Autophagy and haematopoietic stem cell transplantation

Abstract

Allogeneic haematopoietic stem cell transplantation (HSCT) represents the only curative therapy for the majority of bone marrowderived cancers. Unfortunately, HSCT can result in serious complications such as graft-versus-host disease, graft failure and infection. In the last decade, there have been major advances in the understanding of the role of autophagy in many diseases and cellular processes. Recent findings have demonstrated a crucial role for autophagy in haematopoietic stem cell survival and function, antigen presentation, T-cell differentiation and response to cytokine stimulation. Given the critical requirement for each of these processes in HSCT and subsequent complications, it is surprising that the contribution of autophagy to HSCT per se is relatively unexplored. In addition, the increasing use of autophagy-modulating drugs in the clinic further highlights the need to understand the role of autophagy in allogeneic HSCT. This review will cover established and implicated roles of autophagy in HSCT, suggesting this pathway as an important therapeutic target for improving transplant outcomes. Autophagy is a self-degradative process responsible for the elimination of cytosolic components including most long-lived proteins, aggregated proteins and also damaged organelles (for example, mitochondria, ribosomes, peroxysomes). Research over the last two decades has increased our understanding of the autophagic process, and has provided critical tools for dissecting the role of autophagy in various physiological settings. Autophagy is a multistep process regulated by protein complexes comprised of autophagy-related genes (Atg). Currently, more than 30 Atg genes have been described, and these proteins coordinately regulate the autophagy process. Initiation of autophagy through phosphoinositide 3-kinase class III-dependent activation of the complex ULK1/2-

Innate Immune Activation by Tissue Injury and Cell Death in the Setting of Hematopoietic Stem Cell Transplantation

“…Cells under stress or undergoing starvation utilize autophagy to degrade and recycle organelles and intracellular macromolecules ( 41 , 42 ). The role of autophagy in HSCT is unclear and is likely complex due to both pro- and anti-inflammatory properties of the autophagy process [reviewed by Leveque et al ( 43 )]. Treatment with radiation has been shown to upregulate autophagy in multiple cell types, particularly cells forming the gut barrier ( 44 ) and autophagy is theorized to limit inflammation by degrading inflammasomes ( 25 , 45 ).…”

Autophagy and immunity

“…In this Special Feature, Denton et al 5 discuss the involvement of autophagy in specific cell death pathways and how this may impact on immune responses. Finally, Leveque et al 6 discuss the potentially critical roles of autophagy in haematopoietic stem-cell (HSC) transplantation, both in promoting HSC survival and function and regulating the inflammatory response at the time of engraftment.…”

The contribution of cytokine signals, autophagy and antigen presentation to complications associated with allogeneic stem cell transplantation

“…This includes an important role in the maintenance and function of stem cells in addition to multiple mature immune cells [80,81]. HSC utilize autophagy in order to maintain characteristics that ensure their pluripotency and longevity in the steady state [82]. Chapter 4 on this thesis focuses on the critical requirement for autophagy in the HSC donor graft and extends analysis into the highly inflammatory setting of SCT.…”

“…Thus, autophagy plays an important role in maintaining healthy HSC function and differentiation. In a recent review we proposed that autophagy was likely a key mechanism employed by the donor HSC graft to survive and thrive in the inflammatory conditions of allogeneic stem cell transplantation (SCT) [82]. However, studies examining the role of autophagy in HSCs and HSPCs in the setting of SCT do not encompass GVHD.…”

“…An alternative to these approaches is to enhance the ability of the ingoing cells to successfully engraft. The process of successful engraftment relies on ingoing donor HSCs and HSPCs trafficking to the BM niche and then engaging with the appropriate supporting cells in order to survive and differentiate into all of the mature lineages that constitute whole blood [82]. Cells within the transplanted graft encounter numerous stresses initiated by factors including recipient myelotoxic conditioning, which ablates the tumour burden but also causes additional tissue damage impacting the BM niche and other tissues such as the gut [26,243].…”