Concise Review: Bipotent Megakaryocytic-Erythroid Progenitors: Concepts and Controversies

Abstract

Hematopoietic stem and progenitor cells maintain blood formation throughout our lifetime by undergoing long- and short-term self-renewal, respectively. As progenitor cells progress through the hematopoiesis process, their differentiation capabilities narrow, such that the precursors become committed to only one or two lineages. This Review focuses on recent advances in the identification and characterization of bipotent megakaryocytic-erythroid progenitors (MEP), the cells that can further produce two completely different functional outputs: platelets and red blood cells. The existence of MEP has sparked controversy as studies describing the requirement for this intermediate progenitor stage prior to commitment to the erythroid and megakaryocytic lineages have been potentially contradictory. Interpretation of these studies is complicated by the variety of species, cell sources, and analytical approaches used along with inherent challenges in the continuum of hematopoiesis, where hematopoietic progenitors do not stop at discrete steps on single paths as classically drawn in hematopoietic hierarchy models. With the goal of improving our understanding of human hematopoiesis, we discuss findings in both human and murine cells. Based on these data, MEP clearly represent a transitional stage of differentiation in at least one route to the generation of both megakaryocytes and erythroid cells. Stem Cells 2018;36:1138-1145.

Severe ineffective erythropoiesis discriminates prognosis in myelodysplastic syndromes: analysis based on 776 patients from a single centre

“…Our prior study 13 showed that numbers of BFU-E and CFU-E in MDS patients were obviously lower than healthy controls, which was confirmed in this study after expanding the sample size. In the present study, we further found that levels of HSCs and MEPs, which is a transitional stage of differentiation to both megakaryocytes and erythrocytes earlier than the BFU-E stage 29,30 , had already reduced in MDS. For a long time, the increased apoptosis of BM erythroid cells was considered to be responsible for ineffective erythropoiesis in MDS.…”

The role of the red blood cell and platelet in the evolution of mammalian and avian endothermy

“…The model, unlike the mammalian model, depicts the formation of a polymerizing fibrin clot as the first step in repairing a vessel wall injury (b(iii)) followed by the binding of thrombocytes to collagen and a hard clot-forming with some cross-linking of thrombocytes and trapping of RBCs within the clot (b(iii,iv)) SOSLAU | 123 dearth of knowledge about their role in hemostasis and responses to platelet agonists. The progenitor cell for nonmammalian RBCs and thrombocytes is a bipotential thrombocytic/erythroid progenitor cell (TEPs) derived from self-renewing hematopoietic stem cells (HSCs; Svoboda & Bartunek, 2015;Svoboda et al, 2014;Tanizaki et al, 2015) in a sequence akin to the mammalian system that ultimately yields RBCs and megakaryocytes from the bipotential megakaryocyte/ erythroid progenitor cell (MEPs; Svoboda & Bartunek, 2015;Wong, Dolinska, Sigvardsson, Ekblom & Qian, 2016;Woolthuis & Park, 2016;Xavier-Ferrucio & Krause, 2018). Some evidence indicates that the mammalian bipotential MEP cell and its progeny cells, RBCs, and megakaryocytes, may also arise from alternate pathways (Woolthuis & Park, 2016;Xavier-Ferrucio & Krause, 2018).…”

“…The progenitor cell for nonmammalian RBCs and thrombocytes is a bipotential thrombocytic/erythroid progenitor cell (TEPs) derived from self-renewing hematopoietic stem cells (HSCs; Svoboda & Bartunek, 2015;Svoboda et al, 2014;Tanizaki et al, 2015) in a sequence akin to the mammalian system that ultimately yields RBCs and megakaryocytes from the bipotential megakaryocyte/ erythroid progenitor cell (MEPs; Svoboda & Bartunek, 2015;Wong, Dolinska, Sigvardsson, Ekblom & Qian, 2016;Woolthuis & Park, 2016;Xavier-Ferrucio & Krause, 2018). Some evidence indicates that the mammalian bipotential MEP cell and its progeny cells, RBCs, and megakaryocytes, may also arise from alternate pathways (Woolthuis & Park, 2016;Xavier-Ferrucio & Krause, 2018). The ultimate production of RBCs and thrombocytes/platelets in both nonmammalian and mammalian systems is dictated by levels of TPO (thrombopoietin) and EPO (erythropoietin) that bind to analogous receptors stimulating similar signaling pathways in both cell types (Svoboda & Bartunek, 2015;Svoboda et al, 2014;Tanizaki et al, 2015;Woolthuis & Park, 2016;Xavier-Ferrucio & Krause, 2018).…”

“…Some evidence indicates that the mammalian bipotential MEP cell and its progeny cells, RBCs, and megakaryocytes, may also arise from alternate pathways (Woolthuis & Park, 2016;Xavier-Ferrucio & Krause, 2018). The ultimate production of RBCs and thrombocytes/platelets in both nonmammalian and mammalian systems is dictated by levels of TPO (thrombopoietin) and EPO (erythropoietin) that bind to analogous receptors stimulating similar signaling pathways in both cell types (Svoboda & Bartunek, 2015;Svoboda et al, 2014;Tanizaki et al, 2015;Woolthuis & Park, 2016;Xavier-Ferrucio & Krause, 2018). In fact, it is proposed that TPO and EPO and their respective receptors evolved from single genes that underwent duplication during evolution (Svoboda & Bartunek, 2015).…”

Cell Lineage and Communication Network Inference via Optimization for Single-cell Transcriptomics

“…Hematopoiesis, the hierarchical formation of different blood cell types from a common multipotent stem cell, involves complex cell state transitions and cell fate decision processes that are still incompletely understood (66)(67)(68)(69)(70). A multistep differentiation process involving successively restricted progenitor cell populations has been the dominant model to describe blood formation (71), although in some lineages restriction (to unipotency) may occur much earlier than previously thought (72).…”