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

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

doi:10.1172/jci.insight.143658

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.

Highlights

The spleen influences hematopoietic stem cell transplantation outcomes, yet the mechanisms regulating splenic hematopoiesis posttransplantation are not well understood
We have previously shown that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expands hematopoietic stem and progenitor cell (HSPC) at steady state and enhances hematopoietic regeneration after transplantation and during BM failure [13,14,15]. 15-PGDH inhibition (PGDHi) increases prostaglandin E2 (PGE2) and induces Cxcl12 and Scf expression by BM stromal cells; the impact of PGDHi on the spleen, after transplant, is not well understood
To determine if the spleen responds to 15-PGDH inhibition, we examined 15-PGDH expression levels in splenic tissue

Summary

Introduction

The spleen influences hematopoietic stem cell transplantation outcomes, yet the mechanisms regulating splenic hematopoiesis posttransplantation are not well understood. In the setting of splenic extramedullary hematopoiesis (EMH), CXCL12+ and stem cell factor–positive (SCF+) stromal cell populations promote HSPC activation and myeloerythroid progenitor cell expansion [9], whereas VCAM1+ macrophages retain HSPCs in the spleen [10]. These findings highlight the potential therapeutic utility of strategies to promote or limit EMH, to improve hematopoietic regeneration or limit inflammation mediated by spleen-derived myeloid cells, as occurs in cardiovascular and neurovascular disease [4, 11, 12]

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Results

Conclusion