Tianjin, China
Tianjin, China

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Wang Y.,Peking Union Medical College | Han Z.-B.,Peking Union Medical College | Ma J.,JOINN Laboratories | Zuo C.,JOINN Laboratories | And 10 more authors.
Stem Cells and Development | Year: 2012

Therapies based on stem cells have shown very attractive potential in many clinical studies. However, the data about the safety of stem cells application remains insufficient. The present study was designed to evaluate the overall toxicology of human umbilical cord mesenchymal stem cells (hUC-MSCs) in cynomolgus monkeys with repeated administrations. hUC-MSCs were administered by intravenous injection once every 2 weeks for 6 weeks. The dose levels employed in this study were 2×10 6, 1×10 7 cells/kg body weight. Toxicity was evaluated by clinical observations (body weight, body temperature, and ophthalmology exams), pathology (blood cell counts, clinical biochemistry, urinalysis, and bone marrow smears), immunologic consequences (lymphoproliferation assay, the secretion of interferon-γ and interleukin-4, the percentage of CD3, CD4, CD8 T cells, and the ratio of CD4 and CD8 T cells) and anatomic pathology. Pharmacodynamics in blood and distribution of hUC-MSCs in the tissues of cynomolgus monkeys were measured by real-time polymerase chain reaction. All animals survived until scheduled euthanasia. No stem cells transplantation-related toxicity was found in this study. hUC-MSCs could be found in the blood of cynomolgus monkeys beyond 8 h. The findings of this 6-week toxicity study showed that the transplantation of hUC-MSCs did not affect the general health of cynomolgus monkeys. © Copyright 2012, Mary Ann Liebert, Inc.


Chen K.,Peking Union Medical College | Chen K.,Chinese Academy of Sciences | Wang D.,Peking Union Medical College | Wang D.,Chinese Academy of Sciences | And 12 more authors.
Clinical Immunology | Year: 2010

Human umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) constitute an attractive alternative to bone-marrow-derived MSCs for potential clinical applications because of easy preparation and lower risk of viral contamination. In this study, both proliferation of human peripheral blood mononuclear cells (hPBMCs) and their IFN-γ production in response to mitogenic or allogeneic stimulus were effectively inhibited by hUC-MSCs. Co-culture experiments in transwell systems indicated that the suppression was largely mediated by soluble factor(s). Blocking experiments identified prostaglandin E2 (PGE2) as the major factor, because inhibition of PGE2 synthesis almost completely mitigated the immunosuppressive effects, whereas neutralization of TGF-β, IDO, and NO activities had little effects. Moreover, the inflammatory cytokines, IFN-γ and IL-1β, produced by hPBMCs upon activation notably upregulated the expression of cyclooxygenase-2 (COX-2) and the production of PGE2 by hUC-MSCs. In conclusion, our data have demonstrated for the first time the PGE2-mediated mechanism by which hUC-MSCs exert their immunomodulatory effects. © 2010 Elsevier Inc. All rights reserved.


Gong W.,AmCellGene Co. | Han Z.,Peking Union Medical College | Zhao H.,AmCellGene Co. | Zhao H.,Tianjin University of Commerce | And 7 more authors.
Cell Transplantation | Year: 2012

A great deal of interest has arisen recently with respect to human mesenchymal stem cells (MSCs), due to their broad therapeutic potential. However, the safety and efficacy of MSCs expanded ex vivo for clinical applications remain a concern. In this article, we establish a standardized process for manufacture of human umbilical cord-derived MSCs (UC-MSCs), which encompasses donor screening and testing, recovery, twostage expansion, and administration. The biological properties and safety of UC-MSCs were then characterized and tested. The safety data from use in human patients have also been reported. After clinical-scale expansion, a yield of 1.03-3.78 × 10 8 MSCs was achieved in 10 batch manufacturing runs. The biological properties, such as plastic adherence, morphology, specific surface antigen (CD105, CD73, CD90, positive ≥ 95%; CD45, CD34, CD31, CD11b, CD19, HLA-DR, negative ≤2%), and multipotent differentiation potential (osteogenesis and adipogenesis) were retained. Bacterial and mycoplasma tests were negative and endotoxin levels were lower than 2 EU/ml. No adverse events were noted in two patients treated with intravenously and/or intrathecally administered MSCs. The data obtained indicate that banking UC-MSCs for clinical use is feasible. © 2012 Cognizant Comm. Corp.


Wang D.,Peking Union Medical College | Wang D.,Chinese Academy of Sciences | Chen K.,Peking Union Medical College | Chen K.,Chinese Academy of Sciences | And 12 more authors.
Experimental Cell Research | Year: 2010

Here, the effect of CD14+ monocytes on human umbilical cord matrix stem cell (hUC-MSC)-mediated immunosuppression was studied in vitro. hUC-MSCs exerted a potent inhibitory effect on the proliferation and interferon-γ (IFN-γ) secretion capacities of CD4+ and CD8+ T cells in response to anti-CD3/CD28 stimulation. Transwell co-culture system revealed that the suppressive effect was primarily mediated by soluble factors. Addition of prostaglandin synthesis inhibitors (indomethacin or NS-398) almost completely abrogated the immunosuppression activity of hUC-MSCs, identifying prostaglandin E2 (PGE2) as an important soluble mediator. CD14+ monocytes were found to be able to enhance significantly the immunosuppressive effect of hUC-MSCs in a dose-dependent fashion. Moreover, the inflammatory cytokine IL-1β, either exogenously added or produced by CD14+ monocytes in culture, could trigger expression of high levels of PGE2 by hUC-MSCs, whereas inclusion of the IL-1 receptor antagonist (IL-1RA) in the culture down-regulated not only PGE2 expression, but also reversed the promotional effect of CD14+ monocytes and partially restored CD4+ and CD8+ T cell proliferation and IFN-γ secretion. Our data demonstrate an important role of monocytes in the hUC-MSC-induced immunomodulation, which may have important implications in future efforts to explore the clinical potentials of hUC-MSCs. © 2010 Elsevier Inc.


Sun J.,Peking Union Medical College | Han Z.-B.,Peking Union Medical College | Han Z.-B.,AmCellGene Co. | Liao W.,Peking Union Medical College | And 7 more authors.
Cellular Physiology and Biochemistry | Year: 2011

Background: Systemic and local inflammatory processes play key, mainly detrimental roles in the pathophysiology of acute lung injury (ALI). The present study was designed to determine whether human umbilical cord mesenchymal stem cells (UCMSC) are able to act on CD4+CD25+ Foxp3 +Treg cells and lead to an improvement in ALI. Methods: Mice were administered intratracheally endotoxin (lipopolysaccharide [LPS]) and received intrapulmonary 1×106 UCMSC 4 hours after challenge. The CD4+CD25+ Foxp3+Treg, survival time, body weight, histology and lung injury scores were assessed after transplantation of UCMSC. In addition, anti-inflammatory factor IL10 and pro-inflammatory mediators production including tumor necrosis factor-a (TNF-α), macrophage inflammatory protein-2(MIP-2) and interferon-γ (IFN-γ) were detected. Results: Transplantation of UCMSC resulted in significant increase in the level of CD4+CD25+ Foxp3+Treg in ALI. Increased level of anti-inflammatory factor IL-10 and reduced levels of TNF-α, MIP-2 and IFN-γ were simultaneously observed in ALI in comparison with control mice. Conclusion: Our data demonstrate for the first time that transplantation of UCMSC ameliorates ALI by enhancing the diminished levels of alveolar CD4+CD25+ Foxp3+Treg and balancing anti- and pro-inflammatory factors in ALI mice. © 2011 S. Karger AG, Basel.


Liang L.,Peking Union Medical College | Dong C.,Peking Union Medical College | Chen X.,Peking Union Medical College | Fang Z.,Peking Union Medical College | And 8 more authors.
Cell Transplantation | Year: 2011

Mesenchymal stem cells (MSCs), which are poorly immunogenic and have potent immunosuppressive activities, have emerged as a promising candidate for cellular therapeutics for the treatment of disorders caused by abnormal immune responses. In this study we investigated whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could ameliorate colitis in a trinitrobenzene sulfonic acid (TNBS)-induced colitis model. TNBS-treated colitic mice were infused with hUC-MSCs or vehicle control. The mice were sacrificed on day 1, 3, and 5 after infusion, and their clinical and pathological conditions were evaluated by body weight, colon length, and histological analysis. The expression levels of proinflammatory cytokine proteins in colon were examined by ELISA. The homing of hUC-MSCs was studied by live in vivo imaging and immunofluorescent microscopy. hUC-MSCs were found to migrate to the inflamed colon and effectively treated the colitic mice with improved clinical and pathological signs. The levels of IL-17 and IL-23 as well as IFN-γ and IL-6 were significantly lower in the colon tissues of the hUC-MSC-treated mice in comparison with the vehicle-treated mice. Coculture experiments showed that hUC-MSCs not only could inhibit IFN-γ expression but also significantly inhibit IL-17 production by lamina propria mononuclear cells (LPMCs) or splenocytes of the colitic mice or by those isolated from normal animals and stimulated with IL-23. Systemically infused hUC-MSCs could home to the inflamed colon and effectively ameliorate colitis. In addition to the known suppressive effects on Th1-type immune responses, hUC-MSC-mediated modulation of IL-23/ IL-17 regulated inflammatory reactions also plays an important role in the amelioration of colitis. © 2011 Cognizant Comm. Corp.


Liu J.-F.,Guiyang Medical College | Liu J.-F.,The General Hospital of Huabei Oil Field Company | Du Z.-D.,Capital Medical University | Chen Z.,Capital Medical University | And 2 more authors.
Experimental and Therapeutic Medicine | Year: 2013

Granulocyte colony-stimulating factor (G-CSF) has exhibited efficacy at preventing the progression of pulmonary hypertension (PH); however, the exact mechanism is not completely clear. The aim of the present study was to assess whether this protective effect was mediated by the upregulation of circulating endothelial progenitor cells (EPCs) via the nitric oxide (NO) system. PH was induced in male Sprague-Dawley (SD) rats by the administration of a single subcutaneous injection of monocrotaline (MCT). The rats were treated with recombinant human G-CSF (rhG-CSF, 50 μg/kg/day) by subcutaneous injection from day five to day seven subsequent to the injection of MCT. Nω-nitro-L-arginine methyl ester (L-NAME, 4 mg/kg/day) was intragastrically administered in addition to rhG-CSF as a negative intervention. The changes in hemodynamics and histology, the number and function of circulating EPCs and the concentration of plasma NO were evaluated. With the occurrence of PH in the rat model, the number and function of circulating EPCs were demonstrated to be markedly downregulated. Moreover, a reduced plasma concentration of NO was observed, which was positively correlated with the number of circulating EPCs. Administration of rhG-CSF elevated the plasma level of NO, upregulated the number and function of circulating EPCs and effectively improved pulmonary hemodynamics and vascular reconstruction. Furthermore, the positive correlation between the levels of plasma NO and circulating EPCs was also observed in the rhG-CSF treatment group. However, the protective effect of rhG-CSF in PH was attenuated by L-NAME, which mediated the downregulation of NO and the EPCs. Thus, the present study suggests that G-CSF may attenuate the progression of MCT-induced PH by improving vascular injury repair mechanisms via the NO-mediated upregulation of EPCs.


Liu J.,Guiyang Medical College | Liu J.,The General Hospital of Huabei Oil Field Company | Han Z.,AmCellGene Co. | He Z.,Guiyang Medical College
Experimental and Therapeutic Medicine | Year: 2015

Inflammation and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered the primary pathological feature of pulmonary hypertension (PH). The present study determined that mesenchymal stem cells (MSCs) suppress the expression of calcineurin (CaN) and nuclear factor of activated T‑cells (NFAT) in the pulmonary arteries of rats, and this may exert a therapeutic effect on PH. The potential therapeutic effects of MSCs on PH were assessed via the transplantation of human umbilical cord‑derived MSCs, which were cultured in serum‑free medium, into a monocrotaline (MCT)‑induced PH rat model. Subsequently, the expression levels of tumor necrosis factor (TNF)‑α in lung tissue and plasma, and of CaN and NFATc2 in pulmonary arteries were assessed. In the rat model of MCT‑induced PH, investigated in the present study, TNF‑α expression levels were detected in the lung tissue, and the levels of TNF‑α in the plasma were increased. Furthermore, in addition to hemodynamic changes and the evident medial hypertrophy of the pulmonary muscular arterioles, CaN and NFATc2 expression levels were significantly upregulated in the pulmonary arteries. In the present study, the transplantation of MSCs, cultured in serum‑free medium, decreased the levels of TNF‑α in the lung tissue and plasma of rats, and downregulated CaN and NFATc2 expression in the pulmonary arteries. Furthermore, hemodynamic abnormalities and medial hypertrophy of the pulmonary muscular arterioles were notably improved. Therefore, the results of the present study may suggest that the administration of MSCs in PH may suppress the production of TNF‑α, and downregulate the expression of CaN and NFATc2 in pulmonary arteries, which may provide an effective treatment for PH by suppressing the pathological proliferation of PASMCs. © 2015, Spandidos Publications. All rights reserved.


PubMed | General Engineering Company, Affiliated Hospital of Guiyang Medical College and AmCellGene Co.
Type: Journal Article | Journal: Experimental and therapeutic medicine | Year: 2016

Inflammation-associated overproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered to be involved in the pathogenesis of pulmonary hypertension (PH). The administration of mesenchymal stem cell-conditioned media (MSC-CM) has displayed benefits in the treatment of PH, however, the exact mechanism has yet to be elucidated. The present study aimed to determine whether MSC-CM is able to suppress overproliferation of PASMCs in PH via immunoregulation. By the administration of MSC-CM to monocrotaline (MCT)-induced PH rats, and the development of an


PubMed | P.A. College, General Engineering Company and AmCellGene Co.
Type: Journal Article | Journal: Experimental and therapeutic medicine | Year: 2015

Inflammation and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered the primary pathological feature of pulmonary hypertension (PH). The present study determined that mesenchymal stem cells (MSCs) suppress the expression of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT) in the pulmonary arteries of rats, and this may exert a therapeutic effect on PH. The potential therapeutic effects of MSCs on PH were assessed via the transplantation of human umbilical cord-derived MSCs, which were cultured in serum-free medium, into a monocrotaline (MCT)-induced PH rat model. Subsequently, the expression levels of tumor necrosis factor (TNF)- in lung tissue and plasma, and of CaN and NFATc2 in pulmonary arteries were assessed. In the rat model of MCT-induced PH, investigated in the present study, TNF- expression levels were detected in the lung tissue, and the levels of TNF- in the plasma were increased. Furthermore, in addition to hemodynamic changes and the evident medial hypertrophy of the pulmonary muscular arterioles, CaN and NFATc2 expression levels were significantly upregulated in the pulmonary arteries. In the present study, the transplantation of MSCs, cultured in serum-free medium, decreased the levels of TNF- in the lung tissue and plasma of rats, and downregulated CaN and NFATc2 expression in the pulmonary arteries. Furthermore, hemodynamic abnormalities and medial hypertrophy of the pulmonary muscular arterioles were notably improved. Therefore, the results of the present study may suggest that the administration of MSCs in PH may suppress the production of TNF-, and downregulate the expression of CaN and NFATc2 in pulmonary arteries, which may provide an effective treatment for PH by suppressing the pathological proliferation of PASMCs.

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