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15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration 2 3 Julianne N.P

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15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration 2 3 Julianne N.P bioRxiv preprint doi: https://doi.org/10.1101/2020.09.17.302422; this version posted September 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration 2 3 Julianne N.P. Smith1, Dawn M. Dawson1, Kelsey F. Christo1, Alvin P. Jogasuria1, Mark J. 4 Cameron1, Monika I. Antczak3, Joseph M. Ready3,4, Stanton L. Gerson1,2, Sanford D. 5 Markowitz1,2, Amar B. Desai1 6 7 1Department of Medicine, and Case Comprehensive Cancer Center Case Western Reserve 8 University, Cleveland OH 44106 USA 9 2University Hospitals Seidman Cancer Center, Cleveland OH 44106 US 10 3Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas TX 11 75390 USA 12 4Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas TX 75390 13 USA 14 15 *Correspondence: 16 Amar B. Desai 17 Department of Medicine 18 Case Western Reserve University 19 [email protected] 20 21 Running title: Splenic Activation for Hematologic Regeneration 22 23 Total word count: 6476 24 Abstract word count: 188 25 Figures: 7 26 Tables: 1 27 References: 53 28 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.17.302422; this version posted September 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Abstract 2 The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) 3 function, particularly during demand-adapted hematopoiesis, however practical strategies to 4 enhance splenic support of transplanted HSPCs have proven elusive. We have previously 5 demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the 6 small molecule (+)SW033291 (PGDHi), increases bone marrow (BM) prostaglandin E2 (PGE2) 7 levels, expands HSPC numbers, and accelerates hematologic reconstitution following BM 8 transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, 9 specifically 15-PGDH high-expressing macrophages (MΦs), megakaryocytes (MKs), and mast 10 cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, 11 PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in 12 splenectomized mice. PGDHi induced non-pathologic splenic extramedullary hematopoiesis at 13 steady-state, and pre-transplant PGDHi enhanced the homing of transplanted cells to the 14 spleen. 15-PGDH enzymatic activity localized specifically to MΦs, MK lineage cells, and MCs, 15 identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These 16 findings suggest that 15-PGDH expression marks novel HSC niche cell types that regulate 17 hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to 18 therapeutically target multiple HSC niches and to promote hematopoietic regeneration and 19 improve clinical outcomes of BMT. 20 21 22 23 24 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.17.302422; this version posted September 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Introduction 2 The spleen influences hematopoietic stem cell transplantation outcomes, yet the 3 mechanisms regulating splenic hematopoiesis post-transplantation are not well-understood. In 4 mice, transplanted hematopoietic stem and progenitor cells (HSPCs) home to the spleen prior to 5 the bone marrow (BM) 1 and spleen-homed HSPCs demonstrate superior function relative to 6 BM-homed HSPCs several hours post-transplant 2. In the days to weeks following 7 transplantation, hematopoietic foci form in the spleen 3,4, corresponding to sites of HSPC 8 proliferation and maturation. In humans, splenomegaly portends delayed neutrophil and platelet 9 engraftment 5, however, splenectomy does not improve survival and has been linked to graft 10 versus host disease and lymphoproliferative disease 6,7. Thus the spleen is capable of both 11 positively and negatively regulating hematopoietic reconstitution and further investigation into 12 the interactions between the splenic microenvironment and transplanted HSPCs is necessary. 13 HSPCs lodge in the spleen via CXCL12 expressed by peri-sinusoidal cells in the red 14 pulp 8. In the setting of extramedullary hematopoiesis (EMH), CXCL12+ and SCF+ stromal cell 15 populations also promote HSPC activation and myelo-erythroid progenitor cell expansion 9, 16 while VCAM1+ macrophages retain HSPCs in the spleen 10. These findings highlight the 17 potential therapeutic utility of strategies to promote or limit EMH, to improve hematopoietic 18 regeneration or limit inflammation mediated by spleen-derived myeloid cells, as occurs in 19 cardio- and neuro-vascular disease 4,11,12. 20 We have previously shown that inhibition of 15-hydroxyprostaglandin dehydrogenase 21 (15-PGDH) expands HSPCs at steady-state, and enhances hematopoietic regeneration 22 following transplantation and during BM failure 13-15. 15-PGDH inhibition (PGDHi) increases 23 PGE2 and induces Cxcl12 and Scf expression by BM stromal cells, however the impact of 24 PGDHi on the spleen, particularly post-transplant, is not well-understood. Here we identify 25 splenic 15-PGDH, and specifically 15-PGDH-expressing macrophages, megakaryocytes, and 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.17.302422; this version posted September 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 mast cells, as regulators of EMH and propose that targeting splenic 15-PGDH prior to transplant 2 will enhance homing and regeneration, resulting in improved clinical outcomes. 3 4 Results 5 The spleen is critical for PGDHi-mediated hematopoietic regeneration 6 To determine if the spleen responds to 15-PGDH inhibition, we examined 15-PGDH 7 expression levels in splenic tissue. Splenic 15-PGDH expression was substantially elevated 8 versus that of BM (Fig. 1A). Immunohistochemical staining for 15-PGDH also revealed a 9 striking difference in the abundance of 15-PGDH+ cells (Fig. 1B). While the BM displayed 10 relatively rare 15-PGDH+ cells, which comprised smaller hematopoietic cells and 11 megakaryocytes, splenic 15-PGDH+ cells were highly numerous, particularly within the red pulp 12 (Supplemental Fig. 1). Consistent with these findings, 15-PGDH enzymatic activity was 13 significantly higher in splenic as compared to BM cell lysates (Fig. 1C), demonstrating that the 14 abundant 15-PGDH is enzymatically active. Together these results suggested that the spleen 15 may be more sensitive than the marrow to pharmacologic 15-PGDH targeting. 16 Having established that 15-PGDH is expressed much more highly in the spleen than the 17 marrow, we next sought to determine whether the spleen is required for the hematopoietic 18 protective effects of 15-PGDH inhibition (PGDHi; 14). To test this, we compared short-term 19 hematologic recovery from transplant in splenectomized versus intact mice. Although vehicle- 20 treated splenectomized mice recovered blood counts slightly faster than intact controls, as has 21 been reported 16,17, splenectomy markedly attenuated the impact of PGDHi on neutrophil 22 recovery and abrogated the impact of PGDHi on platelet recovery (Fig. 1D). Importantly, 23 PGDHi-treated mice with spleens reached absolute neutrophil counts of 935 by day 12, as 24 compared to 456 in splenectomized counterparts. Splenectomized mice also failed to show a 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.17.302422; this version posted September 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 PGDHi-dependent acceleration of total white blood cell recovery, suggesting that myeloid to 2 lymphoid lineage skewing was not occurring. In addition, PGDHi did not enhance donor-derived 3 HSPC numbers in the BM of splenectomized mice at day 20 (Fig. 1E and Supplemental Fig. 4 2). These data therefore establish that the spleen is required for PGDHi-mediated hematologic 5 recovery. 6 7 PGDHi induces splenic extramedullary hematopoiesis via EP4 activation 8 To determine if an increase in splenic EMH may underlie PGDHi-mediated 9 hematopoietic protection post-transplant, and thus explain why splenectomized mice do not 10 respond to PGDHi, we characterized the spleens of healthy mice treated for 5 days with PGDHi 11 (Fig. 2A). PGDHi-treated mice showed significant increases in total splenic cellularity and in 12 splenic HSPCs (Fig. 2B), suggesting that at homeostasis, 15-PGDH negatively regulates 13 hematopoiesis in the spleen. PGDHi also increases BM HSPCs at homeostasis 14, however 14 HSPCs are not detectable in the blood of PGDHi-treated mice (Supplemental Fig. 3), therefore 15 it is unlikely that HSPC mobilization from the BM to the spleen accounts for this effect. 16 PGE2 signals via prostaglandin receptors EP1-4 18. Analysis of EP1-4 expression in 17 splenic CD45+ cells revealed a significant predominance in the expression of the gene 18 encoding EP4 relative to EP1, 2, and 3 (Fig. 2C). To determine if PGE2 signaling via EP4 may 19 underlie the PGDHi-induced EMH, we treated mice with the EP4
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