15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration
Julianne N.P. Smith, Dawn M. Dawson, Kelsey F. Christo, Alvin P. Jogasuria, Mark J. Cameron, Monika I. Antczak, Joseph M. Ready, Stanton L. Gerson, Sanford D. Markowitz, Amar B. Desai
Julianne N.P. Smith, Dawn M. Dawson, Kelsey F. Christo, Alvin P. Jogasuria, Mark J. Cameron, Monika I. Antczak, Joseph M. Ready, Stanton L. Gerson, Sanford D. Markowitz, Amar B. Desai
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Research Article Hematology

15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration

Abstract

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 proved elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases BM prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution after BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages, 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 nonpathologic splenic extramedullary hematopoiesis at steady state, and pretransplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to macrophages, 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 HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches, promote hematopoietic regeneration, and improve clinical outcomes of BMT.

Authors

Julianne N.P. Smith, Dawn M. Dawson, Kelsey F. Christo, Alvin P. Jogasuria, Mark J. Cameron, Monika I. Antczak, Joseph M. Ready, Stanton L. Gerson, Sanford D. Markowitz, Amar B. Desai

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Figure 2

PGDHi induces splenic extramedullary hematopoiesis.

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PGDHi induces splenic extramedullary hematopoiesis. (A) Schematic depict...
(A) Schematic depicting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibition (PGDHi) in steady-state mice over the course of 5 days (9 injections). (B) Quantification of splenic cellularity and lineage–c-Kit+Sca-1+ (LSK) cells per spleen after 5 days vehicle (Veh) and PGDHi treatment, expressed as fold change. n = 12–13 mice/group for splenic cellularity and n = 7–8 mice per group for splenic LSK number. Error bars represent SEM. (C) EP1–4 (Ptger1, 2, 3, and 4) expressed as ΔCq relative to B2m control gene expression levels in CD45+ splenocytes. n = 3 mice. Error bars represent SEM. (D) Schematic depicting Rivenprost (Riv) administration in mice over the course of 5 days (9 doses). (E) Quantification of splenic cellularity and LSK numbers after 5 days’ Veh and Riv treatment, expressed as fold change. n = 10–11 mice/group. Error bars represent SEM. *P < 0.05, ****P < 0.0001. Student’s t test used for all except for splenic EP receptor expression, where 1-way ANOVA with Tukey’s multiple comparisons test was used. PGE2 signaling diagrams created with BioRender.com.