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
View: Text | PDF
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

×

Figure 1

The spleen is critical for PGDHi-mediated hematopoietic regeneration.

Options: View larger image (or click on image) Download as PowerPoint
The spleen is critical for PGDHi-mediated hematopoietic regeneration. (A...
(A) Representative detection of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) at 25 kDa and β-actin at 42 kDa in splenocyte and BM cell lysates. Two independent experiments of n = 2 mice per experiment. (B) Representative images of 15-PGDH staining (brown) in splenic red pulp (left) and tibial BM core (right). (Original magnification, ×20.) Three independent experiments of n = 2 mice per experiment. (C) Quantification of 15-PGDH enzymatic activity in spleen and BM, expressed as cpm per mg total protein, per hour. n = 5 mice. Error bars represent SEM. (D) Peripheral WBC, neutrophil (NE), and platelet (PLT) recovery in intact (top) and splenectomized (bottom) transplant recipients treated with either vehicle (Veh; blue) or 15-PGDH inhibitor (PGDHi; red). n = 12–15 mice/group. Data represent mean ± SEM. (E) BM cellularity and quantification of lineage–c-Kit+Sca-1+ (LSK) cells per hind limb of control and splenectomized recipients 20 days after transplant, treated with Veh (-) or PGDHi (+), expressed as fold change. n = 11–14 mice per group. Error bars represent SEM. **P < 0.01, ****P < 0.0001. Student’s t test used for all except peripheral blood recovery, where 2-way ANOVA was used and asterisks denote Veh vs. PGDHi over days 7 through 20.