The changing face of hematopoiesis: a spectrum of options is available to stem cells

Abstract

For more than 30 years, the scheme whereby bone marrow hematopoietic stem cells give rise to the many different types of blood and immune cells has been represented as a lineage tree diagram. In this model, hematopoietic stem cells follow a preferred route to each of the end-cell types and gradually restrict their other lineage options via a series of intermediate oligo-potent progenitors. Recent findings of lineage biases or affiliations within hematopoietic stem and progenitor cells that are either pluripotent or uni-potent show that a continuum of fate options is open to hematopoietic stem cells. These results support the view that in order to close down developmental options, hematopoietic stem cells can make an immediate lineage choice rather than become gradually committed as they progress step-wise through a series of intermediate progenitors. In this scenario, there is inherent versatility in that developing cells are still able to move sideways to adopt an alternative lineage fate. Here, we examine the information that is leading toward this very different viewpoint of blood cell development.

Are Leukaemic Stem Cells Restricted to a Single Cell Lineage?

“…Our 'developmental' view of haematopoiesis is that an HSC selects one lineage from a continuum of all end-cell options, and then differentiates to that cell type ( Figure 2). We provided evidence to support our viewpoint elsewhere [45][46][47]. Though the model shows that affiliation/commitment to a cell lineage can occur as early as during the HSC stage, haematopoiesis still remains dynamic.…”

“…Dispersal of HPCs from the bone marrow in a semisolid medium with the addition of particular growth factors (colony-stimulating factors) leads to the production of colonies containing various cell types depending on the added growth factor(s). We argued that the single cell giving rise to the colony 'shuffles sideways' to adopt various pathways because it is out of its normal environment with regard to the control of cell fate [46]. Single-cell analysis of mixed-lineage states has led to the proposal that bursts of alternative gene expression are an important feature of cell decision making, including the existence of bilineage states [51].…”

“…A supply of haematopoietic cytokines may continuously 'shape' the production of various types of blood cells to meet the overall demand of an organism. This may include diverting HSCs/HPCs towards a certain cell type to deal with particular circumstances or infectious agents [46]. For example, HSCs, rather than multipotent HPCs, drive erythropoiesis during chronic erythroid stress in Epo-transgenic mice.…”

Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand

“…Apart from influencing the survival, expansion and effector function of mature immune cells in peripheral lymphoid organs, cytokines also have a crucial role in the continuous generation of all blood cell lineages (hematopoiesis), which occurs in the bone marrow and thymus. During hematopoiesis cytokines can influence the lineage output of hematopoietic progenitors by selectively promoting their survival, proliferation or developmental potential ( 1 – 3 ). Two of the most important cytokines for the generation of lymphoid cells are Flt3-ligand (FL) and Interleukin-7 (IL-7).…”

The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture

“…Thus, in order to demonstrate their instructive role, it is necessary to use a high level of cytokine in in vitro experiments. A graded response of cells to cytokines may be important for steady state versus hematopoiesis under stress conditions, such as infection, whereby the different requirements are survival/expansion versus survival/expansion coupled to a rapid and emergency, diversion of cells towards a required end cell type [ 101 ]. Recent evidence to support this viewpoint is that Singh and colleagues have observed that during chronic erythroid stress, in Epo transgenic mice, HSC exhibit a vastly committed erythroid progenitor profile together with enhanced cell division [ 102 ].…”