Abstract
Mesenchymal stem cell (MSC) transplantation is a promising treatment for ischemia-reperfusion injury (IRI). However, its effects on hepatic IRI were not consistent in the previous studies. 3D spheroid-cultured MSCs enhance their production of trophic and anti-inflammatory properties, but their effects on hepatic IRI remain unclear. In this study, we compared the 3D spheroid-cultured human umbilical derived MSCs (3D UC-MSCs) with 2D-cultured UC-MSCs (2D UC-MSCs) on treating hepatic IRI. The RNA sequencing data showed that suppression of cell mitosis, response to hypoxia, inflammation, and angiogenesis were the top genetic changes in 3D UC-MSCs compared with 2D UC-MSCs. Although both pro-inflammatory and anti-inflammatory genes were upregulated in the 3D UC-MSCs, the mRNA and protein of an RNase (ZC3H12A), which turnovers the mRNA of pro-inflammatory genes at the post-transcript level, were significantly upregulated in 3D UC-MSCs. 3D UC-MSCs reduced the secretion of many chemokines and growth factors, but increased the secretion of vascular endothelial growth factor. Compared with the vehicle and 2D UC-MSCs, 3D UC-MSCs significantly reduced hepatic IRI in rats, based on the plasma aminotransferase levels, liver damage scores, neutrophil infiltration, hepatocyte apoptosis and expression of inflammation-associated genes. These findings suggest that 3D UC-MSCs therapy is a promising treatment for hepatic IRI.
Highlights
The hepatic ischemia-reperfusion injury (IRI) is a leading cause of primary graft dysfunction after liver transplantation and is associated with poor 1-year graft and patient survival rates of only 55% and 68%, respectively, compared with 90% and 93% for the remainder[1]
During the process of cell culture, the time-lapse microscopy demonstrated that UC-mesenchymal stem cell (MSC) cultured in hanging drops formed a loose network at first, and gradually coalesced into a single central spheroid along the lower surface of the drop (Fig. 1a), The RNA sequencing results showed that among the 19219 screened genes, altogether 831 genes were significantly upregulated and 788 genes were significantly downregulated in 3D umbilical cord lining MSCs (UC-MSCs) compared with 2D UC-MSCs (probability >80% and |log2(fold of gene expression change)|≥1) (Fig. 1b)
The gene ontology analysis using all the differentially regulated genes revealed that biological processes in cell mitosis, response to hypoxia and angiogenesis were still the top changes in 3D UC-MSCs compared with 2D UC-MSCs (Fig. 1d)
Summary
The hepatic ischemia-reperfusion injury (IRI) is a leading cause of primary graft dysfunction after liver transplantation and is associated with poor 1-year graft and patient survival rates of only 55% and 68%, respectively, compared with 90% and 93% for the remainder[1]. While some studies showed that MSC therapy could prevent hepatic IRI by suppressing inflammatory responses, oxidative stress and apoptosis[18,19,20,21], others failed to reduce hepatic IRI with the same kind of MSCs.[22,23,24] One reason for the failure might be that MSCs were short lived and did not migrate beyond the lungs after intravenous infusion[22,23,24] Another reason might be that MSCs could be either pro-inflammatory or anti-inflammatory depending on the levels of inflammatory cytokines[25], and which receptor was activated[26]. We aimed to study the benefit of 3D UC-MSCs for treating hepatic IRI compared with 2D UC-MSCs, and the potential mechanisms
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