Origins of the Vertebrate Erythro/Megakaryocytic System

Abstract

Vertebrate erythrocytes and thrombocytes arise from the common bipotent thrombocytic-erythroid progenitors (TEPs). Even though nonmammalian erythrocytes and thrombocytes are phenotypically very similar to each other, mammalian species have developed some key evolutionary improvements in the process of erythroid and thrombocytic differentiation, such as erythroid enucleation, megakaryocyte endoreduplication, and platelet formation. This brings up a few questions that we try to address in this review. Specifically, we describe the ontology of erythro-thrombopoiesis during adult hematopoiesis with focus on the phylogenetic origin of mammalian erythrocytes and thrombocytes (also termed platelets). Although the evolutionary relationship between mammalian and nonmammalian erythroid cells is clear, the appearance of mammalian megakaryocytes is less so. Here, we discuss recent data indicating that nonmammalian thrombocytes and megakaryocytes are homologs. Finally, we hypothesize that erythroid and thrombocytic differentiation evolved from a single ancestral lineage, which would explain the striking similarities between these cells.

Figure 1

A comparative view of erythrocytes and thrombocytes from zebrafish (Danio rerio), xenopus (Xenopus laevis), chicken (Gallus gallus), or human (Homo sapiens) peripheral blood. Cells were smeared on glass slides and stained with May-Grünwald Giemsa. Photomicrographs were taken at 1000x magnification. Scale bar is 20 μm.

Figure 2

Models of mammalian adult hematopoiesis with respect to the megakaryocytic-erythroid compartment (grey box). Hierarchical [20, 21] (black arrows) and myeloid bypass [25] (red arrowheads) models of hematopoiesis are shown. According to the conventional hierarchical model of hematopoiesis, the bipotent megakaryocyte-erythroid progenitors (MEPs) are able to give rise to megakaryocytes and erythrocytes. The alternative myeloid bypass model predicts the existence of various myeloid repopulating progenitors (MyRPs) as a subset of long-term hematopoietic stem cells (LT-HSCs), such as common myeloid repopulating progenitors (CMRPs), megakaryocyte repopulating progenitors (MkRPs), and megakaryocyte-erythroid repopulating progenitors (MERPs). These progenitors are capable of long-term repopulation and differentiation into the particular cell lineages. ST-HSC: short-term HSC; MPP: multipotent progenitor cell; CLP: common lymphoid progenitor; GMP: granulocyte/monocyte progenitor; CFU-Mk: colony-forming unit-megakaryocyte; BFU-E: burst-forming units-erythroid; CFU-E: colony-forming units-erythroid.

Figure 3

Composite summary of the most prominent factors and signals involved in the regulation of erythro-thrombopoiesis. Erythroid signals are in red, thrombocytic signals are in blue, and signals involved in both differentiation pathways are depicted in black. Human TPO ligand and TPOR are shown in blue; human EPO and EPOR are shown in red. Tyrosine residues (Y, pink lines) in TPOR/EPOR intracellular domains important for receptor signaling are shown. Some of them are highly conserved throughout the vertebrate species as demonstrated in the table. Cytokines' signal peptides are in black and EPO/TPO domains are shown. Receptors' WSXSW motifs are in grey and squared boxes represent Box1/Box2. Cs represent conserved Cys residues; ∗s represent glycosylation sites.

Figure 4

Nonmammalian and mammalian model of erythropoiesis and thrombopoiesis. According to the integrated model of hematopoiesis, mammalian erythrocytes and megakaryocytes have likely evolved from their nonmammalian erythroid and thrombocytic homologs as an evolutionary improvement. Nonmammalian erythrocytes and thrombocytes are phenotypically similar (nucleated, diploid oval-shaped cells), whereas mammalian megakaryocytes and erythrocytes are very different from each other. Numbers indicate the proliferation potential of particular progenitors. TEP: thrombocyte-erythroid progenitor; CFU-T: colony-forming unit-thrombocyte. Modified from Bartunek et al. [16] and Svoboda et al. [17].

Figure 5

The common ancestral erythro-thrombocytic model predicts the existence of unilineage differentiation in ancestral vertebrates, leading to ancient erythroid or thrombocytic cells or erythro-thrombocytic cells with dual function. Hypothetical duplication of cell types and their signalosomes led to the origin of erythrocytes with EPO signaling and to the origin of thrombocytes together with TPO signaling.