Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity

Shobha Regmi,Inho Choi,Shiva Pathak,Chul Soon Yong,Bieong-Kil Kim,Tiep Tien Nguyen,Jun-Beom Park,Kyoung-Oh Doh,Yoojin Seo,Pil-Hoon Park,Jee-Heon Jeong,Hyung-Sik Kim,Jong Oh Kim,Jong-Hyuk Sung,Simmyung Yook,Dong-Mok Lee,Tung Pham Thanh,Ik-Jae Moon

doi:10.1186/s13287-019-1337-3

Abstract

BackgroundSystemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20–50%) due to irreversible cerebral edema or sepsis. Stem cell-based treatment has emerged as a promising alternative therapeutic strategy to prolong the survival of patients suffering from FHF via the inhibition of SIRS due to their immunomodulatory effects.Methods3D spheroids of adipose-derived mesenchymal stem cells (3D-ADSC) were prepared by the hanging drop method. The efficacy of the 3D-ADSC to rescue FHF was evaluated in a d-galactosamine/lipopolysaccharide (GalN/LPS)-induced mouse model of FHF via intraportal transplantation of the spheroids.ResultsIntraportally delivered 3D-ADSC better engrafted and localized into the damaged livers compared to 2D-cultured adipose-derived mesenchymal stem cells (2D-ADSC). Transplantation of 3D-ADSC rescued 50% of mice from FHF-induced lethality, whereas only 20% of mice survived when 2D-ADSC were transplanted. The improved transplantation outcomes correlated with the enhanced immunomodulatory effect of 3D-ADSC in the liver microenvironment.ConclusionThe study shows that the transplantation of optimized 3D-ADSC can efficiently ameliorate GalN/LPS-induced FHF due to improved viability, resistance to exogenous ROS, and enhanced immunomodulatory effects of 3D-ADSC.

Highlights

Systemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20–50%) due to irreversible cerebral edema or sepsis
Intraportal delivery of 3D-ADSC1000 ameliorated FHF Dosage of GalN and LPS was optimized, and 1500 mg/kg GalN and 20 μg/kg LPS were chosen for the induction of FHF in BALB/c nude mice, which resulted in the deaths of 2 out of 3 mice 24 h after administration (Additional file 1: Figure S1)
Intraportal delivery of 3D-adipose-derived mesenchymal stem cells (ADSC) led to the mesenchymal stem cells (MSC) engraftment into the liver and enhanced therapeutic outcomes in a mouse model of FHF

Summary

Introduction

Systemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20–50%) due to irreversible cerebral edema or sepsis. Many aspects of hepatocyte culture, including their isolation, expansion, and preservation, have proven to be difficult, and poor engraftment efficacy limits the hepatocyte transplantation [9, 10]. In this context, mesenchymal stem cells (MSC) are promising candidates for cell therapy because of their multipotent differentiation ability and immunomodulatory activity [11,12,13]. MSC have been reported to rescue impaired hepatocytes by differentiating into hepatocyte-like cells and/or by improving the inflammatory, fibrotic microenvironment through paracrine effects [14] and preventing further liver damage during FHF [15]. 3D culture methods offer a means of improving the efficacy of stem cell therapies and eliminate the need for genetic modification and growth factor delivery

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