Erythropoiesis: Model systems, molecular regulators, and developmental programs

Abstract

SummaryHuman erythropoiesis is a complex multistep developmental process that begins at the level of pluripotent hematopoietic stem cells (HSCs) at bone marrow microenvironment (HSCs niche) and terminates with the production of erythrocytes (RBCs). This review covers the basic and contemporary aspects of erythropoiesis. These include the: (a) cell-lineage restricted pathways of differentiation originated from HSCs and going downward toward the blood cell development; (b) model systems employed to study erythropoiesis in culture (erythroleukemia cell lines and embryonic stem cells) and in vivo (knockout animals: avian, mice, zebrafish, and xenopus); (c) key regulators of erythropoiesis (iron, hypoxia, stress, and growth factors); (d) signaling pathways operating at hematopoietic stem cell niche for homeostatic regulation of self renewal (SCF/c-kit receptor, Wnt, Notch, and Hox) and for erythroid differentiation (HIF and EpoR). Furthermore, this review presents the mechanisms through which transcriptional factors (GATA-1, FOG-1, TAL-1/ SCL/MO2/Ldb1/E2A, EKLF, Gfi-1b, and BCL11A) and miRNAs regulate gene pattern expression during erythroid differentiation. New insights regarding the transcriptional regulation of a-and b-globin gene clusters were also presented. Emphasis was also given on (i) the developmental program of erythropoiesis, which consists of commitment to terminal erythroid maturation and hemoglobin production, (two closely coordinated events of erythropoieis) and (ii) the capacity of human embryonic and umbilical cord blood (UCB) stem cells to differentiate and produce RBCs in culture with highly selective media. These most recent developments will eventually permit customized red blood cell production needed for transfusion.

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

“…Cells committed to differentiation undergo a programmed loss of proliferative capacity, restricted to only a few divisions because of their irreversible growth arrest in G 1 phase, and terminal erythroid differentiation is accompanied by arrest of the cell cycle in the G 1 /G 0 phase. 41 We briefly describe the role of these genes in cell proliferation and differentiation below.…”

Cloning and characterization of polyA-RNA transcripts encoded by activated B1-like retrotransposons in mouse erythroleukemia MEL cells exposed to methylation inhibitors

“…In this case, hypomethylation of LINE-1 promoter has also activated an alternate transcript of cMet, a result that may be related to bladder cancer predisposition and disease progression (12). MEL cell differentiation system has been proven a useful model to uncover cellular and molecular events of erythropoiesis involved in leukemic cell maturation in vitro (13)(14)(15). The promoter-like activity of B1-559 DNA region recently shown (5) and the observed structural similarity of the cloned RNA transcripts with the B1 element located within this locus extend our knowledge on how non-coding RNA molecules derived from genomic repetitive sequences can be generated, un-http://bmbreports.org der conditions where MEL cells are blocked to differentiation by the action of methylation inhibitors.…”

New Experimental Anemic Model by Using a Nitrogen- Containing Bisphosphonate

“…A variety of nuclear factors that are involved in transcriptional regulation are thought to be related to globin gene expression and switching between them [24,25]. Members of the KLF (Kruppel-like factor) family are essential transcription factors that bind GC-rich sequences to regulate the biological dynamic changes in globin expression during development [26].…”