15-PGDH inhibition promotes hematopoietic recovery and enhances HSC function during aging

Abstract

Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell activity. Here, we expand on this work and demonstrate that in aged mice, (1) 15-PGDH expression and activity remain conserved in the bone marrow and spleen, suggesting it remains a viable therapeutic target in aging, (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function, (3) PGDHi-treated bone marrow enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution, and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline. Significance StatementWe identify 15-hydroxyprostaglandin dehydrogenase inhibition (PGDHi) as a strategy to enhance hematopoietic stem cell function in aging. In aged mice, PGDHi expands stem and progenitor populations, accelerates hematopoietic recovery after transplantation, and reduces myeloid bias while maintaining steady-state blood production. These findings highlight a potential therapeutic approach to restore hematopoietic resilience and improve regenerative outcomes in aging. Graphical Abstract15-prostaglandin dehydrogenase inhibition ameliorates multiple facets of age-related hematopoietic decline. Schematic made using BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/648417v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1952ad9org.highwire.dtl.DTLVardef@30169aorg.highwire.dtl.DTLVardef@11bec0corg.highwire.dtl.DTLVardef@2617c8_HPS_FORMAT_FIGEXP M_FIG C_FIG