The enhanced myeloid lineage bias of old hematopoietic stem cells (HSCs) has been implicated to underpin the compromised immunity observed upon aging. In a recent paper in Cell, Poscablo and coworkers now present experimental support for also the dysregulated function of platelets seen during aging, emanating at the aged HSC level; they identified an aging- and platelet-specific differentiation pathway in mice, which, compared to the canonical pathway dominating in young mice, replenishes megakaryocyte progenitors which with faster kinetics and enhanced regenerative potential produce hyper-reactive platelets.

Self-renewing hematopoietic stem cells (HSCs) are sustained throughout life in the bone marrow, in which they guarantee the production of millions of blood cells per second in humans, encompassing all blood cell lineages.1 The turnover and therefore the need for replenishment is particularly high for the short-lived myeloid lineages, including platelets (thrombocytes). Therefore, if the megakaryocyte (platelet) progenitors producing large numbers of platelets are eradicated in response to damages to the bone marrow, such as following cancer chemotherapy, dramatic drops in platelets can occur. Such thrombocytopenia can result in considerable morbidity, hospitalization and need for platelet transfusions,2 reflecting the critical role of platelets in preventing and stopping bleeding (hemostasis).3 In contrast, when dysregulated platelets are hyperactivated, they can cause clotting (thrombosis), as increasingly observed upon aging and closely related to the age-related increase in cardiovascular disease.4 The basis for platelet hyperactivation and thrombosis upon aging has remained unclear, which is probably multifactorial, and both platelet-intrinsic and -extrinsic (including vascular) mechanisms have been proposed.4

Previous studies (1) identified HSCs highly biased or even restricted towards exclusively replenishing platelets unlike the prototypical HSCs that produce all blood cell lineages;5,6 (2) reported additional findings compatible with platelets being produced through more than one HSC-progenitor pathway;7 and (3) demonstrated that platelet-biased HSCs expand upon aging.8 In light of these studies, Poscablo et al.9 used a genetic (FlkSwitch) mouse model to identify and lineage trace two distinct HSC-progenitor pathways replenishing platelets. While an Flk2-positive multilineage pathway was observed in young mice that also contributed to replenishment of all other myeloid as well as lymphoid blood lineages, an alternative Flk2-negative pathway emerged and expanded upon aging. Notably, this aging-specific pathway almost exclusively contributed to replenishment of platelets and to a population of phenotypically defined megakaryocyte progenitors transcriptionally and functionally distinct from those produced through the multilineage pathway, which possessed higher and faster potential for in vivo reconstitution of platelets. Moreover, the platelets produced by the two pathways displayed distinct properties, with the most noteworthy being the enhanced in vitro activation of platelets generated through the aging-specific pathway.

The studies of Poscablo et al. provide several novel biological insights into how platelet production and functions are altered upon aging, with potential clinical implications for platelet regeneration and thrombosis. The studies suggest that the aging pathway replenishes megakaryocyte progenitors functionally superior to those produced through the multilineage canonical pathway, both with regard to speed as well as extent of platelet replenishment in vivo. However, this was based on transplantation of phenotypically defined megakaryocyte-restricted progenitors, which in aged mice surprisingly also replenished other myeloid blood cell lineages, questioning whether they represent the appropriate comparison to megakaryocyte progenitors from young mice.

Although the findings of Poscablo et al. are compatible with two alternative platelet replenishment pathways originating from the same HSC, other recent studies using a similar lineage tracing model and single HSC transplantations from young adult mice rather suggest that the two pathways arise from distinct HSCs.5,10 They also suggest that both pathways are present already in young mice, although in agreement with Poscablo et al., the platelet-biased HSCs responsible for the platelet-restricted pathway expand extensively upon aging.8

Whereas aged platelets produced through the platelet-restricted pathway showed enhanced in vitro activation, aged and young platelets replenished through the multilineage pathway were indistinguishable, compatible with platelets replenished through the platelet-restricted pathway being responsible for the increase in vascular thrombosis observed upon aging and the platelets produced through the canonical pathway being resilient to age-induced dysregulation. If so, this opens a possibility to counteract aging-induced platelet hyperactivation through a selective depletion of aged platelet-biased HSCs and preserving HSCs from which the canonical pathway for platelet production initiates. Of considerable relevance, a recent study demonstrated that depletion of myeloid-biased HSCs (most likely including platelet-biased HSCs) improved parameters of age-related decline in immunity.11,12 However, further studies are required to establish to what degree the platelets produced by the canonical pathway in aged mice are normal and functionally distinct from those produced by the aging platelet-restricted pathway, not the least in light of Poscablo et al. showing that platelets from the two pathways contributed equally in vivo to increased thrombus formation upon vascular insults in aged mice. Nevertheless, the findings of Poscablo et al. open up an exciting and novel avenue towards unraveling and combating the source and role of dysregulated platelets in the enhanced thrombotic events observed upon aging.