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H. Kato et al.
stem and progenitor cells (HSPC) have an exceptionally vigorous ability to produce huge numbers of cells consti- tutively. To maintain its homeostasis, the production pace of each mature cell lineage must be tightly regulated according to environmental changes (“on-demand” hematopoiesis).
Infection is one of the most common challenges facing hematopoiesis and evokes the induction of myelopoiesis as well as the suppression of erythropoiesis.6 Induced myelopoiesis during an infection is an effective way of eliminating pathogens, whereas the repression of ery- thropoiesis may help by limiting the availability of nutri- tional iron supply to pathogens and/or red blood cells as a target of infection, such as in malaria infection.7 However, infection and prolonged inflammation can cause anemia of inflammation, which is the second-most prevalent type of anemia after iron-deficiency anemia.8
As with infection, the activity of HSPC is also altered with aging and in various disease conditions. The pro- duction of erythrocytes is often reduced in elderly peo- ple, leading to anemia,9 and acquired immunity becomes less effective with aging, which can result in increased susceptibility to infectious diseases and malignancy in the elderly.10,11 In contrast, the production of myeloid cells often increases with aging.11,12 This skewed trajecto- ry selection of HSPC induced by aging might be related to the development of aging-related hematopoietic disor- ders, such as myelodysplastic syndrome (MDS). Although the molecular mechanisms by which the func- tion and differentiation of HSPC are altered by aging are still largely unknown, emerging evidence suggests contri- butions of inflammation and/or inflammatory signaling to aging of HSPC.13
In order to facilitate the treatment of infection-associ- ated and aging-associated diseases, it is important to understand the mechanisms by which the differentiation trajectory of HSPC and their commitment are defined at steady state and how these mechanisms are altered in inflammatory conditions. Although accumulating knowledge has shown that transcription factors (TF) play central roles in the differentiation of HSPC, the precise mechanisms underlying the initial lineage commitment and “on-demand” hematopoiesis are still unclear and cannot be wholly attributed to TF. Complicating matters further is the fact that HSPC are substantially heteroge- neous and many appear to be already committed to cer- tain differentiation fates.14-16 It is, therefore, important to distinguish the roles of TF in initiating the commitment of uncommitted progenitors from that of their executive roles in the progression of differentiation toward a par- ticular fate. Thus, the actual point of differentiation com- mitment may need to be reconsidered.
We recently demonstrated the roles of BTB and CNC homology (BACH) TF, BACH1 and BACH2 (BACH fac- tors), in instructing erythroid-myeloid progenitors and lymphoid-myeloid progenitors to respond to environ- mental changes.17-19 BACH factors form heterodimers with small Maf proteins to bind to the Maf recognition element (MARE), which contains an AP-1 site.20 Importantly, AP-1 sites play central roles in hematopoiet- ic cell immune reactions.20,21 BACH1 plays important roles in the maturation of erythrocytes by balancing heme and globin proportions, especially in the condition of iron deficiency,22 whereas BACH2 plays important roles in the development of plasma cells, memory B cells,
regulatory T cells and memory T cells.23-30 These findings suggest ubiquitous roles for BACH factors in the mainte- nance of homeostasis in both steady-state and inflamma- tory-state hematopoiesis, as described below.
In this review, we summarize the latest findings con- cerning the mechanisms underlying lineage commitment of HSPC and potential questions to be addressed. We also discuss gene regulatory networks composed of genes encoding key TF which compete for lineage iden- tities and downstream genes encoding effector mole- cules, focusing particularly on erythroid-myeloid and lymphoid-myeloid differentiation, two major points of commitment in HSPC differentiation. In addition, we review the roles of BACH factors in the myeloid-based model of hematopoiesis, which may provide a new con- cept of the fundamental mechanism in HSPC differentia- tion, and its meaning in an evolutionary perspective. We also discuss the diverse functions of BACH factors in mature hematopoietic cells as a strategy to cope with environmental changes through the maintenance of hematopoiesis. Finally, we describe how changes in line- age commitment can lead to diseases, such as anemia of inflammation and MDS.
Lineage commitment of hematopoietic stem and progenitor cells
The multipotency of HSC has been demonstrated by single-cell transplantation into irradiated mice.31 This led to vigorous investigations into how HSC differentiate into diverse lineages of cells with distinct functions. The isolation and characterization of progenitor cells led to the idea that HSC gradually and systematically lose mul- tipotency, generating progenitor cells with limited differ- entiation trajectories, such as common myeloid progeni- tors (CMP),32 which can generate myeloid cells and ery- throid cells but not lymphoid cells. On the other hand, although all blood cells derive from a FLT3+ multipotent progenitor stage,33 lymphoid-primed multipotent progen- itors (LMPP) preferentially differentiate into lymphoid cells and myeloid cells with a low differentiation poten- tial to erythroid cells.34-36 This led to the recognition that HSC eventually lose their ability to differentiate to ery- throid or lymphoid cells, leaving erythroid-myeloid bifurcation and lymphoid-myeloid bifurcation as the two major subsequent points of branching.
Such subpopulations of progenitors have been defined based on the presence or absence of a limited number of cell surface markers, leaving the potential impurity of these subpopulations as a limitation. Indeed, recent com- prehensive, single-cell transcriptomic analyses have shown that the known subpopulations of HSPC are com- posed of heterogeneous cells in terms of gene expression.14,16 In addition, in vitro and in vivo single-cell differentiation analyses have shown that only a limited number of cells in progenitor cell populations can pro- duce multilineage mature cells and that a majority of the cells in these populations are already committed to become unilineage mature cells.14,15 Furthermore, an in vivo HSC chasing system using endogenous fluorescent tagging revealed that the differentiation trajectory of HSC is already oriented to specific lineage outputs by epigenetic memory.37 These observations raise two pos- sibilities: (i) HSPC can be further divided into subpopula-
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haematologica | 2019; 104(10)