From Erythroblasts to Mature Red Blood Cells: Organelle Clearance in Mammals

Abstract

Erythropoiesis occurs mostly in bone marrow and ends in blood stream. Mature red blood cells are generated from multipotent hematopoietic stem cells, through a complex maturation process involving several morphological changes to produce a highly functional specialized cells. In mammals, terminal steps involved expulsion of the nucleus from erythroblasts that leads to the formation of reticulocytes. In order to produce mature biconcave red blood cells, organelles and ribosomes are selectively eliminated from reticulocytes as well as the plasma membrane undergoes remodeling. The mechanisms involved in these last maturation steps are still under investigation. Enucleation involves dramatic chromatin condensation and establishment of the nuclear polarity, which is driven by a rearrangement of actin cytoskeleton and the clathrin-dependent generation of vacuoles at the nuclear-cytoplasmic junction. This process is favored by interaction between the erythroblasts and macrophages at the erythroblastic island. Mitochondria are eliminated by mitophagy. This is a macroautophagy pathway consisting in the engulfment of mitochondria into a double-membrane structure called autophagosome before degradation. Several mice knock-out models were developed to identify mitophagy-involved proteins during erythropoiesis, but whole mechanisms are not completely determined. Less is known concerning the clearance of other organelles, such as smooth and rough ER, Golgi apparatus and ribosomes. Understanding the modulators of organelles clearance in erythropoiesis may elucidate the pathogenesis of different dyserythropoietic diseases such as myelodysplastic syndrome, leukemia and anemia.

Red blood cell-derived extracellular vesicles mediate intercellular communication in ischemic heart failure

“…To demonstrate the presence of Cre-recombinase in RBC-EVs, we assessed Cre mRNA and protein expression levels in RBC-EVs derived from EpoR-Cre and mTmG mice. Real time PCR showed the presence of Cre-recombinase mRNA in bone marrow cells, but their absence in peripheral blood and RBC-EVs (Figure 1D, E), consistent with the general absence of mRNAs in RBCs (Moras et al, 2017) but the presence of the prototypical RBC miRNA miR-451 in all three compartments (bone marrow cells, RBCs and RBC-EVs). However, western blot confirmed the presence of Cre-recombinase protein in RBC-EVs (Figure 1F), suggesting that Cre protein present in RBCs can be incorporated into RBC-EVs.…”

An interphase contractile ring reshapes primordial germ cells to allow bulk cytoplasmic remodeling

“…PGC lobe formation also shares similarities and differences with erythroblast enucleation. In erythroblasts, the nucleus migrates to one side of the cell, which subsequently forms and constricts an equatorial contractile ring to separate the cytoplasmic compartment from the nuclear compartment (Moras et al, 2017;Ovchynnikova et al, 2018). However, a key difference is in how the contractile ring is regulated.…”

“…Alternatively, some cells discard contents in bulk by creating a compartment that is filled with undesired cellular material and eliminated. For example, during erythropoiesis in mammals, erythroblasts form a subcellular compartment containing the nucleus, which is subsequently removed and digested by macrophages to leave behind an anucleate immature red blood cell (Moras et al, 2017). Similar remodeling events occur in the germ line, such as during spermatogenesis, when many cellular components are discarded in the residual body (Nishimura and L'Hernault, 2017).…”

Integrative proteomics reveals principles of dynamic phospho-signaling networks in human erythropoiesis

“…The first recognizable erythroid precursors are proerythroblasts (ProE), which mature progressively into early basophilic (EBaso) and late basophilic (LBaso) erythroblasts, polychromatic erythroblasts (Poly), orthochromatic (Ortho) erythroblasts and reticulocytes. Terminal erythroid maturation is distinguished by progressive reductions in proliferative capacity and cell size, chromatin condensation, loss of most organelles including the nucleus, and remarkable streamlining of the proteome with expression of specialized cytoskeletal and plasma membrane proteins and finally massive accumulation of hemoglobin (Moras et al, 2017;Nguyen et al, 2017;Zhao et al, 2016b). This finely tuned developmental process generates mature erythrocytes with the highly specialized function of circulatory oxygen/carbon dioxide transport.…”