title: Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation.
abstract: Activation of Gs-coupled receptors enhances engraftment of hematopoietic stem and progenitor cells (HSPCs). We tested the hypothesis that treprostinil, a prostacyclin analog approved for the treatment of pulmonary hypertension, can be repurposed to improve hematopoietic stem cell transplantation. Murine and human HSPCs were isolated from bone marrow and umbilical cord blood, respectively. Prostanoid receptor agonists and the combination thereof with forskolin were tested for their capacity to stimulate [(3)H]cAMP accumulation in HSPCs. Three independent approaches were employed to verify the ability of agonist-activated HSPCs to reconstitute the bone marrow in lethally irradiated recipient mice. The underlying mechanism was explored in cellular migration assays and by blocking C-X-C motif chemokine receptor 4 (CXCR4). Among several prostanoid agonists tested in combination with forskolin, treprostinil was most efficacious in raising intracellular cAMP levels in murine and human HPSCs. Injection of murine and human HSPCs, which had been pretreated with treprostinil and forskolin, enhanced survival of lethally irradiated recipient mice. Survival was further improved if recipient mice were subcutaneously administered treprostinil (0.15 mg kg(-1) 8 h(-1)) for 10 days. This regimen also reduced the number of HSPCs required to rescue lethally irradiated mice. Enhanced survival of recipient mice was causally related to treprostinil-enhanced CXCR4-dependent migration of HSPCs. Treprostinil stimulates the engraftment of human and murine hematopoietic stem cells without impairing their capacity for self-renewal. The investigated dose range corresponds to the dose approved for human use. Hence, these findings may be readily translated into a clinical application.
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kazemi
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Christian
authors.initials: C
authors.lastname: Bergmayr
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Michaela
authors.initials: M
authors.lastname: Prchal-Murphy
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Tahereh
authors.initials: T
authors.lastname: Javaheri
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Madeleine
authors.initials: M
authors.lastname: Themanns
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Ha T T
authors.initials: HT
authors.lastname: Pham
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Strohmaier
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.) michael.freissmuth@meduniwien.ac.at.
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (Z.K., C.B., M.T., M.F., E.Z.-B.); Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria (M.P.-M., V.S.); Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (T.J., H.T.T.P.); SciPharm SàRL, L-2540 Luxembourg (W.S.).
authors.forename: Eva
authors.initials: E
authors.lastname: Zebedin-Brandl
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D058492:Drug Repositioning; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D019718:Receptors, CXCR4 / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000378:metabolism; D016019:Survival Analysis; D014916:Whole-Body Irradiation
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D044006:Receptors, Epoprostenol; D005576:Colforsin; D002772:Cholera Toxin; D011464:Epoprostenol; D000242:Cyclic AMP; C427248:treprostinil