Kupffer cells abrogate homing and repopulation of allogeneic hepatic progenitors in injured liver site

Abstract

Background Allogeneic hepatocyte transplantation is an emerging approach to treat acute liver defects. However, durable engraftment of the transplanted cells remains a daunting task, as they are actively cleared by the recipient’s immune system. Therefore, a detailed understanding of the innate or adaptive immune cells-derived responses against allogeneic transplanted hepatic cells is the key to rationalize cell-based therapies. Methods Here, we induced an acute inflammatory regenerative niche (3–96 h) on the surface of the liver by the application of cryo-injury (CI) to systematically evaluate the innate immune response against transplanted allogeneic hepatic progenitors in a sustained micro-inflammatory environment. Results The resulting data highlighted that the injured site was significantly repopulated by alternating numbers of innate immune cells, including neutrophils, monocytes and Kupffer cells (KCs), from 3 to 96 h. The transplanted allo-HPs, engrafted 6 h post-injury, were collectively eliminated by the innate immune response within 24 h of transplantation. Selective depletion of the KCs demonstrated a delayed recruitment of monocytes from day 2 to day 6. In addition, the intrasplenic engraftment of the hepatic progenitors 54 h post-transplantation was dismantled by KCs, while a time-dependent better survival and translocation of the transplanted cells into the injured site could be observed in samples devoid of KCs. Conclusion Overall, this study provides evidence that KCs ablation enables a better survival and integration of allo-HPs in a sustained liver inflammatory environment, having implications for rationalizing the cell-based therapeutic interventions against liver defects.

1. Introduction

A key pathological feature of the overwhelming liver damage is the massive mobilization of innate and adaptive immune responses leading to acute liver failure [1, 2]. Therapeutically, liver replacement, also known as orthotopic liver transplantation (OLT), remains an essential curative therapy for acute liver failure and end-stage liver injuries [3–5]. However, emerging data indicate that transplantation of healthy hepatocytes in acute and chronic liver failures may substitute the OLT in clinical practice [6–10].

Over the last decade, allogeneic hepatocyte transplantation has actively been pursued as an alternative approach to OLT for the cure of liver-based metabolic defects and acute liver failure [11, 12]. Although encouraging clinical benefits have been observed in patients receiving allogeneic hepatocyte transplantation [13, 14], durable engraftment of the transplanted cells despite using immunosuppression has not yet been achieved [13]. Generally, it is considered that a Kupffer cells (KCs)-derived pronounced hindrance is offered during the translocation of the transplanted cells from the portal spaces into the site of integration at the liver parenchyma, leading to their elimination [15–17]. It has also been reported that the exogenous transplanted cells are recognized by activated instant blood-mediated inflammatory reaction [18–22], in combination with cytokines and chemokines primarily derived from neutrophils and KCs [15, 23]. Recent experimental evidence suggests that survival of the cellular allograft is limited by multiple barriers, including the endothelial lining of the sinusoids and immune rejection followed by spontaneous apoptosis [24–28].