Aging is a major risk factor for chronic disease, driven by declining stem cell and tissue function. Successful mitigation of the impact of aging could profoundly improve human health. Hematopoietic stem cells (HSCs), by virtue of their self-renewal properties, are one of few cell types that truly age without replenishment. The bone marrow, readily sampled across time, is therefore an ideal tissue to study aging and the levers that control this process.
Platelet factor 4 (PF4), produced in megakaryocytes and released from the alpha-granules of activated platelets, will be familiar to many ASH attendees for its well-described role in blood coagulation and immune-related thrombosis. Pleotropic effects in T-cell regulation, angiostasis, and bacterial defense have also been described. More than a decade ago, Sandra Pinho, PhD, then a trainee in the lab of the late Paul S. Frenette, MD,* was part of the team that identified that megakaryocytes regulate HSC quiescence by secreting PF4.1 This seminal discovery was presented during the Plenary Scientific Session at the 2013 ASH Annual Meeting. A subsequent discovery that megakaryocytes predominantly regulate platelet/myeloid-biased HSCs,2 the HSC subset that selectively expands with age, sparked Dr. Pinho’s curiosity to further explore the role of this niche in hematopoietic aging.
During yesterday’s Plenary Scientific Session, the next step of the story was unveiled by Sen Zhang, PhD, a postdoctoral fellow working in the laboratory of Dr. Pinho, who now serves as assistant professor of pharmacology in the Department of Pharmacology and Regenerative Medicine at the University of Illinois at Chicago.
“The phenotype of the aged HSC is well described – less capable at reconstituting hematopoiesis, with a predominance of pro-inflammatory, myeloid-biased HSCs,” Dr. Pinho said. “We also know that PF4 levels decline with age. So, we wondered: What happens to megakaryocytes as they age?”
The investigators went on to show that megakaryocytes from mice aged up to 22 months have an aberrant phenotype – small with reduced ploidy and reduced PF4 expression. But are these observations connected? “We were fascinated to see that the HSC aging phenotype was precisely recapitulated in young mice rendered PF4 deficient,” said Dr. Pinho.
The clincher experiment – implanting subcutaneous pumps to continuously deliver PF4, mimicking PF4 levels observed in young mice – restored the youthful phenotype in aged mice. Observing that reversibility for the first time after a 42-day experiment was “truly an ‘Oh, wow!’ moment,” according to Dr. Pinho. The crucial pump implantation procedure demanded exceptional dexterity – skills perfected by Dr. Zhang using embroidery kits on weekends.
Mechanistically, the team implicate low-density lipoprotein and CXCR3 signaling as the key HSC receptors transmitting the PF4 signal, providing a tantalizing hint that cholesterol and dietary factors may be driving some of these aging processes.
As a self-identified “niche-ologist” and megakaryocyte enthusiast, Dr. Pinho is keen to highlight that “here is an example where the bone marrow niche is driving a key biological process – and delineates a new role for megakaryocytes beyond platelet production.”
Drs. Pinho and Zhang share enthusiasm for the wider implication of their findings and the potential to translate these findings to humans. “We would love to explore whether these findings could be a targetable axis in bone marrow inflammation, which we know is key to promoting clonal hematopoiesis and malignant transformation,” said Dr. Pinho.
Fascinatingly, there are data that PF4 can rejuvenate neurogenesis and restore cognitive function in aged mice.3,4 “We were so excited to see those papers,” said Dr. Pinho. “For us, these data made total sense! Could this be mediated by the same mechanism, whereby PF4 blocks HSC-derived myeloid cell production and consequent inflammation?”
There is satisfaction to be found in following a scientific observation to its subsequent conclusions and beyond. Reflecting on the decade of work, Dr. Pinho says the motivation is simple: "If you fall in love with your science and pass your excitement down to talented trainees like Dr. Zhang, that provides plentiful inspiration."
Their ongoing work serves as a reminder of the discoveries that can emerge when passion and curiosity are met with perseverance, setting the stage for future breakthroughs in the understanding of age-related hematopoietic dysfunction and disease.
*Paul S. Frenette, MD, (1965–2021) was a physician scientist in hematology-oncology and the founding director of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at the Albert Einstein College of Medicine in New York City. The Frenette laboratory made key contributions to the field of HSC biology and cancer pathophysiology.
- Bruns I, Lucas D, Pinho S, et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med. 2014;20(11):1315-1320.
- Pinho S, Marchand T, Yang E, et al. Lineage-biased hematopoietic stem cells are regulated by distinct niches. Dev Cell. 2018;44(5):634-641.e4.
- Schroer AB, Ventura PB, Sucharov J, et al. Platelet factors attenuate inflammation and rescue cognition in ageing. Nature. 2023;620(7976):1071-1079.
- Leiter O, Brici D, Fletcher SJ, et al. Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice. Nat Commun. 2023;14(1):4375.
