Characterization, regulation, and targeting of erythroid progenitors in normal and disordered human erythropoiesis

Abstract

Purpose of review The erythroid progenitors BFU-E (burst-forming unit-erythroid) and CFU-E (colony-forming unit-erythroid) have a critical role in erythropoiesis. They represent a heterogeneous and poorly characterized population of cells with modifiable self-renewal, proliferation and differentiation capabilities. This review focuses on the current state of erythroid progenitor biology with regard to immunophenotypic identification and regulatory programs; in addition, we will discuss the therapeutic implications of using these erythroid progenitors as pharmacologic targets. Recent findings Erythroid progenitors are classically defined by the appearance of morphologically defined colonies in semisolid cultures. However, these prior systems preclude a more thorough understanding of the composite nature of progenitor populations. Recent studies employing novel flow cytometric and cell-based assays have helped to redefine hematopoiesis, and suggest that erythroid progenitors may arise from different levels of the hematopoietic tree. Moreover, the identification of cell surface marker patterns in human BFU-E and CFU-E enhance our ability to perform downstream functional and molecular analyses at the population and single cell level. Advances in these techniques have already revealed novel subpopulations with increased self-renewing capacity, roles for erythroid progenitors in globin gene expression, and insights into pharmacologic mechanisms of glucocorticoids and pomalidomide. Summary Immunophenotypic and molecular characterization resolves the diversity of erythroid progenitors and may ultimately lead to the ability to target these progenitors to ameliorate diseases of dyserythropoiesis.

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

“…The lack of uniform effective approaches to purify or even to consider the MEP as a player in hematopoiesis in different studies that have combined approaches including functional, single cell sequencing and lineage potential assays, suggests that the identification of MEPs and their subpopulations is highly dependent on the gating strategy [14]. Additionally, the more reliable MEP gating strategies published to date [10, 16, 56] demonstrate that these bipotent progenitors comprise a rare population (less than 1% of human CD34+ cells and murine Lin- cells) and are based on populations that are negative for different lineage markers rather than positive for others, as we are still lacking a positive and specific marker for MEP.…”

“…It is estimated that thousands of RBCs are generated from each erythroid committed progenitor. [14] The surface protein used most commonly to identify committed erythroid cells is glycophorin A (Gly A) for human cells and Ter119 for murine cells, as well as the transferrin receptor, CD71. Of note, CD71 is expressed on all dividing cells.…”

“…The controversy related to the existence of MEPs may be attributed in large part to misconceptions sustained by hematopoietic hierarchy models that include immunophenotypes, but which have ignored the fact that classic murine and human MEP gating strategies actually greatly enrich for unipotent erythroid progenitors, as shown in Table 1 [14, 21]. These erythroid-committed cells far outnumber the bipotent MEP within the classic immunophenotypically-defined populations referred to as “MEP.” In the murine system, Akashi et al identified the CD34-Lin-c-Kit+Sca- FcγRlowIL-7Ra- fraction of mouse bone marrow cells as MEP as the progeny of these cells in vitro lacked monocytes and granulocytes.…”

Stress erythropoiesis in atherogenic mice

“…The earliest committed erythroid progenitors identified ex vivo are the BFU-E and the further differentiated CFU-E, two populations of cells with modifiable self-renewal, proliferation and differentiation capabilities (reviewed in 57 ). Stress erythropoiesis increases BFU-E and CFU-E in the spleen 12 , 17 , 24 .…”

Adjunctive Corticosteroid Treatment in Septic Shock

“…Additionally, corticosteroids may have a positive effect on erythropoiesis. 39 At present, this finding should be considered to be hypothesis-generating.…”