15-PGDH inhibition enhances hematopoietic regeneration during aging

Rahul Chaudhary; Brittany A Cordova; Marcus Hong; Bailey R Klein; Lyannah A Contreras; Ritisha Rashmil; Filip Goshevski; Julianne N P Smith; Derek J Taylor; Andrew A Pieper; Sanford Markowitz; Amar B Desai

doi:10.1093/stmcls/sxaf047

15-PGDH inhibition enhances hematopoietic regeneration during aging

Stem Cells. 2025 Jul 3:sxaf047. doi: 10.1093/stmcls/sxaf047. Online ahead of print.

Authors

Rahul Chaudhary¹, Brittany A Cordova¹, Marcus Hong¹, Bailey R Klein¹, Lyannah A Contreras¹, Ritisha Rashmil¹, Filip Goshevski¹, Julianne N P Smith¹, Derek J Taylor^{1

2}, Andrew A Pieper^{3

4

5

6

7

8}, Sanford Markowitz^{1

9}, Amar B Desai¹

Affiliations

¹ Department of Medicine, and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, OH, USA.
² Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
³ Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
⁴ Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA.
⁵ Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA.
⁶ Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
⁷ Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA.
⁸ Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
⁹ University Hospitals Seidman Cancer Center, Cleveland OH 44106 US.

PMID: 40608981
DOI: 10.1093/stmcls/sxaf047

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.

Keywords: aging; drug target; hematopoietic stem cell transplantation; hematopoietic stem cells; stem cells.

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