Autophagy is required for stem cell mobilization by G-CSF

Abstract

Key Points• G-CSF activates autophagy in HSCs and neutrophils.• The response and survival of HSCs mobilized by G-CSF in vivo require autophagy.Granulocyte colony-stimulating factor (G-CSF) is widely used clinically to prevent neutropenia after cytotoxic chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Autophagy, a process of cytoplasmic component recycling, maintains cellular homeostasis and protects the cell during periods of metabolic stress or nutrient deprivation. We have observed that G-CSF activates autophagy in neutrophils and HSCs from both mouse and human donors. Furthermore, G-CSF-induced neutrophil and HSC mobilization is impaired in the absence of autophagy. In contrast, autophagy is dispensable for direct HSC mobilization in response to the CXCR4 antagonist AMD3100. Altogether, these data demonstrate an important role for G-CSF in invoking autophagy within hematopoietic and myeloid cells and suggest that this pathway is critical for ensuring cell survival in response to clinically relevant cytokine-induced stress. These findings have direct relevance to HSC transplantation and the increasing clinical use of agents that modulate autophagy. (Blood. 2015;125(19):2933-2936

Metabolic effects of fasting on human and mouse blood in vivo

“…Contrary to mice, in which all leukocyte subpopulations exhibited signs of enhanced autophagic flux, only neutrophils from healthy volunteers presented an increased number of LC3B C puncta, in line with previous findings showing autophagy activation in this population. 54,55 In addition, it has been previously demonstrated that detection of autophagy in neutrophils can be used to monitor autophagic flux at the whole body level in the context of pathological settings. 56 At present, the reasons for this discrepancy between mice and humans with respect to autophagy induction in all leukocyte subpopulation and neutrophils only, respectively, are elusive.…”

Mechanisms of self-renewal in hematopoietic stem cells

“…The deletion of My-D88, an adaptor protein required for most TLR signaling, attenuated the G-CSFinduced effect on HSCs [4]. More recently, Mouttie et al reported that G-CSF could enhance autophagy in HSCs [77]. Autophagy was previously suggested to be required for HSC maintenance [78].…”

Acute myeloid leukemia stem cell function is preserved in the absence of autophagy

“…However, the use of such agents to potentiate the effects of chemotherapy may be efficacious in some settings. Additionally, modulation of autophagy is likely to have several deleterious effects such as diminishing G-CSF response 6 , impairment of normal HSC function 2 and altering T-cell homeostasis 5 .…”

“…Within the hematopoietic system, autophagy has diverse roles and is required for hematopoietic stem cell (HSC) function 2 , differentiation into erythroid 3 or T-lymphoid lineages 4,5 and response to extracellular cytokine signaling 6 . In blood cancers such as acute myeloid leukaemia (AML), modulating autophagy has been proposed as a novel therapy to treat AML 1,7,8 .…”

“…Similarly, loss of other critical regulators such as Atg5 result in impaired autophagic flux. Autophagy regulates several important processes in the hematopoietic system including HSC maintenance, cytokine responsiveness and T-cell homeostasis 2,3,5,6 .…”