Donor and recipient hematopoietic stem and progenitor cells mobilization in liver transplantation patients

Abstract

Background Hematopoietic stem and progenitor cells (HSPCs) mobilize from bone marrow to peripheral blood in response to stress. The impact of alloresponse-induced stress on HSPCs mobilization in human liver transplantation (LTx) recipients remains under-investigated. Methods Peripheral blood mononuclear cell (PBMC) samples were longitudinally collected from pre- to post-LTx for one year from 36 recipients with acute rejection (AR), 74 recipients without rejection (NR), and 5 recipients with graft-versus-host disease (GVHD). 28 PBMC samples from age-matched healthy donors were collected as healthy control (HC). Multi-color flow cytometry (MCFC) was used to immunophenotype HSPCs and their subpopulations. Donor recipient-distinguishable major histocompatibility complex (MHC) antibodies determined cell origin. Results Before LTx, patients who developed AR after transplant contained more HSPCs in PBMC samples than HC, while the NR group patients contained fewer HSPCs than HC. After LTx, the HSPC ratio in the AR group sharply decreased and became less than HC within six months, and dropped to a comparable NR level afterward. During the one-year follow-up period, myeloid progenitors (MPs) biased differentiation was observed in all LTx recipients who were under tacrolimus-based immunosuppressive treatment. During both AR and GVHD episodes, the recipient-derived and donor-derived HSPCs mobilized into the recipient’s blood-circulation and migrated to the target tissue, respectively. The HSPCs percentage in blood reduced after the disease was cured. Conclusions A preoperative high HSPC ratio in blood characterizes recipients who developed AR after LTx. Recipients exhibited a decline in blood-circulating HSPCs after transplant, the cells mobilized into the blood and migrated to target tissue during alloresponse.

1. Introduction

Liver transplantation (LTx) has been established as an essential clinical option in the treatment of patients with end-stage liver failure [1]. Alloresponse is an immune reaction towards allogeneic antigens, it plays a central role in both acute rejection (AR) and graft versus host disease (GVHD) following LTx to hinder the success of LTx [2]. AR occurs in about 30% of LTx patients on tacrolimus-based immunosuppressive protocols, it increases the risk of graft failure, all-cause mortality, and graft failure-related death by damaging the liver graft [3]. Despite the rarity, GVHD is a deadly immune complication following LTx that severely damages several of the recipient’s target tissues including skin, gastrointestinal tract and hematopoietic tissues [4, 5]. Both of the inflammatory processes trigger stress responses in the transplanted recipients.

Hematopoietic stem and progenitor cells (HSPCs) possess the ability of self-renewal and multi-lineage differentiation to sustain hematopoietic homeostasis. Typically, most of the HSPCs reside in the bone marrow, with only a tiny portion circulating in peripheral blood and tissues. Under emergency stress, hematopoietic stem cells (HSCs) are activated and proliferate, a phenomenon known as emergency myelopoiesis [6, 7]. Several studies have reported that stress-induced conditions, such as infection and inflammation, can induce the mobilization of HSPCs. During this process, HSPCs exhibit the capacity to discern signals indicative of inflammation to mobilize and accumulate within peripheral tissues that are subject to inflammatory processes to contribute to the enhancement of the immune cell population, thereby boosting the tissue’s defensive capabilities against infection [8–10]. However, the HSPC mobilization before and after LTx and during an AR or GVHD episode in LTx recipients has been inadequately explored.