器官移植

2017 Vol. 8, No. 2

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Editorials
Academic Summaries
Experimental Researches
Clinical Researches
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Editorials

2017, 8(2): 85-88. doi: 10.3969/j.issn.1674-7445.2017.02.001

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2017, 8(2): 89-98. doi: 10.3969/j.issn.1674-7445.2017.02.002

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Academic Summaries

Visualization analysis of research highlights and frontiers in deceased organ donation from 2006 to 2016

Luo Aijing, Deng Xuantong, Xie Wenzhao, Wan Qiquan

2017, 8(2): 99-105. doi: 10.3969/j.issn.1674-7445.2017.02.003

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Objective To investigate the research focuses and developmental trends of deceased organ donation by visualization analyzed in English literatures data from 2006 to 2016. Methods The research strength, high impact authors, core journals, high frequency keywords and burst terms related to deceased organ donation from the Web of Science database were statistically analyzed by using CiteSpace. Results A total of 1 278 relevant literatures revealed that the research strength was mainly distributed in the United States with a total quantity of 497 papers, accounting for 28% of the total quantity from 2006 to 2016. Both Ploeg RJ and Parrilla P published 14 papers. The papers written by Kootstra G were the most cited for 192 times. The papers published in Am J Transplant were cited for 917 times. The high frequency keywords included organ donation, transplantation, donation, etc. The high frequency burst terms included waiting-list, beating donor, donor-kidneys, etc. Conclusions In recent decade, the research highlights of deceased organ donation mainly include survival rate of transplantation with donation after cardiac death, prognosis of transplantation with deceased organ donation and preservation techniques of donor organ in deceased organ donation, etc. The research frontiers focus on deceased organ donation rates, the source of donor organ, standard and extended standard of deceased organ donation, etc.

2017, 8(2): 106-114. doi: 10.3969/j.issn.1674-7445.2017.02.004

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Experimental Researches

Study on SCARB1 mediated coagulation dysregulation in recipients after liver xenotransplantation

Li Xiao, Ji Hongchen, Dou Kefeng, Pan Dengke, Chen Hui, Zhou Liang, Tao Kaishan, Liu Zhengcai

2017, 8(2): 115-120. doi: 10.3969/j.issn.1674-7445.2017.02.005

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Objective To investigate the changes in the expression levels of scavenger receptor class B member 1 (SCARB1) in the liver tissues before and after liver xenotransplantation and analyze the relationship between the variations in the SCARB1 expression and coagulation regulating dysfunction in the recipients. Methods The Wuzhishan miniature pig with α-1, 3-galactosyl-transferase gene-knockout (GTKO) was utilized as the donor and Macaca thibetana was chosen as the recipient. Heterotopic auxiliary liver xenotransplantation models were established. The liver tissue specimen was collected before and after liver xenotransplantation. Primary hepatocytes were extracted from the pig using collagenase digestion method. Human peripheral blood mononuclear cells were obtained by immunomagnetic bead sorting. These two types of cells were co-cultured and supplemented with human plasma to establish cell models with coagulation regulating dysfunction following liver xenotransplantation. Quantitative real-time polymerase chain reaction (RT-PCR) and Western blot were performed to quantitatively measure and statistically compared the expression levels of messenger ribonucleic acid (mRNA) and protein of SCARB1 in the tissue and cell samples. At the cellular level, the expression of SCARB1 was interfered by lentiviral vector. The coagulation time was detected to validate the effect upon coagulation function. Results The expression levels of SCARB1 mRNA and protein were significantly down-regulated after liver xenotransplantation (both P < 0.05). In the cell models, the expression levels of SCARB1 mRNA and protein in the porcine hepatocytes co-cultured with human monocytes were significantly down-regulated compared with those in porcine hepatocytes without intervention (both P < 0.05). Compared with the non-intervention group, the coagulation time was significantly prolonged after the expression of SCARB1 was interfered by lentiviral vector (P < 0.05). Conclusions The down-regulated expression of SCARB1 in the liver graft is one of the main causes of mediating coagulation regulating dysfunction. Intervention of SCARB1 expression contributes to resolve the coagulation regulating dysfunction in the recipients after liver xenotransplantation.

Breeding and identification of Wuzhishan miniature pigs with α-1, 3 galactosyltransferase gene-knockout

Long Chuan, Gao Jingbo, Tang Yuting, Du Minjie, Shi Ningning, Feng Chong, Lu Lin, Pan Dengke

2017, 8(2): 121-126. doi: 10.3969/j.issn.1674-7445.2017.02.006

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Objective To summarize the breeding and identification of Wuzhishan miniature pig models with α-1, 3 galactosyltransferase (GGTA1) gene-knockout (GTKO). Methods The breeding and reproduction perform of GTKO Wuzhishan miniature pigs were assessed and the quantity of piglets was counted. The GTKO Wuzhishan miniature pig models with GGTA1gene knockout were validated by polymerase chain reaction (PCR). The αGal phenotype of peripheral blood mononuclear cells (PBMC) in human, wild-type Wuzhishan miniature pigs and GTKO Wuzhishan miniature pigs was detected by fluorescent microscope and flow cytometry. Routine blood test parameters were statistically compared between the GTKO and wild-type Wuzhishan miniature pigs. Results The inheritance of GGTA1 genotype complied with Mendel's law. Flow cytometry detected no fluorescent expression of PBMC in GGTA1^－/－ pig models, which were consistent with the genotype identification results. The mean piglets of the primiparous GTKO Wuzhishan miniature pigs were (6.8±1.8) and (8.3±2.2) for the multiparous Wuzhishan miniature pigs. No statistical significance was noted in routine blood test parameters between the GTKO and wild-type Wuzhishan miniature pigs (all P>0.05). Conclusions Stable inheritance and normal reproductive capacity are observed in two generations of Wuzhishan miniature pigs continuously. GTKO Wuzhishan miniature pig is a reliable donor for heterogeneous organ transplantation.

Monitoring of immune rejection after abdominal aortic patch suture in cynomolgus monkeys

Zhao Chengjiang, Ye Xuejun, Chen Jiao, Zhang Hancheng, Zhou Huidong, Zou Zhicheng, Cai Zhiming, Mou Lisha

2017, 8(2): 127-131. doi: 10.3969/j.issn.1674-7445.2017.02.007

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Objective To establish a platform to monitor the immune rejection after abdominal aortic patch suture in a xenotransplantation model. Methods The carotid was excised from wild-type Guangxi Bama pigs, cut into 2.5 cm × 1.0 cm pieces in shuttle shape and subsequently sutured to the abdominal aorta of cynomolgus monkeys. No immunosuppressive agent was administered. General conditions of the recipient monkeys were observed. The morphological changes of the graft artery were assessed by pathological examination at postoperative 1 year. Before and 7, 14, 28 and 49 d after surgery, the blood samples were collected from the recipient monkeys. The serum levels of IgM and IgG antibodies were quantitatively measured by the red blood cell and peripheral blood mononuclear cell (PBMC) from Guangxi Bama pigs. The quantity of lymphocytes in the recipient monkeys was detected by routine blood test and flow cytometry. Results All 3 monkeys undergoing transplantation survived well. At postoperative 1 year, the lateral tissues of the vascular wall at the artery graft were seen in dark red color. Hematoxylin-eosin (HE) staining revealed a large quantity of red blood cell and platelet deposition, accompanied with lymphocyte infiltration. Using porcine red blood cell and PBMC as target cells, the serum levels of anti-pig IgM and IgG antibodies peaked at postoperative 28 d, and slightly declined at postoperative 49 d. The quantity of lymphocytes and T cell subset also peaked at postoperative 28 d and began to decrease at postoperative 49 d. Conclusions Artery patch suture is a simple and reliable xenotransplantation model. The recipients can maintain normal physiological state without the use of immunosuppressive agents. The grafts can effectively activate the immune system of the recipients, induce the production of anti-pig antibodies and provoke cellular immune rejection. Therefore, this model can be utilized to monitor the immune rejection throughout the xenotransplantation process.

Detection methods of non-Gal xenoantibody in human serum

Ye Xuejun, Lu Xibin, Pan Dengke, Cai Zhiming, Mou Lisha, Zhao Chengjiang

2017, 8(2): 132-137. doi: 10.3969/j.issn.1674-7445.2017.02.008

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Objective To investigate the optimal condition for the detection of anti-non-galactose (Gal) xenoantigen and antibody in human serum. Methods Peripheral blood mononuclear cell (PBMC) obtained from Wuzhishan miniature pig models with α-1, 3-galactosyltransferase gene knockout (GTKO) were used as target cells, mixed and incubated with healthy human serum of different concentrations (4.8%, 16.7% and 100%) for 0.5, 1.0, 2.0, 3.0 and 6.0 h, respectively. The abilities of PBMC to bind with IgM and IgG were detected by flow cytometry. Results At the serum concentration of 16.7%, the ability of non-Gal IgM to bind with PBMC was significantly enhanced from 0.5 h to 3.0 h incubation (P < 0.01), whereas no statistical significance was noted in terms of IgG (P > 0.05). Increasing serum concentration could also enhance the ability of non-Gal IgM to bind with PBMC. At the serum concentration of 100% and incubation for 3 h, the ability of IgM to bind with PBMC was the highest among all groups (P < 0.01). At the serum concentration of 100% and incubation for 6 h, the ability of IgG to bind with PBMC was significantly enhanced (P < 0.05). Prolonging incubation time and increasing serum concentration did not affect the activity of PBMCs. Conclusions The optimal condition for detection of anti-non-Gal xenoantigen and antibody is determined. A quantity of 1×10⁵ PBMC from pig should be incubated with 100% human serum for 3 h for detection of IgM level, or incubated with 100% human serum for 6 h for measurement of IgG level. This optimized condition contributes to screening the donor pigs which lowly express non-Gal antigen.

Differential gene expression profile of miRNAs in mouse models with renal ischemia-reperfusion injury

Wu Ao, Wang Shuiliang, Zhu Ling, Yang Shunliang

2017, 8(2): 138-143. doi: 10.3969/j.issn.1674-7445.2017.02.009

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Objective To screen the differentially-expressed microRNAs (miRNAs) in mouse models with renal ischemia-reperfusion injury (IRI), aiming to offer foundation for unraveling the molecular mechanism of the incidence and progression of IRI. Methods The mouse models with acute IRI were established by renal artery clamping. Fifteen mice were divided into the IRI group and sham surgery group (group E). The animals in the IRI group were subdivided into the A group (45 min ischemia followed by 24 h reperfusion), B group (25 min ischemia followed by 24 h reperfusion), C group (45 min ischemia followed by 4 h reperfusion) and D group (25 min ischemia followed by 4 h reperfusion) (n=3 for each group). The severity of IRI was evaluated by histological changes and renal function. The differentially-expressed miRNAs in the IRI mouse models at different ischemia time (25 and 45 min) and reperfusion time (4 and 24 h) were screened by using cluster analysis of miRNAs microarray data. The differential expression of miR-695 and miR-145 was validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Results Both histological changes and renal function confirmed that the IRI mouse models were successfully established. Compared with the sham surgery group, 71 differentially-expressed miRNAs were detected in the IRI group including 30 down-regulated miRNAs and 40 up-regulated miRNAs. The results of qRT-PCR demonstrated that if the standardized expression level of miRNAs in the E group was 1, the relative expression levels of miR-695 and miR-145 were 11.82 and 0.31 in the IRI group (both P < 0.05), which were consistent with the chip results. Conclusions After renal IRI, different changes occur in the gene expression profile of miRNAs. These differentially-expressed miRNAs act as molecular biomarkers for renal IRI with potential clinical and scientific research values.

Activation of CD8⁺T cells regulated by γ-aminobutyric acid and its receptors

Fan Wenmei, Gao Yu, Sun Yujie, Ma Xihui, He Xiuyun, Xiao Li, Shi Bingyi

2017, 8(2): 144-148. doi: 10.3969/j.issn.1674-7445.2017.02.010

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Objective To evaluate the effect of γ-aminobutyric acid (GABA) and its receptors upon the proliferation of CD8⁺T cells. Methods The splenic CD8⁺T cells of Balb/c mice were obtained by CD8⁺T cell magnetic bead sorting kit. Under the effect of CD3/CD28-activated magnetic bead, CD8⁺T cells were stimulated by GABA of different concentrations. 5-bromo-2-deoxyuridine (BrdU) labeling and flow cytometry were performed to detect the proliferation of CD8⁺T cells. The expression levels of GABA-A and GABA-B receptor before and after CD8⁺T cell activation were compared by fluorescent quantitative real-time polymerase chain reaction (PCR). Results Flow cytometry result revealed that GABA could inhibit the proliferation of activated CD8⁺T cells, manifested as significant decrease in the quantity of CD152⁺CD8⁺T cells. Fluorescent quantitative real-time PCR demonstrated that GABA-A receptor subtypes α2, α6 and GABA-B receptor subtype 1a were expressed only when the CD8⁺T cells were activated. After CD8⁺T cell activation, the quantity of GABA-A receptor subtypes α3, α5, β2, β3, γ1, γ2 and θ were significantly increased, whereas the quantity of GABA-B2R and GABA-B1b did not significantly differ before and after CD8⁺T cell activation. Conclusions GABA can suppress the proliferation of activated CD8⁺T cells. The activation of CD8⁺T cells is regulated by GABA receptors. However, the underlying mechanism remains to be elucidated.

Effect of bone mesenchymal stem cell transplantation on accelerating the vascularization surrounding transplant pancreatic islet

Li Rui, Dong Hongli, Liu Rubin, Liu Baolin

2017, 8(2): 149-153. doi: 10.3969/j.issn.1674-7445.2017.02.011

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Objective To investigate whether pancreatic islet transplantation in combination with bone mesenchymal stem cells (MSC) transplantation can promote the vascularization surrounding the transplant pancreatic islet. Methods The non-obese diabetic (NOD) mice were utilized as the recipients and randomly divided into pancreatic islet transplantation combined with MSC transplantation group (co-transplantation group, n=6), pancreatic islet transplantation group (n=6), MSC transplantation group (n=6) and sham transplantation group (n=3). The variation in blood glucose level and survival rate post-transplantation of NOD mice in each group was observed. The proliferation and apoptosis of the transplant pancreatic islet in the pancreatic islet transplantation group and co-transplantation group at 1, 2 and 4 weeks after pancreatic islet transplantation were analyzed by 5-ethynyl-2'-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The vascular density surrounding the transplanted pancreatic islet in the pancreatic islet transplantation group and co-transplantation group at postoperative 2, 4 and 8 weeks were observed under light microscope and quantitatively analyzed by histochemical and immunohistochemical staining. Results Both MSC combined with pancreatic islet transplantation and pancreatic islet transplantation significantly improved the blood glucose level and enhanced the survival rate of NOD mouse models after transplantation. In addition, it could accelerate the regeneration of pancreatic islet cells and decrease cell apoptosis. MSC combined with pancreatic islet transplantation significantly enhanced the vascular density surrounding the transplant pancreatic islet compared with pancreatic islet transplantation alone. Conclusions MSC transplantation can accelerate the vascularization surrounding the transplant pancreatic islet, increase the blood supply and protect the function and activity of the transplant pancreatic islet.

Clinical Researches

Relationship between CNTN-1 and VEGF-C expression levels and recurrence, metastasis and prognosis of hepatocellular carcinoma patients after liver transplantation

Cao Yi, Lyu Lizhi, Jiang Yi, Pan Fan, Yang Hejun

2017, 8(2): 154-160. doi: 10.3969/j.issn.1674-7445.2017.02.012

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Objective To investigate the relationship between contactin (CNTN)-1 and vascular endothelial growth factor (VEGF)-C expression levels and the recurrence, metastasis and prognosis of hepatocellular carcinoma (HCC) patients after liver transplantation. Methods Clinical data and pathological specimen of 105 patients diagnosed with primary HCC undergoing orthotopic liver transplantation were collected. The expression levels of CNTN-1 and VEGF-C in the cancerous and para-cancerous liver tissues were quantitatively measured by immunohistochemical staining. The relationship between the CNTN-1 and VEGF-C expression levels and clinicopathological characteristics, postoperative recurrence, metastasis and prognosis was statistically analyzed. Results The high expression rate of CNTN-1 and VEGF-C in liver cancerous tissues was 46.7% and 39.0%, significantly higher compared with 11.4% and 19.0% in the para-cancerous tissues (both P < 0.05). Spearman correlation analysis revealed that the expression level of CNTN-1 was positively correlated with that of VEGF-C (P < 0.005). χ² test demonstrated that the expression of CNTN-1 protein was positively correlated with the level of alpha fetoprotein (AFP) (P=0.017), tumor, node, metastasis (TNM) staging (all P < 0.001), and negatively correlated with the degree of differentiation (P < 0.001). High expression of VEGF-C was positively correlated with TNM staging (P < 0.001). Cox multivariate analysis revealed that overall survival rate was significantly correlated with gender, AFP, degree of tumor differentiation, microvascular invasion, tumor diameter and high expression of CNTN-1 (P < 0.05-0.001). The recurrence-free survival was correlated with TNM staging, envelope integrity and high CNTN-1 expression (P < 0.05-0.001). Kaplan-Meier survival analysis revealed that postoperative overall survival curve and recurrence-free survival curve significantly differed between patients with high and low expression levels of CNTN-1 (both P < 0.01). Recurrence-free survival curve significantly differed between patients with high and low expression levels of VEGF-C (P=0.005). Conclusions CNTN-1 protein is highly expressed in HCC tissues and correlated with the expression of VEGF-C. It is associated with postoperative recurrence and metastasis of HCC after liver transplantation and affects the clinical prognosis of patients.

Evaluation of application value of acoustic radiation force impulse imaging of transplant liver in early recovery after transplantation

Fan Juner, Zhu Xiansheng, Wang Shasha, Zhou Lili, Cheng Qi

2017, 8(2): 161-164. doi: 10.3969/j.issn.1674-7445.2017.02.013

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Objective To evaluate the application value of acoustic radiation force impulse imaging (ARFI) in the early recovery of transplant liver. Methods Nineteen patients undergoing orthotopic liver transplantation were assigned into the study group and 12 healthy adults were recruited in the control group. In the study group, patients received bedside conventional ultrasound and ARFI examination at 1, 2, 3, 5 and 7 d after liver transplantation to observe the change of transplant liver elasticity, and those in the control group underwent once conventional ultrasound and ARFI examination. Two-dimensional liver ultrasound, color Doppler ultrasound and ARFI findings were statistically compared between the study and control groups. Results Conventional ultrasound demonstrated that the liver graft was properly recovered within 1 week after liver transplantation. ARFI revealed that the shear ware velocity (SWV) at 1, 2, 3, 5 and 7 d after liver transplantation was significantly higher than that in the control group (all P < 0.05). The SWV at postoperative 1 d was significantly higher than that at postoperative 7 d (P < 0.05). Conclusions ARFI can distinguish the liver stiffness between patients early after liver transplantation and healthy controls, and reflect the early variation of liver stiffness with good clinical application value.