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To be red or white: lineage commitment and maintenance of the hematopoietic system by the “inner myeloid”
1Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan and 3Present address, Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
ABSTRACT
Differentiation of hematopoietic stem and progenitor cells is tightly regulated depending on environmental changes in order to maintain homeostasis. Transcription factors direct the development of hematopoietic cells, such as GATA-1 for erythropoiesis and PU.1 for myelopoiesis. However, recent findings obtained from single-cell analyses raise the question of whether these transcription factors are “initiators” or just “executors” of differentiation, leaving the initiation of hematopoietic stem and progenitor cell differentiation (i.e. lineage commitment) unclear. While a stochastic process is likely involved in commitment, it cannot fully explain the homeostasis of hematopoiesis nor “on-demand” hematopoiesis in response to environmental changes. Transcription factors BACH1 and BACH2 may regulate both commitment and on-demand hematopoiesis because they control erythroid-myeloid and lymphoid-myeloid differentia- tion by repressing the myeloid program, and their activities are repressed in response to infectious and inflammatory conditions. We summarize possi- ble mechanisms of lineage commitment of hematopoietic stem and progen- itor cells suggested by recent findings and discuss the erythroid and lym- phoid commitment of hematopoietic stem and progenitor cells, focusing on the gene regulatory network composed of genes encoding key transcription factors. Surprising similarity exists between commitment to erythroid and lymphoid lineages, including repression of the myeloid program by BACH factors. The suggested gene regulatory network of BACH factors sheds light on the myeloid-based model of hematopoiesis. This model will help to understand the tuning of hematopoiesis in higher eukaryotes in the steady-state condition as well as in emergency conditions, the evolutional history of the system, aging and hematopoietic disorders.
Introduction
Hematopoietic stem cells (HSC) possess the abilities of self-renewal and multi- lineage differentiation, including that to red and white blood cells and platelets (i.e., erythrocytes, megakaryocytes, innate immune cells and acquired immune cells).1 Salient aspects of the hematopoietic system include its potential to pro- duce huge numbers of cells with distinct functions throughout the life span of a human and its tunability, by which the output is balanced in response to environ- mental changes, such as from the steady state to an infectious state.
Erythrocytes are the most abundant cells in the human body, accounting for around 70% of the total cell number2 and 200x109 erythrocytes are produced daily.3 Although the estimated number of white blood cells is much lower than that of erythrocytes,2 the short life span of myeloid cells necessitates the produc- tion of a huge number of these cells as well. For instance, the circulating half-life of neutrophils is 6-8 h, and their estimated production rate is 50-100x109 cells per day.4 In line with this, label tracing analyses of HSC have revealed that the pro- duction rate of erythroid-myeloid progenitors is about 180 times higher than that of lymphoid progenitors in unperturbed hematopoiesis.5 Thus, hematopoietic
Ferrata Storti Foundation
Haematologica 2019 Volume 104(10):1919-1927
Hiroki Kato1,2,3 and Kazuhiko Igarashi1
Correspondence:
KAZUHIKO IGARASHI
igarashi@med.tohoku.ac.jp
Received: February 14, 2019. Accepted: May 10, 2019. Pre-published: September 12, 2019.
doi:10.3324/haematol.2019.216861
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/10/1919
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