantation/methods , Cryopreservation , Fetal Blood/metabolism , Hematopoietic Stem Cells/drug effects , Humans , Parathyroid Hormone/pharmacology , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction
16.
Int J Mol Sci ; 14(9): 17986-8001, 2013 Sep 03.
Article in English | MEDLINE | ID: mdl-24005862

ABSTRACT

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.


Subject(s)
Adipose Tissue/cytology , Bone Marrow Cells/cytology , Cell- and Tissue-Based Therapy/methods , Fetal Blood/cytology , Mesenchymal Stem Cells/cytology , Adolescent , Adult , Angiopoietin-1/metabolism , Blotting, Western , Child , Humans , Immunophenotyping , Interleukin-1alpha/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Young Adult
17.
J Transl Med ; 10: 58, 2012 Mar 23.
Article in English | MEDLINE | ID: mdl-22443810

ABSTRACT

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.


Subject(s)
Blood Transfusion/methods , Cerebral Palsy/therapy , Cognition Disorders/prevention & control , Fetal Blood/transplantation , Psychomotor Disorders/prevention & control , Brain/diagnostic imaging , Cerebral Palsy/complications , Cerebral Palsy/diagnostic imaging , Child , Child, Preschool , Cognition Disorders/diagnostic imaging , Cognition Disorders/etiology , Diffusion Tensor Imaging , Feasibility Studies , Female , Humans , Infusions, Intravenous , Magnetic Resonance Imaging , Male , Neurologic Examination , Pilot Projects , Psychomotor Disorders/diagnostic imaging , Psychomotor Disorders/etiology , Radiography , Transfusion Reaction , Transplantation, Autologous/adverse effects
18.
Pediatr Res ; 72(3): 277-84, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22669296

ABSTRACT

BACKGROUND: Severe brain injury induced by neonatal stroke causes significant mortality and disability, and effective therapies are currently lacking. We hypothesized that human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) can attenuate severe brain injury induced by permanent middle cerebral artery occlusion (MCAO) in rat pups. METHODS: After confirming severe brain injury involving more than 50% of the ipsilateral hemisphere volume at 1 h after MCAO using diffusion-weighted magnetic resonance imaging (MRI) in postnatal day (P)10 rats, human UCB-derived MSCs were transplanted intraventricularly. The brain MRI was evaluated periodically up to 28 d after MCAO (P38). Sensorimotor function and histology in the peri-infarct tissues were evaluated at the end of the experiment. RESULTS: Severe brain injury induced by permanent MCAO resulted in decreased survival and body weight gain, increased brain infarct volume as measured by MRI, impaired functional tests such as the rotarod and cylinder test, and histologic abnormalities such as increased terminal deoxynucleotidyl transferase nick-end labeling, reactive microglial marker, and glial fibrillary acidic protein-positive cells in the penumbra. All of these abnormalities were significantly improved by MSC transplantation 6 h after MCAO. CONCLUSION: These results suggest that human UCB-derived MSCs are a promising therapeutic candidate for the treatment of severe perinatal brain injury including neonatal stroke.


Subject(s)
Mesenchymal Stem Cell Transplantation , Middle Cerebral Artery/pathology , Animals , Animals, Newborn , Brain Injuries/prevention & control , Immunohistochemistry , In Situ Nick-End Labeling , Magnetic Resonance Imaging , Rats
19.
J Pediatr Hematol Oncol ; 34(7): 491-6, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23007338

ABSTRACT

Osteoblasts, which are derived from pluripotent mesenchymal stem cells (MSCs), play an important role in hematopoiesis. Human parathyroid hormone (hPTH) induces osteoblasts to produce many factors that are essential to hematopoietic stem cells. However, little is known about the impact of hPTH on MSCs to enhance hematopoiesis. We determined the optimal dose of hPTH that was necessary in vitro for increased osteoblast function. In addition, we compared MSC and osteoblast function to explore the role of hPTH in hematopoiesis. The mRNA expression levels of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 6, stromal cell-derived factor 1, insulin-like growth factor 1 (IGF-1), IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-2, and IGFBP-3 were comparable in osteoblasts and human cord blood-derived MSCs. However, G-CSF, GM-CSF, IGF-2, IGFBP-1, IGFBP-2, and IGFBP-3 expression levels in osteoblasts were markedly increased after treatment with 50 or 100 nM of hPTH. In conclusion, hPTH does not affect the ability of MSCs to differentiate into osteoblasts. In addition, hPTH may enhance hematopoiesis by activating the IGF system (IGF-2, IGFBP-1, IGFBP-2, and IGFBP-3) and hematopoietic growth factors (G-CSF and GM-CSF) in osteoblasts, but not in MSCs.


Subject(s)
Gene Expression Regulation/drug effects , Hematopoiesis/drug effects , Mesenchymal Stem Cells/drug effects , Osteoblasts/drug effects , Parathyroid Hormone/pharmacology , RNA, Messenger/analysis , Somatomedins/genetics , Alkaline Phosphatase/genetics , Cells, Cultured , Granulocyte Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Humans , Mesenchymal Stem Cells/metabolism , Osteoblasts/metabolism
20.
Bioengineering (Basel) ; 9(4)2022 Apr 18.
Article in English | MEDLINE | ID: mdl-35447737

ABSTRACT

Mesenchymal stem cells (MSCs) are one of the most extensively studied stem cell types owing to their capacity for differentiation into multiple lineages as well as their ability to secrete regenerative factors and modulate immune functions. However, issues remain regarding their further application for cell therapy. Here, to demonstrate the superiority of the improvement of MSCs, we divided umbilical cord blood-derived MSCs (UCB-MSCs) from 15 donors into two groups based on efficacy and revealed donor-dependent variations in the anti-inflammatory effect of MSCs on macrophages as well as their immunoregulatory effect on T cells. Through surface marker analyses (242 antibodies), we found that HLA-A2 was positively related to the anti-inflammatory and immunoregulatory function of MSCs. Additionally, HLA-A2 mRNA silencing in MSCs attenuated their therapeutic effects in vitro; namely, the suppression of LPS-stimulated macrophages and phytohemagglutinin-stimulated T cells. Moreover, HLA-A2 silencing in MSCs significantly decreased their therapeutic effects in a rat model of hyperoxic lung damage. The present study provides novel insights into the quality control of donor-derived MSCs for the treatment of inflammatory conditions and diseases.

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