Enhanced therapeutic effects of umbilical cord mesenchymal stem cells after prolonged treatment for HBV-related liver failure and liver cirrhosis

Jia et al. Stem Cell Research & Therapy (2020) 11:277 https://doi.org/10.1186/s13287-020-01787-4 RESEARCH Open Access Enhanced therapeutic effects of umbilical cord mesenchymal stem cells after prolonged treatment for HBV-related liver failure and liver cirrhosis Yifan Jia1†, Xin Shu1†, Xiaoan Yang1, Haixia Sun1, Huijuan Cao1, Hong Cao1*, Ka Zhang1* , Qihuan Xu1, Gang Li1 and Yang Yang2 Abstract Background: Umbilical cord mesenchymal stem cells (UCMSCs) have been demonstrated to have good therapeutic effects in the treatment of HBV-related liver diseases. However, the therapeutic effect of UCMSCs on HBV-related liver failure and liver cirrhosis and the variations in the efficacy of UCMSCs after different treatment courses remain poorly understood. Therefore, this study was designed to answer these two questions. Methods: This was an observational study that retrospectively considered a 3-year period during which 513 patients who received stem cell infusion and met the criteria of hepatic failure and liver cirrhosis were identified from the databases of the Third Affiliated Hospital of Sun Yat-sen University. The eligible patients were categorized into the liver failure group and liver cirrhosis group. The two groups were divided into different subgroups according to the duration of stem cell therapy. In the liver failure group, group A received more than 4 weeks and group B received less than 4 weeks of stem cell therapy. In the liver cirrhosis group, patients who received more than 4 weeks of stem cell therapy belonged to group C, and the patients in group D received less than 4 weeks of stem cell therapy. The patients were followed up for 24 weeks. The demographics, clinical characteristics, biochemical factors, and model for end-stage liver disease (MELD) scores were recorded and compared among different groups. (Continued on next page) * Correspondence: ; Yifan Jia and Xin Shu share the first authorship. 1 Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jia et al. Stem Cell Research & Therapy (2020) 11:277 Page 2 of 10 (Continued from previous page) Results: A total of 64 patients met the criteria for liver failure, and 59 patients met the criteria for liver cirrhosis. After UCMSC treatment, the levels of alanine aminotransferase (ALT), glutamic-oxaloacetic transaminase (AST), and total bilirubin (TBIL) at all postbaseline time points were significantly lower than those at baseline in the liver failure group and liver cirrhosis group; the prothrombin activity (PTA) and MELD scores gradually improved in only the liver failure group. Four weeks after UCMSC treatment, patients who received prolonged treatment with UCMSCs had a larger decrease in TBIL levels than patients who terminated treatment with UCMSCs. After more than 4 weeks of UCMSC treatment, there were no statistically significant differences in the changes in ALT, AST, TBIL, and PTA values and MELD scores between patients with liver failure who received prolonged treatment with UCMSCs and patients with liver cirrhosis who received prolonged treatment with UCMSCs at any time point. However, the median decrease and cumulative decrease in the TBIL level of patients with liver failure with a standard 4-week treatment course were larger than those of patients with liver cirrhosis with a standard 4-week treatment course. Conclusion: Peripheral infusion of UCMSCs showed good therapeutic effects for HBV-related liver failure and liver cirrhosis. Prolonging the treatment course can increase the curative effect of UCMSCs for end-stage liver disease, especially for patients with cirrhosis. Keywords: Umbilical cord mesenchymal stem cell transplantation, Hepatitis B virus, Liver failure, Liver cirrhosis, Therapeutic effects Introduction Liver failure and cirrhosis are the results of chronic liver damage caused by many factors, including alcohol, drugs, and hepatitis virus (HBV, HCV, etc.), among which hepatitis B virus (HBV) infection is the most common cause of liver failure and cirrhosis, with high mortality and a large economic burden [1]. HBV-related end-stage liver disease mainly includes liver failure and decompensated cirrhosis. Due to its rapid progression and poor prognosis, liver transplantation is considered the most effective treatment for patients with HBV-related end-stage liver disease [2]. However, the application of liver transplantation is limited by the shortage of donor livers, the risks of transplantation, and the long-term use of immunosuppressants after transplantation [3]. Therefore, the majority of gastroenterologists/hepatologists have been looking for new treatment methods to treat patients with HBV-related end-stage liver disease. Twenty years ago, Theise et al. [4] reported that Y chromosome-positive hepatocyte-like cells were present in the livers of women who had received allogenic bone marrow transplantations from male donors and concluded that pluripotent stem cells may exist among bone marrow cells. Stem cell therapy has been applied in the treatment of end-stage liver disease, and its clinical efficiency is satisfactory [5]. Many basic and clinical studies have provided evidence that MSCs are safe and effective in the treatment of liver failure and cirrhosis. With advancements in research, scholars have also proposed a series of hypotheses related to the factors that influence MSCs during the treatment of liver failure and cirrhosis, such as the type of MSCs, the time of infusion, the method of infusion, and the dosage of infusion [6, 7]. Previous research in our department showed that allogeneic bone marrow-derived MSCs are safe and effective for patients with HBV-related acute-on-chronic liver failure (ACLF) [8, 9]. However, autologous mesenchymal stem cel (...truncated)