Regenerative Therapy for Liver Cirrhosis Based on Intrahepatic Arterial Infusion of Autologous Subcutaneous Adipose Tissue-Derived Regenerative (Stem) Cells: Protocol for a Confirmatory Multicenter Uncontrolled Clinical Trial

Abstract

Background Liver cirrhosis results from chronic hepatitis, and is characterized by advanced fibrosis due to long-term hepatic inflammation. Cirrhosis ultimately leads to manifestations of jaundice, ascites, and encephalopathy, and increases the risk of hepatocellular carcinoma. Once cirrhosis is established, resulting in hepatic failure, no effective treatment is available. Therefore, novel therapies to inhibit disease progression of cirrhosis are needed. Objective The objective of this investigator-initiated clinical trial is to assess the safety and efficacy of autologous adipose tissue-derived regenerative (stem) cell therapy delivered to the liver via the hepatic artery in patients with liver cirrhosis. Methods Through consultation with the Japan Pharmaceuticals and Medical Devices Agency, we designed a clinical trial to assess a therapy for liver cirrhosis based on autologous adipose tissue-derived regenerative (stem) cells, which are extracted using an adipose tissue dissociation device. The primary endpoints of the trial are the serum albumin concentration, prothrombin activity, harmful events, and device malfunction. Results Enrollment and registration were initiated in November 2017, and the follow-up period ended in November 2019. Data analysis and the clinical study report will be completed by the end of March 2020. Conclusions Completion of this clinical trial, including data analysis, will provide data on the safety and efficacy of this novel liver repair therapy based on autologous adipose tissue-derived regenerative (stem) cells using an adipose tissue dissociation device. Trial Registration UMIN Clinical Trials Registry UMIN000022601; https://tinyurl.com/w9uqw3q International Registered Report Identifier (IRRID) DERR1-10.2196/17904

Characterization of adipose tissue-derived stromal cells of mice with nonalcoholic fatty liver disease and their use for liver repair

“…Stromal cells of adipose tissues have beneficial reparative/regenerative effects, since they contain somatic pluripotent MSCs [ 4 ], which are thought to be advantageous owing to their pluripotency as well as their immunomodulatory effects for the treatment of various injured organs, including cirrhotic livers [ 6 ]. Furthermore, autologous cells are relatively accessible and easy to obtain [ 20 ] from a patient's own adipose tissue; thus, the use of the freshly isolated autologous adipose tissue-derived stromal cells for reparation/regeneration therapy for injured organs is a practical approach [ 8 , [21] , [22] , [23] , [24] ]. However, it is necessary to characterize freshly isolated u-ADSCs from affected hosts and to determine their effects on cirrhotic liver.…”

“…Clinical studies of freshly isolated adipose tissue-derived stromal cells are ongoing in various fields [ 28 ]. We have also conducted a clinical study [ 29 ] and an investigator-initiated trial [ 8 ] using freshly isolated autologous adipose tissue-derived stromal cells without culture for the treatment of liver cirrhosis. Moreover, cultured adipose tissue-derived stem cells have been investigated extensively for repair and regenerative therapy [ 30 , 31 ], and such studies are expected to provide important information for the development of novel cell therapies.…”

“…Therefore, u-ADSCs are promising for repairing and/or regenerating injured organs, especially under harmful inflammation [ 7 ]. Moreover, u-ADSCs can be obtained in an autologous manner from subcutaneous tissues [ 8 ]. However, u-ADSCs obtained from individuals with NASH have not been comprehensively characterized, and comparative analyses of their therapeutic efficacy with that of u-ADSCs from unaffected individuals are needed.…”

Regenerative effect of mesenteric fat stem cells on ccl4-induced liver cirrhosis, an experimental study

“…Few animal studies administered adipose stem cells (ADSC) for hepatic regeneration with different methods [ 24 , 25 ]. Sakai et al also enrolled a clinical trial in 2017 based on intrahepatic arterial infusion of autologous subcutaneous adipose tissue stem cells for liver cirrhosis, but it is not completed yet [ 26 ]. It seems that the therapeutic effect on the symptoms of cirrhosis is based on ADSC-secreted growth factors such as hepatocyte growth factor (HGF) & vascular endothelial growth factor (VEGF), anti-inflammatory effects on hepatic stellate cells, and the anti-fibrotic and angiogenic effects of ADSC-secreted proteins [ 27 ].…”

Regenerative Effect of Mesenteric Fat Stem Cells on ccl4-Induced Liver Cirrhosis

“…Sakai etal. also enrolled a clinical trial in 2017 based on intrahepatic arterial infusion of autologous subcutaneous adipose tissue stem cells for liver cirrhosis, but it is not completed yet (26). It seems that the therapeutic effect on the symptoms of cirrhosis is based on ADSC-secreted growth factors (HGF & VEGF), anti-in ammatory effects on hepatic stellate cells, and the anti-brotic and angiogenic effects of ADSC-secreted proteins (27).…”