Abstract
ObjectivesTransfusion of umbilical cord‐derived mesenchymal stem cells (UC‐MSCs) is a novel strategy for treatment of various liver diseases. However, the therapeutic effect of UC‐MSCs is limited because only a few UC‐MSCs migrate towards the damaged regions. In this study, we observed the effects of autophagy on the migration of UC‐MSCs in vitro and in a model of liver ischaemia/reperfusion (I/R) injury.Materials and MethodsWe investigated the effects of autophagy on the status of the cell, release of anti‐inflammatory factors and migration of UC‐MSCs in vitro. The therapeutic effects and in vivo migration of rapamycin‐preconditioned UC‐MSCs were observed in a C57/B6 mouse model of liver I/R injury.ResultsInduction of autophagy by rapamycin enhanced the ability of UC‐MSCs to migrate and release anti‐inflammatory cytokines as well as increased expression of CXCR4 without affecting cell viability. Inhibition of CXCR4 activation markedly decreased migration of these cells. In a mouse model of liver I/R injury, we found significantly upregulated expression of CXCR12 in the damaged liver. More rapamycin‐preconditioned UC‐MSCs migrated towards the ischaemic regions than 3‐methyladenine‐preconditioned or non‐preconditioned UC‐MSCs, leading to improvement in hepatic performance, pathological changes and levels of inflammatory cytokines. These effects were abolished by AMD3100.ConclusionsPreconditioning of UC‐MSCs by rapamycin afforded increased protection against liver I/R injury by enhancing immunosuppression and strengthening the homing and migratory capacity of these cells via the CXCR4/CXCL12 axis.
Highlights
Liver ischaemia/reperfusion (I/R) injury is a complicated pathophysi‐ ological process that can lead to initial poor function or primary non‐ function of the liver as well as increased morbidity and mortality after hepatectomy and liver transplantation.[1]
Witte showed that pre‐treatment with various cytokines was benefit for umbilical cord‐derived mesenchymal stem cells (UC‐Mesenchymal stem cells (MSCs)) to treat inflamma‐ tory liver disease by promoting their immunomodulatory capacity,[20] and Dang et al demonstrated that treated with cytokines before ap‐ plication could enhance the roles of MSCs in improving experimental autoimmune encephalomyelitis via upregulating their immunoregu‐ latory function.[21]
We evaluated the efficiency of rapamycin‐treated umbilical cord‐derived (UC)‐MSCs in an in vivo liver I/R injury model
Summary
Liver ischaemia/reperfusion (I/R) injury is a complicated pathophysi‐ ological process that can lead to initial poor function or primary non‐ function of the liver as well as increased morbidity and mortality after hepatectomy and liver transplantation.[1]. Several previous studies have reported hypoxia‐ preconditioned MSCs played a beneficial effect on atten‐ uating acute kidney injury via enhancing the ability of angiogenesis and anti‐oxidation, and strengthened the therapeutic effects for renal I/R injury through upregulated SDF‐1‐CXCR4/CXCR7 axis and chemotaxis.[18,19]. Witte showed that pre‐treatment with various cytokines was benefit for UC‐MSCs to treat inflamma‐ tory liver disease by promoting their immunomodulatory capacity,[20] and Dang et al demonstrated that treated with cytokines before ap‐ plication could enhance the roles of MSCs in improving experimental autoimmune encephalomyelitis via upregulating their immunoregu‐ latory function.[21]. Some studies have shown a correlation between autophagy in MSCs and immunosuppression.[21,27] It is unclear whether induc‐ tion of autophagy would strengthen homing of MSCs to damaged liver tissue or have a therapeutic effect in liver I/R injury. We evaluated the efficiency of rapamycin‐treated UC‐MSCs in an in vivo liver I/R injury model
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