Platelet-Biased Stem Cells and Their Role in Hematopoietic Aging

The hematopoietic system is one of the most well-studied and well-characterized differentiation hierarchies in the mammalian body, and hematopoiesis has for decades served as a paradigm for how stem cells generate complex, self-renewing tissues and maintain them under homeostatic, physiological stress and regenerative conditions. The hematopoietic stem cell (HSC) plays a central role in all of these scenarios: HSCs provide the developmental origin of definitive hematopoiesis, sustain baseline blood cell production and are activated in response to physiological stress. In addition, HSC are capable of regenerating the hematopoietic system in response to injury, or after HSC transplantation, the latter being far the most common form of stem cell therapy, used for congenital disorders of the hematopoietic system, as well as in cancer therapy, most notably in acute myeloid leukemia.

In recent years it has become increasingly clear that HSCs are functionally heterogeneous. In particular, both single cell transplantation and in vivo fate mapping have shown that HSCs can contribute selectively to hematopoietic lineages. However, the rules and cellular mechanisms that govern biased HSC lineage contributions have not been identified.

Recently, by performing large-scale single cell transplantation analysis we have found that a significant proportion of HSCs are fate-restricted: after transplantation they provide long-term reconstitution of a subset of the hematopoietic lineages, and this lineage-restriction is stable upon serial transplantation. Importantly, the fate options of repopulating HSCs are hierarchically organized, with platelet-restricted HSCs as the only uni-lineage HSC subtype (Carrelha et al, 2018). At the cellular level HSC fate restriction is generated through selective repopulation of the downstream progenitor hierarchy. In particular, platelet-restricted HSCs generate few, if any preMegE and MkP progenitors, indicating that they use an abbreviated cellular pathway for platelet generation. However, despite their stable fate-restriction in vivo, lineage-restricted HSCs, including platelet-restricted HSCs, remain multi-potent, as they retain the ability to produce all hematopoietic lineages in vitro.

During ageing the size and composition of the HSC compartment changes. Using both single cell RNA sequencing and single HSC transplantation we have found that with age HSCs become increasingly biased towards platelet production, both molecularly and functionally. In addition, ageing was accompanied by a decrease in the proportion of HSCs capable of generating lymphoid lineage output, with direct antagonism between platelet and lymphoid lineage programming as a possible underlying mechanisms (Grover et al, 2016).

These observations all point to an important physiological role of lineage restricted HSCs, and the implications of HSC heterogeneity for hematopoiesis during steady state and stress conditions, as well as ageing, will be discussed.

Carrelha J, Meng Y, Kettyle LM et al. Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells. Nature 2018; 554: 106-111.

Grover A, Sanjuan-Pla A, Thongjuea S et al. Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells. Nat Commun 2016; 7: 11075.