We have described the differentiation of HSCs through various oligopotent, and eventually unipotent, terminal effector cells. A considerable body of work has emerged to explain how this is controlled, so that sufficient but not excessive numbers of fully differentiated cells are generated in response to infection and inflammation.
The role of cytokine signalling
Cytokinesprovide a signal to cells to proliferate and differentiate. For example, dormant HSCs can be stimulated by the cytokine interferon-a(IFNa) to produce more proliferative oligopotent stem cells that can then differentiate into other cells such as neutrophils. Other cytokines such as granulocyte–macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) drive differentiation of progenitor cells into neutrophils and monocytes.
Permissive versus instructive signalling
An ongoing debate on the role of cytokine signalling is whether cytokines merely provide a permissive environment for HSCs to differentiate into a specific role (permissive model) or whether they have a more direct role, driving the HSCs down a specific differentiation lineage (instructive model).
Permissive signalling
Mice in which the receptor for M-CSFhad been removed produced only low numbers of monocytes. However, when the myeloid cells were rescued by the expression of the anti-apoptotic gene BCL2, the monocyte numbers increased. This study suggests that the role of cytokines is to allow the survival of HSCs, which enables them to fully differentiate.
Instructive signalling
In one study, the exogenous expression of specific cytokine receptors (interleukin-2 and GM-CSF) in progenitor cells that had already commenced lymphoid development enabled transdifferentation of the cells into myeloid development. This study suggests that cytokine signalling can regulate cell-fate decisions.
Overlapping role of cytokines
Different cytokines can activate the same receptors, and different receptors can have overlapping downstream effects. For example, although knockout of the erythropoietin receptor results in the absence of mature erythrocytes, early erythroid progenitors can still persist, in part because of the likely compensatory effect of thrombopoietin signalling, which normally regulates platelet production.
The role of specific transcription factors
Figure 1.3
Transcription factors can transdifferentiatecells committed to other lineages. For example, the overexpression of the CEBPAgene in common lymphoid progenitor (CLP) cells makes the transcription factor C/EBPa, which at high enough levels can reprogram CLPs into mature myeloid cells such as neutrophils, rather than normal lymphocytes.
Transcription factors are vital in the regulation of haematopoiesis.
Evidence for this is seen through the disruption of haematopoiesis in both mouse models and in familial patterns of disease. Haematopoietic cells are exquisitely sensitive to subtle variations in expression levels of transcription factors. For example, a simple twofold increase in the levels of the transcription factor GATA binding protein 2blocks differentiation of haematopoietic cells in mice. Powerful experimental data also show the ability of ectopically expressed transcription factors to transdifferentiate committed haematopoietic cells into different lineages (Figure 1.3).
One important master regulator of haematopoiesis is the gene RUNX1 (AML1). This gene is essential for the emergence of HSCs in the developing embryo. A complete absence of RUNX1 results in the death of the developing embryo. A dysfunctional copy of RUNX1is inherited in familial platelet disease. Affected family members, who inherit this condition in an autosomal dominant manner, are thrombocytopenic with a predisposition to the development of acute myeloid leukaemia (AML).
C/EBPa is another important transcription factor in haematopoiesis Mice with a knockout of the CEBPA gene lack mature neutrophils, suggesting that this gene is vital for their development.Recent studies have shown that germline mutations in CEBPA are associated with an increased risk of developing AML2 with a documented penetrance rate of 100%. The importance of transcription factors in haematopoiesis is underlined by the ability of C/EBPato transdifferentiate cells into neutrophils (see Figure 1.3). Using retroviral vectors, over expression of CEBPA can rapidly force lymphoid progenitors, lymphocytes and even AML cells into mature myeloid cells such as neutrophils.
Finally, there is an appreciation that transcription factors regulate each other’s activities and form a network that defines the identity and function of each cell. Elucidating these networks will allow the de novo generation of different components of the haematopoietic system (e.g. artificial blood) and help us to understand how they might be subverted in leukaemia.
