Platelet factor 4 (PF4) has been the subject of interesting research in recent years. Researchers have found that delivery of PF4 can dampen neuroinflammation in old animals and restore cognitive function. PF4 doesn’t cross the blood-brain barrier to enter the brain, and the effect appears mediated by changes in the immune system. Here, researchers show that PF4 is involved in the regulation of hematopoietic stem cell function, and delivery of PF4 thus rejuvenates the generation of immune cells in aged animals. This seems promising for other strategies that also improve hematopoietic stem cell function, such as use of CASIN and derived compounds under development at Mogling Bio.
Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs.
Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
