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Extended myeloid-based model of lineage commitment
tion commitment has already been decided. However, there may be pitfalls associated with these observations, similar to those regarding erythroid-myeloid bifurcation. The presence of myeloid-lymphoid progenitors is also supported by the findings of an analysis of lym- phopoiesis in human embryos. This progenitor popula- tion first emerges as a myeloid progenitor and later acquires myeloid-lymphoid bipotential, co-expressing genes affiliated with the two lineages in single cells.67
A number of key TF have been identified as important factors for the development of lymphoid cells, including the C/EBP family, PU.1, E2A, IKAROS and FOXO1. An analysis combining RNA sequencing and chromatin immunoprecipitation sequencing has suggested the exis- tence of gene regulatory networks that are important for lymphoid-myeloid bifurcation49 (Figure 3). However, which component in the gene regulatory networks of these TF define lineage commitments and how the expression of the TF is altered in response to environ- mental changes remain unclear. The initiators of the lym- phoid or myeloid lineage commitment also have yet to be clarified, and there may in fact be multiple entry points for commitment.
We previously reported that BACH factors are required for efficient commitment of multipotent progenitors and common lymphoid progenitors to the lymphoid fate.17,18 BACH factors repress the expression of C/EBP, and C/EBP repress the expression of BACH factors. The gene regulatory networks of these TF therefore define lym- phoid or myeloid lineage commitment depending on fluctuations of the expression of C/EBP and BACH TF (Figure 4). Since the expression of these TF is affected by environmental changes,18,19,59 these TF may be initiators of lymphoid or myeloid lineage commitment responding to environmental changes. The development of fetal myeloid-lymphoid progenitors mentioned above67 may reflect changes in the interplay between BACH factors and C/EBP. Since steady-state hematopoiesis and emer-
gency hematopoiesis are contrasting, it is still unclear to what extent the altered expression in response to extra- cellular signals would affect lineage commitment. Further understanding of these issues will help to clarify the mechanisms of lineage commitment in steady-state and emergency conditions. To this end, taking advantage of using TF reporter mice exposed or not to stress might be helpful to expand the TF-based analysis further. Identification of surrogate marker genes whose expres- sion reports activity of particular TF will also be impor- tant.
Myeloid cells as the default and evolutionary prototype pathway of hematopoietic stem and progenitor cells
The lineage commitment of HSPC is the process in which these cells lose their multipotency. For erythroid cell differentiation, the progenitor cells first lose their capacity for lymphoid differentiation, resulting in ery- throid-myeloid common progenitors,32,35 at which point the decision of erythroid or myeloid lineage commit- ment is made. In contrast, for lymphoid cell differentia- tion, the progenitor cells first lose their capacity for ery- throid differentiation, resulting in lymphoid-myeloid common progenitors,34,35 at which point the decision of lymphoid or myeloid lineage commitment is made.
Interestingly, it has been reported that, even after lym- phoid commitment, T-cell or B-cell progenitors retain the capacity to differentiate into myeloid cells.68-70 Indeed, myeloid differentiation potential might remain until just before terminal differentiation. Results from studies using five blood-lineage marking, which is a precise method of detecting erythroid cells and platelets in addi- tion to myeloid, B and T cells after transplantation, also support the notion that myeloid differentiation potential is retained after losing either erythroid or lymphoid dif- ferentiation potential.71 In addition, at least some platelets are derived from HSC possessing myeloid line- age potential.72,73 Myeloid cell differentiation might, therefore, be a default and/or prototypical pathway of
Figure 4. Gene regulatory networks of BACH and C/EBP transcription factors for myeloid and non-myeloid gene expression. The transcription factor (TF) BACH represses C/EBP and myeloid genes and induces lymphoid/erythroid genes. In contrast, the TF C/EBP represses BACH and lymphoid/erythroid genes and induces myeloid genes. Therefore, both stochastic fluctuation and environ- ment-derived changes in the expression of BACH and C/EBP can induce differ- entiation commitment in progenitor cells.
Figure 3. Gene regulatory networks controlling lymphoid cell differentiation.
Several factors have been identified as important regulators of lymphoid cell dif- ferentiation commitment.49 Each factor works as an activator and/or repressor of other factors forming complex gene regulatory networks, suggesting the exis- tence of a precise mechanism underlying lymphoid cell differentiation. However, how the activities of these factors are controlled at the initial point of lineage commitment remains unclear.
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