脐血间充质干细胞对半相合造血干细胞移植预处理后急性药物性肝损害的保护作用
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摘要
背景:半相合造血干细胞移植是目前国内移植的主流模式,制约其广泛开展的主要原因是移植物抗宿主病及植入失败发生率高于全相合造血干细胞移植。为了解决这两大难题,目前部分移植中心采用联合间充质干细胞共移植的方法促进造血干细胞植入,同时降低移植物抗宿主病的发生率。已有研究显示间充质干细胞对肝硬化及肝炎患者损伤肝细胞有促进修复的作用。共移植间充质干细胞能否预防急性药物性肝损害尚不明确。目的:观察半相合造血干细胞移植时输注脐血间充质干细胞对急性药物性肝损害的预防保护作用。方法:回顾性分析2010年1月至2017年8月期间行半相合造血干细胞移植患者的临床资料,其中观察组8例在回输造血干细胞前4-6 h内输注脐血间充质干细胞1×10~6/kg,对照组17例未联合输注脐血间充质干细胞,观察两组患者在预处理后1 d、2周及4周的肝功能指标变化以及治疗转归。经西安交通大学医学院第一附属医院伦理委员会评审,此试验方案及知情同意书可行,符合伦理原则(批件号:2016伦审临字第(20)号)。结果与结论:①两组患者预处理后均有不同程度的肝脏生化学指标异常,2周达高峰,4周后趋于正常;②在预处理后1d及2周时,观察组谷丙转氨酶、谷草转氨酶、碱性磷酸酶、谷氨酰胺转移酶、直接胆红素值较对照组降低,差异有显著性意义(P <0.05);③两组患者输注造血干细胞及脐血间充质干细胞期间无发热、血压升高/降低、心律失常及溶血等不良反应;④结果表明,半相合造血干细胞移植中共回输脐血间充质干细胞能降低预处理后急性药物性肝损害的程度,对肝脏起到一定的保护作用,需要进一步扩大病例数进行临床观察。
BACKGROUND: Haploidentical hematopoietic stem cell transplantation is currently the mainstream mode of transplantation in China, but its widespread development is restricted by the higher incidence of graft-versus-host disease and implantation failure as compared with HLA identical hematopoietic stem cell transplantation. In order to solve these two problems, co-transplantation of mesenchymal stem cells and hematopoietic stem cells is used in some transplant centers to promote hematopoietic stem cell transplantation, and to reduce the incidence of graft-versus-host disease. Studies have shown that mesenchymal stem cells can promote the repair of liver cells in liver cirrhosis and hepatitis patients. It is unclear whether co-transplantation of mesenchymal stem cells and hematopoietic stem cells can prevent acute drug-induced liver injury.OBJECTIVE: To investigate the preventive and protective effects of infusion of umbilical cord blood mesenchymal stem cells on acute drug-induced liver injury after conditioning in haploidentical hematopoietic stem cell transplantation.METHODS: Clinical data of patients who underwent haploidentical hematopoietic stem cell transplantation from January 2010 to August 2017 was retrospectively analyzed. Eight cases were transfused with umbilical cord blood mesenchymal stem cells 1×10~6/kg within 4-6 hours before transfusion of hematopoietic stem cells. Seventeen-seven cases in the control group were not given umbilical cord blood mesenchymal stem cells. The changes of liver function indicators and treatment outcomes at 1 day, 2 weeks and 4 weeks after transplantation conditioning were observed. The study protocol was approved by the ethics committee of the First Affiliated Hospital of Xi'an Jiao Tong University with the approval No. 2016(20). Written informed consent was obtained prior to the initiation of the study.RESULTS AND CONCLUSION:(1) Patients in both groups had abnormalities in the biomedical indicators of liver function to different extent.These indicators peaked at 2 weeks post preconditioning, and then became normal after 4 weeks.(2) The levels of alanine aminotransferase,aspartate aminotransferase, alkaline phosphatase, transglutaminase, and direct bilirubin were significantly lower in the observation group than the control group at 1 day and 2 weeks after transplantation conditioning(P < 0.05).(3) There were no adverse reactions such as fever, blood pressure increase/decrease, arrhythmia and hemolysis in the two groups during the infusion of hematopoietic stem cells and umbilical cord blood mesenchymal stem cells. These findings reveal that co-transfusion of umbilical cord blood mesenchymal stem cells during haploidentical hematopoietic stem cell transplantation may reduce acute drug-induced liver injury after transplantation conditioning, and it needs to be further investigated duo to limit numbers of patients.
BACKGROUND: Haploidentical hematopoietic stem cell transplantation is currently the mainstream mode of transplantation in China, but its widespread development is restricted by the higher incidence of graft-versus-host disease and implantation failure as compared with HLA identical hematopoietic stem cell transplantation. In order to solve these two problems, co-transplantation of mesenchymal stem cells and hematopoietic stem cells is used in some transplant centers to promote hematopoietic stem cell transplantation, and to reduce the incidence of graft-versus-host disease. Studies have shown that mesenchymal stem cells can promote the repair of liver cells in liver cirrhosis and hepatitis patients. It is unclear whether co-transplantation of mesenchymal stem cells and hematopoietic stem cells can prevent acute drug-induced liver injury.OBJECTIVE: To investigate the preventive and protective effects of infusion of umbilical cord blood mesenchymal stem cells on acute drug-induced liver injury after conditioning in haploidentical hematopoietic stem cell transplantation.METHODS: Clinical data of patients who underwent haploidentical hematopoietic stem cell transplantation from January 2010 to August 2017 was retrospectively analyzed. Eight cases were transfused with umbilical cord blood mesenchymal stem cells 1×10~6/kg within 4-6 hours before transfusion of hematopoietic stem cells. Seventeen-seven cases in the control group were not given umbilical cord blood mesenchymal stem cells. The changes of liver function indicators and treatment outcomes at 1 day, 2 weeks and 4 weeks after transplantation conditioning were observed. The study protocol was approved by the ethics committee of the First Affiliated Hospital of Xi'an Jiao Tong University with the approval No. 2016(20). Written informed consent was obtained prior to the initiation of the study.RESULTS AND CONCLUSION:(1) Patients in both groups had abnormalities in the biomedical indicators of liver function to different extent.These indicators peaked at 2 weeks post preconditioning, and then became normal after 4 weeks.(2) The levels of alanine aminotransferase,aspartate aminotransferase, alkaline phosphatase, transglutaminase, and direct bilirubin were significantly lower in the observation group than the control group at 1 day and 2 weeks after transplantation conditioning(P < 0.05).(3) There were no adverse reactions such as fever, blood pressure increase/decrease, arrhythmia and hemolysis in the two groups during the infusion of hematopoietic stem cells and umbilical cord blood mesenchymal stem cells. These findings reveal that co-transfusion of umbilical cord blood mesenchymal stem cells during haploidentical hematopoietic stem cell transplantation may reduce acute drug-induced liver injury after transplantation conditioning, and it needs to be further investigated duo to limit numbers of patients.
引文
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[2]Chang YJ,Zhao XY,Huang XJ.Strategies for Enhancing and Preserving Anti-leukemia Effects Without Aggravating Graft-Versus-Host Disease.Front Immunol.2018;9:3041.
[3]罗小雨,刘海林.骨髓间充质干细胞的免疫调节功能及其在治疗肝脏疾病中的应用[J].中华消化杂志,2013,33(9):643-646.
[4]孙文静,刘凯军,文良志,等.骨髓间充质干细胞对肝脏的影响[J].实用肝脏杂志,2017,20(40):394-396.
[5]张秋艳,熊艳,叶殷发.骨髓间充质干细胞修复肝脏缺血-再灌注损伤研究进展[J].中华实验外科杂志,2016,33(1):871-875.
[6]侯一琚,王丽萍,许烂漫,等.骨髓间充质干细胞移植对急性肝功能衰竭大鼠肝脏信号转导子和转录活化子3表达的影响[J].中华传染病杂志,2014,32(1):13-18.
[7]张丽霞,严祥.骨髓间充质干细胞移植在肝脏疾病中的应用[J].国际消化病杂志,2016,36(1):43-46.
[8]王晓媛,李栋,周盼盼,等.人脐带间充质干细胞治疗环磷酰胺导致的大鼠药物性肝损伤[J].世界华人消化杂志,2017,25(33):2956-2966.
[9]陈良,冯啸,袁泽南,等.人脐带间充质干细胞来源的外泌体对肝脏再生的影响[J].中华实验外科杂志,2017,34(10):1684-1687.
[10]马军.血液病患者药物性肝损害的预防和规范化治疗专家共识(2016版)[J].中华血液学杂志,2016,37(6):441-453.
[11]Babaei A,Katoonizadeh A,Ranjbar A,et al.Directly injected native bone-marrow stem cells cannot incorporate into acetaminophen-induced liver injury.Biologicals.2018;52:55-58.
[12]Zhao Z,Leow WQ.Concurrent Hepatic Tuberculosis and Hepatic Graft-versus-host Disease in an Allogeneic Hematopoietic Stem Cell Transplant Recipient:A Case Report.Transplant Proc.2017;49(7):1659-1662.
[13]Alessandrino F,Tirumani SH,Krajewski KM,et al.Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre:chemotherapy,haematopoietic stem cell transplantation,molecular targeted therapies,and immune checkpoint inhibitors.Clin Radiol.2017;72(7):521-533.
[14]Hu M,Li S,Menon S,et al.Expansion and Hepatic Differentiation of Adult Blood-Derived CD34+Progenitor Cells and Promotion of Liver Regeneration After Acute Injury.Stem Cells Transl Med.2016;5(6):723-732.
[15]Phinney DG,Pittenger MF.Concise Review:MSC-Derived Exosomes for Cell-Free Therapy.Stem Cells.2017;35(4):851-858.
[16]Kusuma GD,Carthew J,Lim R,et al.Effect of the Microenvironment on Mesenchymal Stem Cell Paracrine Signaling:Opportunities to Engineer the Therapeutic Effect.Stem Cells Dev.2017;26(9):617-631.
[17]姜华,高建鹏.骨髓间充质干细胞治疗肝脏疾病研究进展[J].实用肝脏病杂志,2015,18(2):217-221.
[18]Margini C,Vukotic R,Brodosi L,et al.Bone marrow derived stem cells for the treatment of end-stage liver disease.World J Gastroenterol.2014;20(27):9098-9105.
[19]郭世民,魏巍.间充质干细胞用于肝纤维化及肝硬化治疗的研究进展[J].肝脏,2017,22(6):551-554.
[20]冯兰艳,张大志.间充质干细胞在慢加急性肝衰竭中的临床应用及研究进展[J].中华肝脏病杂志,2017,25(9):651-654.
[21]张迪,张雅敏,刘子荣,等.间充质干细胞在自身免疫性肝病中的应用[J].实用器官移植电子杂志,2017,5(1):56-60.
[22]薛红利,曾维政.不同来源间充质干细胞在肝病治疗中应用的研究进展[J].世界华人消化杂志,2013,21(11):990-995.
[23]骆海飞,杨小安,张卡,等.人脐带间充质干细胞治疗乙肝肝硬化失代偿期疗效观察[J].中华实验和临床病毒学杂志,2015,29(3):239-241.
[24]陈振娟,曲乃方.间充质干细胞移植治疗终末期肝衰竭研究进展[J].中国肝脏病杂志(电子版),2017,9(1):7-10.
[25]Peng L,Xie DY,Lin BL,et al.Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B:short-term and long-term outcomes.Hepatology.2011;54(3):820-828.
[26]Zhang Z,Lin H,Shi M,et al.Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients.J Gastroenterol Hepatol.2012;27 Suppl 2:112-120.
[27]Wang L,Li J,Liu H,et al.Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis.J Gastroenterol Hepatol.2013;28 Suppl1:85-92.
[28]奉婷,朱卫民,余泽波.脐血间充质干细胞治疗肝病的研究进展[J].国际消化病杂志,2013,33(3):176-178.
[29]Jiang W,Tan Y,Cai M,et al.Human Umbilical Cord MSC-Derived Exosomes Suppress the Development of CCl4-Induced Liver Injury through Antioxidant Effect.Stem Cells Int.2018;2018:6079642.
[30]Chen L,Zhang J,Yang L,et al.The Effects of Conditioned Medium Derived from Mesenchymal Stem Cells Cocultured with Hepatocytes on Damaged Hepatocytes and Acute Liver Failure in Rats.Stem Cells Int.2018;2018:9156560.
[2]Chang YJ,Zhao XY,Huang XJ.Strategies for Enhancing and Preserving Anti-leukemia Effects Without Aggravating Graft-Versus-Host Disease.Front Immunol.2018;9:3041.
[3]罗小雨,刘海林.骨髓间充质干细胞的免疫调节功能及其在治疗肝脏疾病中的应用[J].中华消化杂志,2013,33(9):643-646.
[4]孙文静,刘凯军,文良志,等.骨髓间充质干细胞对肝脏的影响[J].实用肝脏杂志,2017,20(40):394-396.
[5]张秋艳,熊艳,叶殷发.骨髓间充质干细胞修复肝脏缺血-再灌注损伤研究进展[J].中华实验外科杂志,2016,33(1):871-875.
[6]侯一琚,王丽萍,许烂漫,等.骨髓间充质干细胞移植对急性肝功能衰竭大鼠肝脏信号转导子和转录活化子3表达的影响[J].中华传染病杂志,2014,32(1):13-18.
[7]张丽霞,严祥.骨髓间充质干细胞移植在肝脏疾病中的应用[J].国际消化病杂志,2016,36(1):43-46.
[8]王晓媛,李栋,周盼盼,等.人脐带间充质干细胞治疗环磷酰胺导致的大鼠药物性肝损伤[J].世界华人消化杂志,2017,25(33):2956-2966.
[9]陈良,冯啸,袁泽南,等.人脐带间充质干细胞来源的外泌体对肝脏再生的影响[J].中华实验外科杂志,2017,34(10):1684-1687.
[10]马军.血液病患者药物性肝损害的预防和规范化治疗专家共识(2016版)[J].中华血液学杂志,2016,37(6):441-453.
[11]Babaei A,Katoonizadeh A,Ranjbar A,et al.Directly injected native bone-marrow stem cells cannot incorporate into acetaminophen-induced liver injury.Biologicals.2018;52:55-58.
[12]Zhao Z,Leow WQ.Concurrent Hepatic Tuberculosis and Hepatic Graft-versus-host Disease in an Allogeneic Hematopoietic Stem Cell Transplant Recipient:A Case Report.Transplant Proc.2017;49(7):1659-1662.
[13]Alessandrino F,Tirumani SH,Krajewski KM,et al.Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre:chemotherapy,haematopoietic stem cell transplantation,molecular targeted therapies,and immune checkpoint inhibitors.Clin Radiol.2017;72(7):521-533.
[14]Hu M,Li S,Menon S,et al.Expansion and Hepatic Differentiation of Adult Blood-Derived CD34+Progenitor Cells and Promotion of Liver Regeneration After Acute Injury.Stem Cells Transl Med.2016;5(6):723-732.
[15]Phinney DG,Pittenger MF.Concise Review:MSC-Derived Exosomes for Cell-Free Therapy.Stem Cells.2017;35(4):851-858.
[16]Kusuma GD,Carthew J,Lim R,et al.Effect of the Microenvironment on Mesenchymal Stem Cell Paracrine Signaling:Opportunities to Engineer the Therapeutic Effect.Stem Cells Dev.2017;26(9):617-631.
[17]姜华,高建鹏.骨髓间充质干细胞治疗肝脏疾病研究进展[J].实用肝脏病杂志,2015,18(2):217-221.
[18]Margini C,Vukotic R,Brodosi L,et al.Bone marrow derived stem cells for the treatment of end-stage liver disease.World J Gastroenterol.2014;20(27):9098-9105.
[19]郭世民,魏巍.间充质干细胞用于肝纤维化及肝硬化治疗的研究进展[J].肝脏,2017,22(6):551-554.
[20]冯兰艳,张大志.间充质干细胞在慢加急性肝衰竭中的临床应用及研究进展[J].中华肝脏病杂志,2017,25(9):651-654.
[21]张迪,张雅敏,刘子荣,等.间充质干细胞在自身免疫性肝病中的应用[J].实用器官移植电子杂志,2017,5(1):56-60.
[22]薛红利,曾维政.不同来源间充质干细胞在肝病治疗中应用的研究进展[J].世界华人消化杂志,2013,21(11):990-995.
[23]骆海飞,杨小安,张卡,等.人脐带间充质干细胞治疗乙肝肝硬化失代偿期疗效观察[J].中华实验和临床病毒学杂志,2015,29(3):239-241.
[24]陈振娟,曲乃方.间充质干细胞移植治疗终末期肝衰竭研究进展[J].中国肝脏病杂志(电子版),2017,9(1):7-10.
[25]Peng L,Xie DY,Lin BL,et al.Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B:short-term and long-term outcomes.Hepatology.2011;54(3):820-828.
[26]Zhang Z,Lin H,Shi M,et al.Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients.J Gastroenterol Hepatol.2012;27 Suppl 2:112-120.
[27]Wang L,Li J,Liu H,et al.Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis.J Gastroenterol Hepatol.2013;28 Suppl1:85-92.
[28]奉婷,朱卫民,余泽波.脐血间充质干细胞治疗肝病的研究进展[J].国际消化病杂志,2013,33(3):176-178.
[29]Jiang W,Tan Y,Cai M,et al.Human Umbilical Cord MSC-Derived Exosomes Suppress the Development of CCl4-Induced Liver Injury through Antioxidant Effect.Stem Cells Int.2018;2018:6079642.
[30]Chen L,Zhang J,Yang L,et al.The Effects of Conditioned Medium Derived from Mesenchymal Stem Cells Cocultured with Hepatocytes on Damaged Hepatocytes and Acute Liver Failure in Rats.Stem Cells Int.2018;2018:9156560.
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