Cytomegalovirus latency exacerbated small-for-size liver graft injury through activation of CCL19/CCR7 in hepatic stellate cells

Abstract

Background: The interplay between cytomegalovirus (CMV) latency and graft malfunction after living donor liver transplantation (LDLT) remains poorly defined due to the complexity of clinical confounding factors. Here, we aimed to investigate the effects of CMV latency on small-for-size graft injury and to get further insight on the pathogenic role of hepatic stellate cells (HSCs) in this process.

Methods: Rat orthotopic liver transplantation with small-for-size grafts was performed in a CMV latent model developed in immunocompetent Sprague Dawley (SD) rats using Priscott strain. Post-transplant graft injury including hepatocyte damage, stellate cell activation and fibrogenesis were evaluated. Differential gene expression of HSCs in response to CMV latency was screened by cDNA microarray. Clinical validation was further conducted in human biopsies.

Results: CMV latency aggravated hepatocyte apoptosis/necrosis in the early phase, enhanced HSC expansion and graft fibrosis during the middle-late phase in small-for-size liver grafts of the rat model. cDNA microarray mining revealed CCL19/CCR7 as one of the most noteworthy pathways bridging HSC activation and liver graft injury in the presence of CMV latency. Together with CCL19 upregulation, coherent overexpression of CCR7 in accumulated HSCs was confirmed in both rat and human CMV latent recipients. Moreover, addition of CCL19 in vitro promoted HSC migration by increasing the level of matrix metalloproteinase-2 (MMP2).

Conclusion: Our data demonstrated that CMV latency aggravated early/late phase liver graft damage and fibrogenesis via CCL19/CCR7/HSCs axis. Blockade of CMV latency-related stellate cell activation may shed light on the strategy of graft protection clinically.