15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration
Julianne N.P. Smith, … , Sanford D. Markowitz, Amar B. Desai
Julianne N.P. Smith, … , Sanford D. Markowitz, Amar B. Desai
Published February 18, 2021
Citation Information: JCI Insight. 2021;6(6):e143658. https://doi.org/10.1172/jci.insight.143658.
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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 3

PGDHi expands functional hematopoietic stem and progenitor cells in the spleen.

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PGDHi expands functional hematopoietic stem and progenitor cells in the ...
(A) Schematic depicting the transplantation of splenocytes from PGDHi-treated or vehicle-treated (Veh-treated) donors into irradiated, untreated recipients. (B) Overall survival time of mice that received splenocytes from Veh-treated or PGDHi-treated donors. n = 16 mice/group. Statistical testing by log rank (Mantel-Cox) test. (C) Quantification of peripheral blood neutrophils (NE), platelets (PLT), and RBCs in mice that received splenocytes from either Veh-treated or PGDHi-treated donors, 22 days after transplant. n = 6–8 mice/group. Error bars represent SEM. (D) Quantification of BM cellularity and lineage–c-Kit+ (LK) BM cells in recipient mice, 22 days after transplant, expressed as fold change. n = 6–8 mice/group. Error bars represent SEM. (E) Schematic depicting the competitive transplantation of splenocytes from PGDHi-treated or Veh-treated donors together with BM from untreated CD45.1+ donors into irradiated, untreated recipients. (F) PB chimerism at indicated time points after transplant, as measured by the percent CD45.2+ cells in total PB, CD11b+ Myeloid PB, and B220+/CD3ε+ lymphoid PB. n = 9–11 recipients/group. Data represent mean ± SEM. (G) Total BM cell chimerism at 15 weeks after transplant, as measured by the percentage of CD45.2+ cells. n = 9–11 recipients/group. Error bars represent SEM. *P < 0.05, **P < 0.01. Statistical testing of (C and D) was done by Student’s t test, except in the case of LK cell fold change, where a Mann-Whitney U test was performed. Statistical testing of (F) was done by Student’s t test of the area under the curve of Veh vs. PGDHi curves.