Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs

Abstract

The effectiveness of human bone marrow mesenchymal stem cell (hBMSC) transplantation to treat acute and chronic liver injury has been demonstrated in animal models and in a few nonrandomized clinical trials. However, no studies have investigated hBMSC transplantation in the treatment of fulminant hepatic failure (FHF), especially in large animal (pig) models. The aim of this study was to demonstrate the safety, effectiveness, and underlying mechanism of hBMSC transplantation for treating FHF in pigs through the intraportal route. Human BMSCs (3 3 10 7 ) were transplanted into pigs with FHF via the intraportal route or peripheral vein immediately after D-galactosamine injection, and a sham group underwent intraportal transplantation (IPT) without cells (IPT, peripheral vein transplantation [PVT], and control groups, respectively, n 5 15 per group). All of the animals in the PVT and control groups died of FHF within 96 hours. In contrast, 13 of 15 animals in the IPT group achieved long-term survival (>6 months). Immunohistochemistry demonstrated that transplanted hBMSC-derived hepatocytes in surviving animals were widely distributed in the hepatic lobules and the liver parenchyma from weeks 2 to 10. Thirty percent of the hepatocytes were hBMSC-derived. However, the number of transplanted cells decreased significantly at week 15. Only a few single cells were scattered in the regenerated liver lobules at week 20, and the liver tissues exhibited a nearly normal structure. Conclusion: Immediate IPT of hBMSCs is a safe and effective treatment for FHF. The transplanted hBMSCs may quickly participate in liver regeneration via proliferation and transdifferentiation into hepatocytes during the initial stage of FHF. This method can possibly be used in future clinical therapy. (HEPATOLOGY 2012;56:1044-1052 E nd-stage hepatic failure is a potentially lifethreatening condition for which orthotopic liver transplantation is the only effective treatment. 1,2 However, a shortage of available donor organs for transplantation results in the death of many patients awaiting liver transplantation. Hepatocyte transplantation provides a promising alternative, and numerous experiments have demonstrated that hepatocyte transplantation improves liver function in animals with hepatic failure and innate liver-based metabolic disorders. 3,4 However, hepatocyte transplantation has rarely produced therapeutic effects, because mature hepatocytes cannot be effectively expanded in vitro and the availability of hepatocytes is often limited by shortages of donor organs. 5,6 Thus, previous studies have focused on the development of various stem cells that could be readily isolated using noninvasive procedures to yield hepatocytes in vitro and in vivo.Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts, adipocytes, and other mesenchymal cell lineages. 7-10 The hepatocyte differentiation capacity of human BMSCs (hBMSCs) has been Abbreviations: ALB, albumin; ALT, alanine aminotransferase; BMSC, bone marrow mesenchymal stem cell;...

Bone marrow-derived mesenchymal stem cells attenuate acute liver injury and regulate the expression of fibrinogen-like-protein 1 and signal transducer and activator of transcription 3

“…Recently, studies have demonstrated that BMSCs reinforce liver regeneration and have significant suppressive effects on hepatocyte apoptosis (36)(37)(38). BMSCs suppress proapoptotic protein expression and enhance anti-apoptotic protein expression, consequently attenuating hepatocyte degeneration and subsequent apoptosis, as well as accelerating hepatocyte regeneration (39).…”

Efficacy of coupled low-volume plasma exchange with plasma filtration adsorption in treating pigs with acute liver failure: A randomised study

“…ALF was induced with D-galactosamine, as described previously by our laboratory [29][30][31][32]. Animals were fasted for 8 hours prior to catheterisation.…”

Decellularized spleen matrix for reengineering functional hepatic-like tissue based on bone marrow mesenchymal stem cells

“…This strategy possesses more significant potential for liver tissue engineering compared with hepatocytes or cells from embryos, because of its easy accessibility, rapid proliferation, multipotent differentiation, and immunological tolerance. [17][18][19] Several studies [20][21][22][23] have also showed that transplantation of BMSCs or BMSC-derived hepatocytes could improve the liver function in laboratory animals or patients suffering from liver damage.…”