Safety of UC-MSC Transfusion for ACLF Patients

Acute-on-chronic liver failure (acute-on-chronic liver failure, ACLF) is a special type of rapid deterioration of liver function that occurs on the basis of cirrhosis or non-cirrhosis, which is characterized by sequential multiple organ failure and high short-term (28 days) mortality (15%). ACLF was first proposed by Jalan R and Williams R. in 2002. It is a newly discovered type of critically ill liver disease characterized by high short-term mortality after hospitalization [1]. At present, the pathophysiological mechanism of ACLF is not clear, and its definition in Europe and Asia-Pacific is still controversial. However, severe systemic inflammatory response is often closely related to the cause, accompanied by single or multiple organ failure are three important characteristics of ACLF. In the past ten years, the prevalence of ACLF has increased. Due to the rapid progress of the disease and the close relationship between mortality and organ failure, there is no effective method to improve the survival rate of ACLF patients except liver transplantation. The latest literature review shows that the 28-day and 90-day mortality rates are as high as 27.8-37.6% and 40-, respectively. 51.2%[2].

In 2013, European Association for the Study of Chronic Acute Liver Failure（EASL-CLIF） conducted a prospective multi-center EASL-CLIF Chronic Acute Liver Failure (CANONIC) study in 29 liver disease treatment centers in eight European countries, and proposed chronic liver failure-sequential organ failure assessment（CLIF-SOFA）score is used as the clinical diagnostic criteria for alcoholic and hepatitis B virus（HBV）related ACLF. According to the CLIF-SOFA score, the 90-day mortality rate of ACLF patients is as high as 51%, while that of non-ACLF patients is 10% [3]. The European CANONIC study also shows that systemic inflammation is the main driving force of multiple organ failure, which is a typical pathogenesis of ACLF patients with western liver cirrhosis [4]. For another, the current Asian ACLF diagnostic criteria is the Asia Pacific Association for the Study of Liver Diseases (APASL) criteria, which reached a consensus in 2009, and the guidelines were improved in 2014, but there is still a lack of multi-center, prospective evidence-based medical evidence to support . In 2016, led by the person in charge of this project, an oriental ACLF prospective multi-center observation cohort was established in China, which included 3970 ACLF high-risk patients, filling the gap in the natural course and mortality of oriental ACLF patients, and established a 90-day oriental ACLF diagnostic criteria for mortality [5]. The person in charge of this project also explored the pathophysiological mechanism of ACLF patients in areas with high prevalence of oriental HBV. The study showed that submassive hepatic necrosis is an important histological feature in ACLF patients with HBV-related cirrhosis. The systemic inflammatory response of multiple organ failure caused by parenchymal liver cells has a similar mechanism to that of western alcoholic ACLF [6]. Although the causes of ACLF type are not the same in the East and the West, the cohorts from the East and the West have confirmed the short-term high mortality rate of ACLF. Systemic inflammation, sub-large necrosis, and aseptic inflammation may all important reasons that lead to multiple organ failure and eventual death of ACLF patients.

Due to the high short-term mortality of ACLF and the limited liver source for liver transplantation, exploring new methods for the treatment of ACLF is a major issue facing clinical research. Mesenchymal stem cells have great application prospects in regenerative medicine because of their strong self-renewal, low immunogenicity, non-tumorigenicity and strong immune regulation ability[7]. Many previous documents have confirmed that mesenchymal stem cells in animal models can promote liver cell regeneration, resist inflammation, regulate local microenvironment and anti-fibrosis [8-10]. Among them, umbilical cord mesenchymal stem cells (UC-MSC) have attracted attention of researchers because they are easily obtained from the medical waste-the umbilical cord, are not invasive, and have high expansion capabilities in vitro [11]. The possible mechanism of UC-MSC in the treatment of end-stage liver disease is that it can repair the liver. At present, there are the following opinions: ① Cell rehabilitation. In the case of liver failure, MSC can differentiate into hepatocytes and play an alternative therapeutic effect. A large number of studies have shown that MSC can be differentiated into functional hepatocytes in different inducing factors and culture systems in vitro, capable of storing glycogen and urea synthesis. Function; ②Immune regulation. Studies have shown that MSC can regulate immune cells by secreting a variety of cytokines in the body, and play an immunomodulatory effect; ③Anti-fibrosis. MSC can induce hepatic stellate cell apoptosis or inhibit its activation, and can secrete anti-fibrotic substances such as granulocyte colony stimulating factor and matrix metallopeptidase 9（MMP-9）to reduce the deposition of extracellular matrix and inhibit the formation of liver fibrosis.

According to the results of a single-center clinical trial published by the Third Affiliated Hospital of Sun Yat-sen University in the previous period, there were no serious adverse reactions at 6 hours and 72 weeks after intravenous infusion of MSCs. The dose was (1-6)*10^7 cells/time for 4 times, confirming the safety and effectiveness of both low-dose and high-dose treatments. Another open clinical trial of Beijing 302 Hospital used mesenchymal stem cells at a dose of 5*10^5 cells/kg (based on the patient's weight of 60kg, the dose was 3*10^7 cells/time), excluded severe ACLF patients accompanied by severe infections and other sever complications. In addition, previous pharmacokinetic tests showed that the half-life of mesenchymal stem cells in animals is 3 days.

Therefore, this research plans to carry out a single-center open clinical trial to confirm the safety of umbilical cord-derived mesenchymal stem cells in the treatment of ACLF, and provide stronger clinical evidence for the safety of UC-MSCs in the treatment of ACLF.