Zongcai Liu1, Fanwei Meng1, Chan Li1, Xin Zhou1, Xiaoping Zeng1, Yixin He1, Randall J Mrsny2, Muyun Liu1, Xiang Hu1, Ji-Fan Hu3, Tao Li4. 1. Shenzhen Beike Cell Engineering Research Institute, Yuanxing Science and Technology Building, Nanshan, Shenzhen, PR China. 2. GMR Epigenetics, Palo Alto, California, USA; Department of Pharmacy & Pharmacology, University of Bath, Bath, England. 3. VA Palo Alto Health Care System, Stanford University Medical School, Palo Alto, California, USA; GMR Epigenetics, Palo Alto, California, USA. Electronic address: jifan@stanford.edu. 4. Shenzhen Beike Cell Engineering Research Institute, Yuanxing Science and Technology Building, Nanshan, Shenzhen, PR China. Electronic address: litao@beike.cc.
Abstract
BACKGROUND AIMS: Acute liver failure (ALF), a life-threatening disease characterized by the sudden loss of hepatic function, can occur after an accidental or intentional acetaminophen overdose. METHODS: With the use of an ALF mouse model, we examined both the preventive and therapeutic potential of intravenously administered human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). Primary hUCMSCs were purified from freshly collected full-term umbilical cords and intravenously transplanted into BALB/c mice either before and after ALF induced by acetaminophen intoxication. We found that hUCMSCs significantly improved survival rates and relative liver weight of mice in both pre-ALF and post-ALF animals. Correspondingly, serum levels of markers that reflect hepatic injury (ie, aspartate aminotransferase, alanine aminotransferase and total bilirubin) were significantly attenuated in the group receiving hUCMSC therapy. RESULTS: Mechanistically, we found that the protective potential of intravenously administered hUCMSCs was mediated by paracrine pathways that involved antioxidants (glutathione, superoxide dismutase), the reduction of inflammatory agents (tumor necrosis factor-α, interleukin-6) and elevated serum levels of hepatocyte growth factor. CONCLUSIONS: Through these paracrine effects, intravenously administered hUCMSCs reduced hepatic necrosis/apoptosis and enhanced liver regeneration. Thus, our data demonstrate that intravenously administered hUCMSCs may be useful in the prevention or treatment of acetaminophen-induced ALF.
BACKGROUND AIMS: Acute liver failure (ALF), a life-threatening disease characterized by the sudden loss of hepatic function, can occur after an accidental or intentional acetaminophenoverdose. METHODS: With the use of an ALFmouse model, we examined both the preventive and therapeutic potential of intravenously administered human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). Primary hUCMSCs were purified from freshly collected full-term umbilical cords and intravenously transplanted into BALB/c mice either before and after ALF induced by acetaminophen intoxication. We found that hUCMSCs significantly improved survival rates and relative liver weight of mice in both pre-ALF and post-ALF animals. Correspondingly, serum levels of markers that reflect hepatic injury (ie, aspartate aminotransferase, alanine aminotransferase and total bilirubin) were significantly attenuated in the group receiving hUCMSC therapy. RESULTS: Mechanistically, we found that the protective potential of intravenously administered hUCMSCs was mediated by paracrine pathways that involved antioxidants (glutathione, superoxide dismutase), the reduction of inflammatory agents (tumor necrosis factor-α, interleukin-6) and elevated serum levels of hepatocyte growth factor. CONCLUSIONS: Through these paracrine effects, intravenously administered hUCMSCs reduced hepatic necrosis/apoptosis and enhanced liver regeneration. Thus, our data demonstrate that intravenously administered hUCMSCs may be useful in the prevention or treatment of acetaminophen-induced ALF.