Clinical Therapeutic Effects of Human Umbilical CordeDerived Mesenchymal Stem Cells Transplantation in the Treatment of End-Stage Liver Disease H.-L. Xue, W.-Z. Zeng*, X.-L. Wu, M.-D. Jiang, S.-M. Zheng, Y. Zhang, and H.-Y. Li Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan Province, People’s Republic of China
ABSTRACT We aimed to evaluate clinical therapeutic effects of human umbilical cordederived mesenchymal stem cell (UCMSC) transplantation in the treatment of end-stage liver diseases. The human UCMSCs were cultured and prepared, and then transplanted into the hepatic tissues of 50 patients with decompensated cirrhosis. The liver function, thrombin function, Model for End-Stage Liver Disease (MELD) score, and hemodynamic index value were detected during a 24-week follow-up period, with the addition of hepatoprotective, antiviral, and other conventional treatments. No complications or serious side effects were observed. In the first 2e3 weeks after surgery, symptoms including abdominal distension, oliguria, edema, and others decreased significantly, with increased appetite compared with before surgery. In the 24-week follow-up period, the levels of serum albumin and prealbumin increased significantly compared with the preoperative levels; the decrease of coagulation indicators was not significant. The MELD scores were also markedly increased. Alpha-fetoprotein levels increased without significance after treatment. There was no significant difference in the hemodynamic changes in the portal and splenic veins according to ultrasound. Moreover, no significant differences in the liver and thrombin functions between the hepatitis B virus group and the other-etiology group were observed.
L
IVER disease, one of the major causes of human mortality and morbidity worldwide, is a serious clinical syndrome [1]. Generally, acute or chronic liver damages could be caused by alcohol consumption, hepatotoxic drugs, and virus infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV) [2,3]. Liver transplantation offers an effective cure and is the criterion standard for treatment of end-stage liver disease [4]. However, several limitations regarding transplantation currently restrict its application, such as limited numbers of donor organs, long waiting lists, high cost, and potential serious complications. Therefore it is an urgent task to explore new treatment options for liver disease. Recently, studies on stem cells have demonstrated promising results that afford new opportunities for the treatment of end-stage liver disease [5,6]. Mesenchymal stem cells (MSCs), derived from mesenchymal and connective tissues [7], represent an archetype of multipotent adult stem cells and are considered to be a new treatment in stem cellebased liver regenerative medicine [8]. Bone marrow is the main source of 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.10.048
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MSCs, but they considerably decrease with aging. Alternate sources, including placenta, umbilical cord blood, and umbilical cord, have been explored recently [9,10]. They have been shown to have great potential for clinical application and are widely used in preliminary studies of cardiovascular diseases, nervous system diseases, skeletal muscle, diabetes, and liver disease [9,11,12]. Umbilical cordederived mesenchymal stem cells (UCMSCs) are a type of multipotent stem cells that can be isolated from umbilical cord Wharton jelly easily and safely. Because the umbilical cord is protected by the placental barrier, the probability of contamination with viral or bacterial antigens is low. Additionally, it could be preserved for decades *Address correspondence to Wei-Zheng Zeng, Department of Gastroenterology, Chengdu Military General Hospital, No 270 Tian Hui Road, Jinniu District, Chengdu 610083, Sichuan Province, People’s Republic of China. E-mail: zengweizheng@163. com ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 412e418 (2015)
CLINICAL THERAPEUTIC EFFECTS OF HUMAN UCMSC
413
Fig 1. Influence of human umbilical cord mesenchymal stem cells (hUCMSCs) therapy on liver function in decompensated liver cirrhosis patients. (A) Serum albumin, (B) serum prealbumin, (C) total bilirubin, (D) glutamate pyruvate transaminase (ALT), and (E) glutamic oxaloacetic transaminase (AST). *Difference between before UCMSC treatment and after treatment (P < .05). #Difference between week 1 and other time points (P < .05). DDifference between week 24 and other time points.
at a low temperature. UCMSCs have been used to treat acute graft-versus-host disease in allogeneic transplantation [13]. Accordingly, many hospitals have applied human UCMSCs to treating end-stage liver cirrhosis. The Zhang group reported that human UCMSC treatment of 45 patients with decompensated liver cirrhosis improved liver function and ascites in the patients [6]. However, it remains obscure whether human UCMSC treatment exerts therapeutic effects. In the present study, we used human UCMSCs to treat end-stage liver disease and explored clinical therapeutic effects of the treatment. Hopefully, this method will provide a new effective method for the treatment of chronic liver disease.
MATERIALS AND METHODS Patients Cirrhosis is defined as the histologic development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury, which leads to portal hypertension and end-stage liver disease [14]. A system known as the Child-Pugh-Turcotte (CPT) score was introduced to evaluate the severity of the cirrhosis [15], and decompensated cirrhosis refers to advanced cirrhosis (CPT class B or C). There are obvious abnormal liver functions and decompensated signs, such as serum albumin (ALB)
ABSTRACT We aimed to evaluate clinical therapeutic effects of human umbilical cordederived mesenchymal stem cell (UCMSC) transplantation in the treatment of end-stage liver diseases. The human UCMSCs were cultured and prepared, and then transplanted into the hepatic tissues of 50 patients with decompensated cirrhosis. The liver function, thrombin function, Model for End-Stage Liver Disease (MELD) score, and hemodynamic index value were detected during a 24-week follow-up period, with the addition of hepatoprotective, antiviral, and other conventional treatments. No complications or serious side effects were observed. In the first 2e3 weeks after surgery, symptoms including abdominal distension, oliguria, edema, and others decreased significantly, with increased appetite compared with before surgery. In the 24-week follow-up period, the levels of serum albumin and prealbumin increased significantly compared with the preoperative levels; the decrease of coagulation indicators was not significant. The MELD scores were also markedly increased. Alpha-fetoprotein levels increased without significance after treatment. There was no significant difference in the hemodynamic changes in the portal and splenic veins according to ultrasound. Moreover, no significant differences in the liver and thrombin functions between the hepatitis B virus group and the other-etiology group were observed.
L
IVER disease, one of the major causes of human mortality and morbidity worldwide, is a serious clinical syndrome [1]. Generally, acute or chronic liver damages could be caused by alcohol consumption, hepatotoxic drugs, and virus infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV) [2,3]. Liver transplantation offers an effective cure and is the criterion standard for treatment of end-stage liver disease [4]. However, several limitations regarding transplantation currently restrict its application, such as limited numbers of donor organs, long waiting lists, high cost, and potential serious complications. Therefore it is an urgent task to explore new treatment options for liver disease. Recently, studies on stem cells have demonstrated promising results that afford new opportunities for the treatment of end-stage liver disease [5,6]. Mesenchymal stem cells (MSCs), derived from mesenchymal and connective tissues [7], represent an archetype of multipotent adult stem cells and are considered to be a new treatment in stem cellebased liver regenerative medicine [8]. Bone marrow is the main source of 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.10.048
412
MSCs, but they considerably decrease with aging. Alternate sources, including placenta, umbilical cord blood, and umbilical cord, have been explored recently [9,10]. They have been shown to have great potential for clinical application and are widely used in preliminary studies of cardiovascular diseases, nervous system diseases, skeletal muscle, diabetes, and liver disease [9,11,12]. Umbilical cordederived mesenchymal stem cells (UCMSCs) are a type of multipotent stem cells that can be isolated from umbilical cord Wharton jelly easily and safely. Because the umbilical cord is protected by the placental barrier, the probability of contamination with viral or bacterial antigens is low. Additionally, it could be preserved for decades *Address correspondence to Wei-Zheng Zeng, Department of Gastroenterology, Chengdu Military General Hospital, No 270 Tian Hui Road, Jinniu District, Chengdu 610083, Sichuan Province, People’s Republic of China. E-mail: zengweizheng@163. com ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 412e418 (2015)
CLINICAL THERAPEUTIC EFFECTS OF HUMAN UCMSC
413
Fig 1. Influence of human umbilical cord mesenchymal stem cells (hUCMSCs) therapy on liver function in decompensated liver cirrhosis patients. (A) Serum albumin, (B) serum prealbumin, (C) total bilirubin, (D) glutamate pyruvate transaminase (ALT), and (E) glutamic oxaloacetic transaminase (AST). *Difference between before UCMSC treatment and after treatment (P < .05). #Difference between week 1 and other time points (P < .05). DDifference between week 24 and other time points.
at a low temperature. UCMSCs have been used to treat acute graft-versus-host disease in allogeneic transplantation [13]. Accordingly, many hospitals have applied human UCMSCs to treating end-stage liver cirrhosis. The Zhang group reported that human UCMSC treatment of 45 patients with decompensated liver cirrhosis improved liver function and ascites in the patients [6]. However, it remains obscure whether human UCMSC treatment exerts therapeutic effects. In the present study, we used human UCMSCs to treat end-stage liver disease and explored clinical therapeutic effects of the treatment. Hopefully, this method will provide a new effective method for the treatment of chronic liver disease.
MATERIALS AND METHODS Patients Cirrhosis is defined as the histologic development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury, which leads to portal hypertension and end-stage liver disease [14]. A system known as the Child-Pugh-Turcotte (CPT) score was introduced to evaluate the severity of the cirrhosis [15], and decompensated cirrhosis refers to advanced cirrhosis (CPT class B or C). There are obvious abnormal liver functions and decompensated signs, such as serum albumin (ALB)
