Shenzhen Beike Cell Engineering Research Institute

Shenzhen, China

Shenzhen Beike Cell Engineering Research Institute

Shenzhen, China
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Yang W.-Z.,Guangdong Medical College | Zhang Y.,Shenzhen Beike Cell Engineering Research Institute | Wu F.,Guangdong Medical College | Min W.-P.,University of Western Ontario | And 7 more authors.
Journal of Translational Medicine | Year: 2010

Background: The current paradigm for cord blood transplantation is that HLA matching and immune suppression are strictly required to prevent graft versus host disease (GVHD). Immunological arguments and historical examples have been made that the use of cord blood for non-hematopoietic activities such as growth factor production, stimulation of angiogenesis, and immune modulation may not require matching or immune suppression.Methods: 114 patients suffering from non-hematopoietic degenerative conditions were treated with non-matched, allogeneic cord blood. Doses of 1-3 × 107cord blood mononuclear cells per treatment, with 4-5 treatments both intrathecal and intravenously were performed. Adverse events and hematological, immunological, and biochemical parameters were analyzed for safety evaluation.Results: No serious adverse effects were reported. Hematological, immunological, and biochemical parameters did not deviate from normal ranges as a result of therapy.Conclusion: The current hematology-based paradigm of need for matching and immune suppression needs to be revisited when cord blood is used for non-hematopoietic regenerative purposes in immune competent recipients. © 2010 Yang et al; licensee BioMed Central Ltd.

Wang X.H.,Shandong University | Wang X.H.,Chinese University of Hong Kong | Lu G.,Chinese University of Hong Kong | Hu X.,Chinese University of Hong Kong | And 10 more authors.
BMC Neuroscience | Year: 2012

Background: Gait deficits are important clinical symptoms of Parkinson's disease (PD). However, existing behavioral tests for the detection of motor impairments in rodents with systemic dopamine depletion only measure akinesia and dyskinesia, and data focusing on gait are scarce. We evaluated gait changes in the methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced C57BL/6 murine model of PD by using a computer-assisted CatWalk system. Correlations of gait parameters with tyrosine hydroxylase (TH) protein levels in the substantia nigra (SN) were also investigated.Results: The gait readouts, including the walking duration, variation of walking speed, step cycle, duty cycle, stance, initial dual stance, terminal dual stance, three- and four-point supports, and the base of support between hind limbs was noted to increase significantly one week after MPTP injection. In contrast, values of the stride length, cadence, swing speed, and diagonal dual support decreased substantially following MPTP treatment (p < 0.05). All of these changes lasted for three weeks after the last MPTP administration. Except for the stance in the fore limbs and the swing speed in the hind limbs, the gait variability in the PD mice showed a closer correlation with the protein levels of TH in the SN than the walking distances in the conventional open field test. Coordination parameters of the regularity index and step pattern were not affected in mice treated with MPTP.Conclusion: Data of the study suggest that the computer-assisted CatWalk system can provide reliable and objective criteria to stratify gait changes arising from MPTP-induced bilateral lesions in C57/BL6 mice. The extent of gait changes was noted to correlate with the expression of the biomarker for dopaminergic neurons. This novel analytical method may hold promise in the study of disease progression and new drug screening in a murine PD model. © 2012 Wang et al.; licensee BioMed Central Ltd.

Liu Y.,Kunming Medical University | Liu Y.,Chinese University of Hong Kong | Ao L.J.,Kunming Medical University | Lu G.,Chinese University of Hong Kong | And 10 more authors.
Behavioural Brain Research | Year: 2013

Gait analysis is a systematic collection of quantitative information on bodily movements during locomotion. Gait analysis has been employed clinically in stroke patients for their rehabilitation planning. In animal studies, gait analysis has been employed for the assessment of their locomotive disturbances in ischemic stroke, spinal cord injury and Parkinson's disease. The aims of the work reported here were to identify the gait parameters, collected from the computer-generated CatWalk System, that change after unilateral intracerebral hemorrhage (ICH) in the acute stage and long term up to 56 days post-ICH. The results showed that with the collagenase-induced unilateral striatal lesion, the rats displayed a significant contralateral decrease in print and maximum contact area and paw intensity, a diagonal increase in the stance duration of the left front and right hind paws, a significant decrease in the stride length of all four limbs, and foot pattern instability as reflected by the base of support, support on styles, and cadence. These deficits, including those in print area, stance and pressure, were demonstrated throughout the long-term period following ICH. The correlations between the gait parameters, lesion volume and asymmetrical forelimb use were also reported in this paper. This work has provided a systematic description on gait parameters in the classical striatal ICH model, which might become an essential assessment tool in future studies of pathophysiology and the development of novel treatments for experimental unilateral intracerebral hemorrhage with gait deficits. © 2013 The Authors.

Di G.-H.,Tianjin University | Jiang S.,Shenzhen Beike Cell Engineering Research Institute | Li F.-Q.,Beijing Institute of Radiation Medicine | Sun J.-Z.,Chinese PLA General Hospital | And 4 more authors.
Cytotherapy | Year: 2012

Background aims. Mesenchymal stromal cells (MSC) have been shown to be a promising candidate for tissue regeneration and cancer therapy. However, their therapeutic potential against chemotherapy-induced side-effects remains unclear. Methods. We treated murine Lewis lung carcinoma (LLC) and xenograft human colon tumors with adriamycin (ADM) for 3 consecutive days followed by one intravenous (i.v.) injection of human umbilical cord (hUC) MSC for several cycles. Results. MSC treatment mitigated ADM-induced cardiomyopathy, reduced the extent of ADM-induced apoptosis in intestinal crypts, suppressed body weight loss in mice treated with ADM and increased the survival rate of mice treated with a lethal dose of ADM. The examination of hematologic parameters indicated a moderate recovery in MSC-injected mice. Systemic administration of MSC did not increase the growth of murine LLC cells and human colon carcinoma in vivo while it strongly inhibited the lung metastases of LLC cells. Conclusions. We evaluated the prophylactic and therapeutic action of hUC MSC on the chemotherapy agent ADM-induced side-effects in two different tumor models. Our observations suggest that MSC can be used as auxiliary means in chemotherapy for certain tumor types. © 2012 Informa Healthcare.

Mesples A.,Diabetes Education and Research | Majeed N.,Shenzhen Beike Cell Engineering Research Institute | Zhang Y.,Shenzhen Beike Cell Engineering Research Institute | Xiang H.,Diabetes Education and Research
Medical Science Monitor | Year: 2013

Background: Bone marrow stem cell treatment has been proven a promising therapeutic strategy and showed significant results given the strong immune modulating properties. We have investigated the safety and efficacy of autologous bone marrow stem cell transplantation through liver puncture in two patients with recently diagnosed type 1 diabetes mellitus. Material/Methods: The procedure was approved by the Institutional Ethics Committee. In 2011, in three young patients, type 1 diabetes mellitus diagnosis was confirmed, with the presence of positive antibodies and ketoacidosis. Two patients was treated with autologous bone marrow stem cell stimulated with filgrastim and transplantation, through liver puncture, as immune modulators. One patients was treated with conventional treatment and participate in this experiment as a control group. The families of the patients signed the informed consent. No specific statistical analysis was performed. The patients had less than 8 years old, diagnosis of type 1 diabetes for less than 60 days, body mass index less than 22 kg/m2, normal complete blood count, coagulation and renal function, no lesions in target organs, glycosylated hemoglobin (HbA1c) level less than 13.70%, c-peptide level less than 0.67 ng/ml, positive results of Islets Cells Antibody (ICA), Glutamic Acid Decarboxylase (GAD) and insulin antibody. Results: Conclusions: In two patients treated, the follow up at 12 months showed negative value in ICA, GAD and anti insulin antibody levels, with an increased levels of c peptide and decreased levels of blood glucose and HbA1c. PERSONAONLY Treatment with autologous bone marrow stem cells is easy and effective as it reversed the production and effect of anti pancreatic islet antibody and significantly resulted in an increased c-peptide concentration. © Med Sci Monit, 2013.

Jiang B.,Central South University | Zhang P.,Central South University | Zhou D.,Central South University | Zhang J.,Shenzhen Beike Cell Engineering Research Institute | And 2 more authors.
PLoS ONE | Year: 2013

Objectives:To treat traumatic optic neuropathy (TON) with transplantation of human umbilical cord blood stem cells (hUCBSC) and explore how transplanted stem cells participate in the neuron repairing process.Methods:A total of 195 Sprague-Dawley rats were randomly assigned to three groups: sham-surgery, optic nerve injury, and stem cell transplant group. Optic nerve injury was established in rats by directly clamping the optic nerve for 30 seconds. hUCBSC was microinjected into the vitreous cavity of injured rats. Optic nerve function was evaluated by flash visual evoked potentials (F-VEP). Apoptosis in retina tissues was detected by TUNEL staining. GRP78 and CHOP gene expression was measured by RT-PCR.Results:After injury, transplantation of hUCBSC significantly blunted a reduction in optic nerve function indicated by smaller decreases in amplitude and smaller increases in peak latency of F-VEP waveform compared to the injury alone group. Also, significant more in retinal ganglion cell (RGC) count and less in RGC apoptosis were detected after transplantation compared to injured rats. The protective effect correlated with upregulated GRP78 and downregulated CHOP mRNA expression.Conclusion:Intravitreal transplantation of hUCBSCs significantly blunted a reduction in optic nerve function through increasing RGC survival and decreasing retinal cell apoptosis. The protective role of transplantation was associated with upregulation of GRP78 expression and downregulation of CHOP expression in retinal cells. © 2013 Jiang et al.

Li T.,Shenzhen Beike Cell Engineering Research Institute | Li T.,Jilin University | Li T.,Stanford University | Chen H.,Central South University | And 8 more authors.
Human Molecular Genetics | Year: 2014

Aberrant imprinting of the insulin-like growth factor II (IGF2) gene is a molecular hallmark of many tumors. Reactivation of thenormally suppressed maternal allele leads to upregulation of the growth factor that promotes tumor growth. However, the mechanisms underlying the loss of imprinting (LOI) remain poorly defined. We examined the epigenotypes at the gene promoters that control IGF2 allelic expression. Using chromatin immunoprecipitation,wefound that in cells characterized by maintenance of IGF2 imprinting, three IGF2promoters were differentiallymodified, with the suppressed allele heavily methylated at histone H3K27 while the active allelewasunmethylated. In the LOI tumors,however, both alleleswere unmethylated,andcorrespondingly there wasnobinding of SUZ12, the docking factor of thepolycomb repressive complex 2 (PRC2),andof the zinc fingercontaining transcription factor (CTCF) that recruits the PRC2. Using chromatin conformation capture, we found that the CTCF-orchestrated intrachromosomal loop between the IGF2 promoters and the imprinting control region was abrogated in cells with LOI. SUZ12, which docks the PRC2 to IGF2 promoters for H3K27 methylation, was downregulated in LOI cells. These data reveal a new epigenetic control pathway related to the loss of IGF2 imprinting in tumors. © The Author 2013. Published by Oxford University Press. All rights reserved.

PubMed | Guangzhou University, Shenzhen Beike Cell Engineering Research Institute and Saban Research Institute
Type: Journal Article | Journal: Stem cell research & therapy | Year: 2016

Interstitial pneumonia in connective tissue diseases (CTD-IP) featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells (MSCs) may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders.Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts (HLFs) from patients pathologically diagnosed with usual interstitial pneumonia (UIP) and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals (HBMSCs) on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro.Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell (Treg) level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of -smooth muscle actin (-SMA). The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis (IPF). HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked -SMA activation in CTD-UIP HLFs through a TGF-1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice.Impairment of TGF- signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.

PubMed | Shenzhen Beike Cell Engineering Research Institute, Jinan University, Sun Yat Sen University and Guangzhou University
Type: | Journal: Molecular psychiatry | Year: 2016

The enteric nervous system (ENS) is recognized as a second brain because of its complexity and its largely autonomic control of bowel function. Recent progress in studying the interactions between the ENS and the central nervous system (CNS) has implicated alterations of the gut/brain axis as a possible mechanism in the pathophysiology of autism spectrum disorders (ASDs), Parkinsons disease (PD) and other human CNS disorders, whereas the underlying mechanisms are largely unknown because of the lack of good model systems. Human induced pluripotent stem cells (hiPSCs) have the ability to proliferate indefinitely and differentiate into cells of all three germ layers, thus making iPSCs an ideal source of cells for disease modelling and cell therapy. Here, hiPSCs were induced to differentiate into neural crest stem cells (NCSCs) efficiently. When co-cultured with smooth muscle layers of ganglionic gut tissue, the NCSCs differentiated into different subtypes of mature enteric-like neurons expressing nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), choline acetyltransferase (ChAT) or calretinin with typical electrophysiological characteristics of functional neurons. Furthermore, when they were transplanted into aneural or aganglionic chick, mouse or human gut tissues in ovo, in vitro or in vivo, hiPSC-derived NCSCs showed extensive migration and neural differentiation capacity, generating neurons and glial cells that expressed phenotypic markers characteristic of the enteric nervous system. Our results indicate that enteric NCSCs derived from hiPSCs supply a powerful tool for studying the pathogenesis of gastrointestinal disorders and brain/gut dysfunction and represent a potentially ideal cell source for enteric neural transplantation treatments.Molecular Psychiatry advance online publication, 25 October 2016; doi:10.1038/mp.2016.191.

PubMed | Chinese University of Hong Kong, South University of Science and Technology of China and Shenzhen Beike Cell Engineering Research Institute
Type: Journal Article | Journal: PloS one | Year: 2017

Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5) in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-B and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-B inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.

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