Apoptosis: role in myeloid cell development

Abstract

Hematopoiesis is the process that generates blood cells in an organism from the pluripotent stem cells. Hematopoietic stem cells are characterized by their ability to undergo self-renewal and differentiation. The self-renewing ability ensures that these pluripotent cells are not depleted from the bone marrow niche. A proper balance between cell death and cell survival is necessary to maintain a homeostatic condition, hence, apoptosis, or programmed cell death, is an essential step in hematopoiesis. Recent studies, however, have introduced a new aspect to this process, citing the significance of the apoptosis mediator, caspase, in cell development and differentiation. Extensive research has been carried out to study the possible role of caspases and other apoptosis related factors in the developmental processes. This review focuses on the various apoptotic factors involved in the development and differentiation of myeloid lineage cells: erythrocytes, megakaryocytes, and macrophages.

Keywords: Apoptosis; Caspase; Differentiation; Erythrocyte; Megakaryocyte; Monocyte.

Fig. 1. Extrinsic and intrinsic pathways of apoptosis. The extrinsic pathway is initiated by ligation of death receptors with death ligands. This interaction results in the formation of the death inducing signaling complex (DISC), which contains the death receptor, an adaptor molecule, and pro-caspase 8. Adaptor molecules possess a death domain (DD) and a death effector domain (DED). At the DISC, caspase 8 is autocatalytically activated and subsequently transmits the death signal to effector executioner caspases, resulting in apoptotic cell death. The intrinsic pathway signaling cascade is triggered by a number of factors, including DNA damage, hypoxia, growth factor deprivation, and ER stress. The death signal is sensed initially by the BH3-only protein, which then interacts with the downstream mediators of apoptosis (BAX and BAK). BAX and BAK undergo distinct conformational changes, which lead to the formation of mitochondrial pores or increases the permeability of the mitochondrial outer membrane, thereby releasing apoptogenic compounds, e.g. cytochrome c. Released cytochrome c binds to APAF-1 to facilitate formation of the apoptosome, a wheel-shaped heptameric complex, which can then recruit and activate pro-caspase 9. As a consequence, caspase 9 activates effector caspases (caspase 3, 6, or 7) and eventually leading to apoptosis. Abbreviations: TNF, tumor necrosis factor; TRAIL, TNF related apoptosis inducing ligand; FADD, Fas-associated death domain protein; TRADD, TNF receptor-associated death domain protein; BID, BH3 interacting-domain death agonist; tBID, truncated BID; BAX, Bcl-2 homologous antagonist/killer; BAK, Bcl-2 associated X protein; APAF-1, apoptotic protease activating factor-1.

Fig. 2. Major steps in hematopoiesis. Multiple caspases and apoptotic factors are involved in myeloid cell development. Apoptosis is a major mechanism utilized by the hematopoietic system to regulate blood cell production.