Deciphering the complexity of blood progenitor cells

Blood production by haematopoietic stem and progenitor cells is complex, with multiple proposed models of differentiation. In this blog post originally published in Phenotype, Zahra Aboukhalil, Bilyana Stoilova & Dimitris Karamitros discuss how the Vyas lab is using single-cell technologies to uncover the ways in which blood progenitors generate mature cells.  They have discovered that differentiation occurs primarily through single-cells that only produce one mature cell type, and rarely through progenitors that retain the ability to generate multiple cell types. Dysregulation of haematopoiesis can lead to blood cancer, and an improved understanding of these fundamental processes may provide insight into how to target the disease.

10 billion new, blood cells are produced every day. This process, known as haematopoiesis, generates a range of cell types. These include red blood cells that carry oxygen to tissues, platelets that are responsible for blood clotting, and white blood cells that fight infection. This process is tightly regulated and its dysregulation can lead to haematopoietic deficiency, immunodeficiency, and blood cancer (leukaemia).

At the top of the blood cell hierarchy are haematopoietic stem cells (HSCs) (Figure 1). HSCs have the unique ability of both producing more of themselves (self-renew) and generating the range of mature blood cells. Downstream of the HSCs are several intermediate, progenitor cells. These have a decreased ability to self-renew and are more restricted in the types of cell they can produce. These progenitors may generate the bulk of blood cells, while HSCs remain mostly inactive (1). However, the exact mechanisms of haematopoietic differentiation remain unclear.

Figure 1. Mechanisms of haematopoietic differentiation: The schematic on the left depicts a classic model of differentiation with discrete progenitor cell types that bifurcate in a tree structure. The schematic on the right depicts an updated model where rare single cells have multi-lineage ability but the majority of single cells are lineage restricted.

Traditionally it was thought that haematopoietic differentiation occurred through discrete progenitor cell types that bifurcate in a tree model of differentiation. These studies were based on bulk populations of progenitors cells that have shown the potential to produce multiple blood cell types. However, recent advances in technology now allow us to study cells at the single-cells level, uncovering a previously unknown heterogeneity among the individual cells. 

It has come to light that many progenitor populations are a heterogeneous mix of single-cells. Previously, multiple potentials had been seen from a bulk population of cells. It is now proposed this often arises from a collection of single-cells, each with a distinct differentiation potential. When analysing many cells together, these scenarios cannot be distinguished. But by studying single-cells, we are able to make this distinction.

In haematopoiesis, our understanding of differentiation from HSCs to mature blood cells has advanced. Many researchers have proposed that downstream of HSCs there is a pool of progenitors, each of which is only able to generate one mature cell type (2). This abolishes the idea of progenitors that generate multiple mature cell types.

We have shown, using pioneering single-cells techniques, that the differentiation mechanism is complex (3). We have studied around 5,000 single haematopoietic progenitor cells both functionally and by gene expression. The vast majority of single-cells do only produce one cell type. However, we uncovered rare progenitor cells that possessed the ability to generate multiple cell types.

Our work shows that HSCs are not the only cells in haematopoiesis that generate multiple mature blood cell types. Rare progenitor cells retain this ability. In addition to these rare cells are the majority of progenitors, each of which are primed towards their goal output. These single-cells have restricted their differentiation potential and are fated towards one cell type.

There must be, tight regulatory mechanisms controlling this fine balance between lineage-restricted and multi-lineage single-cells. When this regulation is lost, cancer can cripple the system. Acute myeloid leukaemia (AML) is the most common acute adult blood cancer and in patients cancerous progenitor-like cells, instead of generating healthy, mature blood, propagate the disease. By studying how these healthy progenitors generate their vital mature output, we may provide insight into targeting their diseased counterparts in AML.

References

1. Sun J, et al. (2014) Clonal dynamics of native haematopoiesis. Nature 514(7522):322–327.
2. Paul F, et al. (2015) Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors. Cell 163(7):1663–1677.
3. Karamitros D, et al. (2017) Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells. Nat Immunol 19(1):85.