An erk-dependent feedback mechanism prevents hematopoietic stem cell exhaustion

Hematopoietic stem cells (HSCs), which are located in the bone marrow, also circulate in cord and peripheral blood. Despite high availability, HSCs from steady state peripheral blood are little known and not used for research or cell therapy. HSC, which ensure the permanent renewal of mature blood cells along life and exhibit capacity of long-term hematopoietic reconstitution, are located in the bone marrow, where they are surrounded by a variety of different cells. Bone marrow was the principal source of HSCs for many years, however basic and clinical strategies, and some therapeutic approaches have been developed using HSCs from cord blood or mobilized peripheral blood. HSCs give rise to blood and immune cells of the body and are therefore essential for our survival. The authors have shown how intracellular signaling can safeguard this delicate balance between activation and dormancy. Their results are published in the Journal of Cell Stem Cell .

Blood is the juice of life, as while circulating through the body it delivers vital substances such as oxygen and nutrients to cells and tissues. Chemotherapy, radiotherapy and blood loss, in general, impoverish the system. A special kind of cells in the bone marrow, called HSCs is able to replenish the impoverished system by giving rise not only to red blood cells but also to cells of the immune system. Thus, HSCs play an absolutely crucial role for survival.

The mechanism limiting the strength of MEK/ERK and AKT/mTORC1 signals during the activation of hematopoietic stem cells. The mechanism hinges on the negative feedback phosphorylation of MEK1 by activated ERK and is required to prevent HSC exhaustion.

Feedback phosphorylation of MEK1 by ERK limits AKT/ mTORC1 activation

ERK-mediated MEK1 phosphorylation returns activated HSCs to quiescence

To compensate for blood loss, HSCs, which are usually dormant, start to actively self-renew and differentiate into all blood cell types. After completing their task, however, HSCs need to revert back to their dormant state very rapidly, or they will exhaust. This requires a very delicate balance.

HSC activation is driven in part through the phosphatidylinositol 3-kinase (PI3K)/ AKT/mTORC1 signaling pathway. In this research, they delineated an ERK-dependent, rate-limiting feedback mechanism that controls HSC fitness and their re-entry into quiescence. They show that the MEK/ERK and PI3K pathways are synchronously activated in HSCs during emergency hematopoiesis and that feedback phosphorylation of MEK1 by activated ERK counterbalances AKT/ mTORC1 activation and MEK inhibitors developed for cancer therapy may find additional utility in controlling HSC activation. Genetic or chemical ablation of this feedback loop tilts the balance between HSC dormancy and activation, increasing differentiated cell output and accelerating HSC exhaustion.

Nguyen Van Tinh, PhD

Ref: Christian Baumgartner et al., 2018. Cell Stem Cell, 2018; DOI: 10.1016/j.stem.2018.05.003