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

Abstract

Purpose of review: The erythroid progenitors burst-forming unit-erythroid and colony-forming unit-erythroid have a critical role in erythropoiesis. These cells represent a heterogeneous and poorly characterized population 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 characterized 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 burst-forming unit-erythroid and colony-forming unit-erythroid 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.

Figure 1. Erythroid lineage potential arises from different progenitor subsets according to revised hematopoietic hierarchy

(A) Classical view of hematopoiesis suggests that erythroid progenitors are derived from discrete multipotent progenitors populations that undergo a series of differentiation steps whereby these progenitor cells become increasingly erythroid restricted. (B–C) New insights reveal that hematopoiesis is specific of the developmental stage and progenitor populations are heterogeneous. A simplified view of these findings with an emphasis on erythroid differentiation is depicted. During fetal hematopoiesis (B), erythroid potential arises from multipotent, oligopotent and unipotent progenitors. Conversely, the adult erythroid lineage (C) is derived from multipotent stem and predominantly unipotent progenitors. Finally, and common to both, erythroid progenitors can arise from a bypass directly from the multipotent progenitor.

Figure 2. Pomalidomide and glucocorticoids are hypothesized to act on different erythroid progenitor populations

(A) During steady-state erythropoiesis in the adult, the BFU-E population contains a small minority of HbF-producing cells (purple), and cells possess limited self-renewal. BFU-Es differentiate into CFU-Es followed by erythroid precursors and erythrocytes containing mainly adult hemoglobin (HbA). (B) Glucocorticoids appear to affect erythroid progenitors in a species-specific manner. In mice, glucocorticoids increase BFU-E self-renewal (green), whereas increased CFU-Es may result from glucocorticoid treatment in humans. The proportion of HbF-producing cells (purple) remains unchanged by glucocorticoid treatment. (C) Pomalidomide exerts its effect at BFU-E or on the BFU-E to CFU-E transition to induce HbF and increase BFU-E numbers through two potential mechanisms: (i) stimulate the expansion of pre-programmed HbF producing BFU-E (purple) or (ii) reprogram adult progenitors to prevent γ-globin repression (striped).