The role of graft injury in mobilization of endothelial progenitor cells, myeloid derived suppressor cells and regulatory T cells afterlive transplantation

Abstract

Liver transplantation is the best therapy for patients with end-stage liver diseases and unresectable early hepatocellular carcinoma (HCC). Living donor liver transplantation (LDLT) has been successfully implemented as an alternative to deceased donor liver transplantation (DDLT) and likewise offers comparable excellent survival rate. However, the inferior post-transplant oncological outcomes are found in LDLT recipients with HCC. The liver grafts used in LDLT are usually small-for-size and less effective in coping with shear stress from transient portal hypertension, which results in small-for-size liver graft injury. Acute phase small-for-size liver graft injury may promote late phase tumor recurrence, whereas the underlying mechanism remains unclear.

CXCL10, an inflammatory chemokine, initiates liver inflammatory response during hepatic ischemia-reperfusion (IR) injury and may link acute phase small-for-size liver graft injury and late phase tumor recurrence, yet the precise mechanisms remain elusive. Endothelial progenitor cells (EPCs) participate in tissue repair for graft recovery and also provide an angiogenic environment for tumor growth. Myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) can suppress the activation of the immune system and play a critical role in graft rejection and cancer development.

We here established the rat orthotopic liver transplantation with whole graft or small-for-size graft model to study the impact of acute phase small-for-size liver graft injury on the mobilization of EPCs, MDSCs and Tregs, and intragraft CXCL10 and its receptor, CXCR3,gene expressions. We further subjected CXCL10-/-mice and CXCR3-/-mice to hepatic IR injury and major hepatectomy to study the role of CXCL10/CXCR3 signaling on the mobilization of EPCs, MDSCs and Tregs. We also investigated the effect of CXCL10 on EPC migration and tube formation in vitroas well as intratumoral microvessel density (MVD) in the rat liver transplantation with tumor growth model and EPCs on tumor growth in nude mice.

Key findings:

1. Liver transplantation with small-for-size graft resulted in severe intragraft vascular injury and higher CXCL10 andCXCR3 gene expressions as well as more EPC, MDSC and Treg cell mobilizationin circulation than whole graft.

2. CXCL10-/-mice and CXCR3-/-mice had less circulating EPCs, MDSCs and Tregs than WT mice after hepatic IR injury and major hepatectomy.

3. CXCL10 recruited EPCs in dose-dependent and CXCR3-dependent manners and promoted EPC tube formation in vitro.

4. Higher intratumoral MVD was observed in small-for-size graft than in whole graft in liver transplantation with tumor growth model.

5. Tumor grew more quickly by combining EPC infusionin nude mouse orthotopic liver tumor model.

In conclusion, acute phase small-for-size liver graft injury significantly mobilizes EPCs, MDSCs and Tregs after transplantation through CXCL10/CXCR3 signaling. More EPC mobilization and intragraft differentiation after transplantation with small-for-size liver graft may be related to higher intratumoral MVD in small-for-size liver graft after transplantation with tumor development. Therefore, targeting at post-transplant CXCL10/CXCR3 signaling may not only attenuate early phase liver graft injury but also prevent late phase tumor recurrence.