PT  - JOURNAL ARTICLE
AU  - Julianne N.P. Smith
AU  - Dawn M. Dawson
AU  - Kelsey F. Christo
AU  - Alvin P. Jogasuria
AU  - Mark J. Cameron
AU  - Monika I. Antczak
AU  - Joseph M. Ready
AU  - Stanton L. Gerson
AU  - Sanford D. Markowitz
AU  - Amar B. Desai
TI  - 15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration
AID  - 10.1101/2020.09.17.302422
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.17.302422
4099  - http://biorxiv.org/content/early/2020/09/18/2020.09.17.302422.short
4100  - http://biorxiv.org/content/early/2020/09/18/2020.09.17.302422.full
AB  - The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis, however practical strategies to enhance splenic support of transplanted HSPCs have proven elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases bone marrow (BM) prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution following BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages (MΦs), megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced non-pathologic splenic extramedullary hematopoiesis at steady-state, and pre-transplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to MΦs, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks novel HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches and to promote hematopoietic regeneration and improve clinical outcomes of BMT.Competing Interest StatementThe authors (A. Desai, J.M. Ready, S.L. Gerson, and S.D. Markowitz) hold patents relating to use of 15-PGDH inhibitors in bone marrow transplantation that have been licensed to Rodeo Therapeutics. Drs. Markowitz, Gerson, and Ready are founders of Rodeo Therapeutics, and Drs. Markowitz, Gerson, Ready, and Desai are consultants to Rodeo Therapeutics. Conflicts of interest are managed according to institutional guidelines and oversight by Case Western Reserve University and the University of Texas at Southwestern. No conflict of interest pertains to any of the remaining authors.