title: Prostaglandin E2 increases hematopoietic stem cell survival and accelerates hematopoietic recovery after radiation injury.
abstract: Hematopoietic stem and progenitor cells (HSPCs), which continuously maintain all mature blood cells, are regulated within the marrow microenvironment. We previously reported that pharmacologic treatment of naïve mice with prostaglandin E2 (PGE2) expands HSPCs. However, the cellular mechanisms mediating this expansion remain unknown. Here, we demonstrate that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate. In a murine model of sublethal total body irradiation (TBI), in which HSPCs are rapidly lost, treatment with a long-acting PGE2 analog (dmPGE2) reversed the apoptotic program initiated by TBI. dmPGE2 treatment in vivo decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity. The antiapoptotic effect of dmPGE2 on HSPCs did not impair their ability to differentiate in vivo, resulting instead in improved hematopoietic recovery after TBI. dmPGE2 also increased microenvironmental cyclooxygenase-2 expression and expanded the α-smooth muscle actin-expressing subset of marrow macrophages, thus enhancing the bone marrow microenvironmental response to TBI. Therefore, in vivo treatment with PGE2 analogs may be particularly beneficial to HSPCs in the setting of injury by targeting them both directly and also through their niche. The current data provide rationale for in vivo manipulation of the HSPC pool as a strategy to improve recovery after myelosuppression.
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Porter
authors.forename: Mary A
authors.initials: MA
authors.lastname: Georger
authors.forename: Olga
authors.initials: O
authors.lastname: Bromberg
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: McGrath
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Frisch
authors.forename: Michael W
authors.initials: MW
authors.lastname: Becker
authors.forename: Laura M
authors.initials: LM
authors.lastname: Calvi
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D060833:Cellular Microenvironment / Q000187:drug effects / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014916:Whole-Body Irradiation
chemical_list: D000199:Actins; D011837:Radiation-Protective Agents; C544013:alpha-smooth muscle actin, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone