Dysregulation in platelet production and function during ageing is a known contributor to platelet disorders affecting older individuals. A new study in Cell demonstrates a distinct haematopoietic platelet differentiation pathway that is enriched in ageing mice, which results in platelets that are hyper-reactive compared with canonical platelet populations and can induce excessive clot formation in aged mice. To the study investigators’ knowledge, this is the first age-specific stem cell pathway that has been described.

The investigators used the FlkSwitch lineage-tracing mouse model to map differentiation pathways from HSCs. During ageing, the platelet lineage diverged from the canonical FLK2-dependent platelet differentiation pathway. Compared with MkPs in the canonical pathway, age-enriched MkPs from the divergent pathway were found to be transcriptionally distinct and have a greater capacity to proliferate and engraft. Furthermore, age-enriched MkPs had greater platelet restoration capacity in situ and when transplanted into young or old mice with thrombocytopenia. This gain in functional capacity is attributable to their specification from HSCs via the shortcut differentiation pathway, which is characterized by the sustained expression of numerous stem cell progenitor genes. Moreover, the age-induced platelet pathway was also found to mediate platelet hyper-reactivity. The resulting age-enriched platelet subpopulation caused steady-state thrombocytosis and contributed to excessive clot formation after vascular insult in old mice.