Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation
ObjectiveThe expanding field of hematopoietic cell transplantation (HCT) for non-malignant diseases, including those amenable to gene therapy or gene editing, faces challenges due to limited donor availability and the toxicity associated with cell collection methods. Umbilical cord blood (CB) repres...
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Frontiers Media S.A.
2025-01-01
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| author | Michaela Prchal-Murphy Julia Zehenter Marlene Fischer Anita Pirabe Madeleine Themanns Behnaz Afrashteh Eva Maria Putz Karoline Kollmann José Basílio José Basílio Manuel Salzmann Wolfgang Strohmaier Günther Krumpl Alex Farr Veronika Sexl Michael Freissmuth Eva Zebedin-Brandl |
| author_facet | Michaela Prchal-Murphy Julia Zehenter Marlene Fischer Anita Pirabe Madeleine Themanns Behnaz Afrashteh Eva Maria Putz Karoline Kollmann José Basílio José Basílio Manuel Salzmann Wolfgang Strohmaier Günther Krumpl Alex Farr Veronika Sexl Michael Freissmuth Eva Zebedin-Brandl |
| author_sort | Michaela Prchal-Murphy |
| collection | DOAJ |
| description | ObjectiveThe expanding field of hematopoietic cell transplantation (HCT) for non-malignant diseases, including those amenable to gene therapy or gene editing, faces challenges due to limited donor availability and the toxicity associated with cell collection methods. Umbilical cord blood (CB) represents a readily accessible source of hematopoietic stem and progenitor cells (HSPCs); however, the cell dose obtainable from a single cord blood unit is frequently insufficient. This limitation can be addressed by enhancing the potency of HSPCs, specifically their capacity to reconstitute hematopoiesis. In our study, we investigated the combined effects of treprostinil, a prostaglandin analog, and cinacalcet, a calcium-sensing receptor modulator, on the reconstitution of hematopoiesis.MethodsA Lineage Cell Depletion Kit was employed to isolate lineage-negative (lin−) HSPCs from mouse bone marrow. A Human CB CD34 Positive Selection Kit was utilized to isolate CD34+ cells from the CB of healthy donors. In vitro, the effects of treprostinil, cinacalcet, and their combination on the migration, adhesion, and differentiation of HSPCs were assessed. In vivo, homing and engraftment were examined. Eight-week-old female and male C57BL/6J, BALB/c, or female NSG mice served as recipient models.ResultsWhen administered concomitantly, treprostinil and cinacalcet exhibited mutual antagonism: the survival of recipient animals was lower when both drugs were administered together compared to either agent alone. Conversely, a sequential regimen involving priming with treprostinil/forskolin followed by cinacalcet treatment in vivo enhanced survival, irrespective of whether hematopoiesis was reconstituted by human or murine HSPCs. In vitro assays demonstrated enhanced migration and adhesion in response to the presence of treprostinil and cinacalcet, suggesting potential synergistic effects. Colony formation confirmed synergism.ConclusionAugmenting the bone marrow reconstitution potential of HSPCs with treprostinil and cinacalcet shows promise for rescuing patients undergoing HCT. This approach is particularly beneficial for those patients at high risk of transplant failure due to limited numbers of available HSPCs. Furthermore, enhancing the potency of HSPCs has the potential to alleviate the burden and risks associated with HSPC donation, as it would reduce the number of cells needed for collection. |
| format | Article |
| id | doaj-art-0e8835b5d1e84c6784babc19b12287b0 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-0e8835b5d1e84c6784babc19b12287b02025-01-09T10:27:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.14443111444311Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantationMichaela Prchal-Murphy0Julia Zehenter1Marlene Fischer2Anita Pirabe3Madeleine Themanns4Behnaz Afrashteh5Eva Maria Putz6Karoline Kollmann7José Basílio8José Basílio9Manuel Salzmann10Wolfgang Strohmaier11Günther Krumpl12Alex Farr13Veronika Sexl14Michael Freissmuth15Eva Zebedin-Brandl16Department for Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, AustriaInstitute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, AustriaInstitute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, AustriaDepartment for Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, AustriaInstitute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, AustriaInstitute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, AustriaInstitute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, AustriaDepartment for Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, AustriaInstitute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, AustriaDepartment of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, AustriaDivision of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, AustriaAOP Orphan Pharmaceuticals GmbH, Vienna, AustriaAOP Health International Management AG, Ruggell, LiechtensteinDepartment of Obstetrics and Gynecology, Division of Obstetrics and Feto-Maternal Medicine, Medical University of Vienna, Vienna, AustriaDepartment for Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, AustriaInstitute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, AustriaInstitute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, AustriaObjectiveThe expanding field of hematopoietic cell transplantation (HCT) for non-malignant diseases, including those amenable to gene therapy or gene editing, faces challenges due to limited donor availability and the toxicity associated with cell collection methods. Umbilical cord blood (CB) represents a readily accessible source of hematopoietic stem and progenitor cells (HSPCs); however, the cell dose obtainable from a single cord blood unit is frequently insufficient. This limitation can be addressed by enhancing the potency of HSPCs, specifically their capacity to reconstitute hematopoiesis. In our study, we investigated the combined effects of treprostinil, a prostaglandin analog, and cinacalcet, a calcium-sensing receptor modulator, on the reconstitution of hematopoiesis.MethodsA Lineage Cell Depletion Kit was employed to isolate lineage-negative (lin−) HSPCs from mouse bone marrow. A Human CB CD34 Positive Selection Kit was utilized to isolate CD34+ cells from the CB of healthy donors. In vitro, the effects of treprostinil, cinacalcet, and their combination on the migration, adhesion, and differentiation of HSPCs were assessed. In vivo, homing and engraftment were examined. Eight-week-old female and male C57BL/6J, BALB/c, or female NSG mice served as recipient models.ResultsWhen administered concomitantly, treprostinil and cinacalcet exhibited mutual antagonism: the survival of recipient animals was lower when both drugs were administered together compared to either agent alone. Conversely, a sequential regimen involving priming with treprostinil/forskolin followed by cinacalcet treatment in vivo enhanced survival, irrespective of whether hematopoiesis was reconstituted by human or murine HSPCs. In vitro assays demonstrated enhanced migration and adhesion in response to the presence of treprostinil and cinacalcet, suggesting potential synergistic effects. Colony formation confirmed synergism.ConclusionAugmenting the bone marrow reconstitution potential of HSPCs with treprostinil and cinacalcet shows promise for rescuing patients undergoing HCT. This approach is particularly beneficial for those patients at high risk of transplant failure due to limited numbers of available HSPCs. Furthermore, enhancing the potency of HSPCs has the potential to alleviate the burden and risks associated with HSPC donation, as it would reduce the number of cells needed for collection.https://www.frontiersin.org/articles/10.3389/fphar.2024.1444311/fullCD34+ HSPCscord bloodstem cell transplantationdrug repurposingengraftment efficiencybone marrow reconstitution |
| spellingShingle | Michaela Prchal-Murphy Julia Zehenter Marlene Fischer Anita Pirabe Madeleine Themanns Behnaz Afrashteh Eva Maria Putz Karoline Kollmann José Basílio José Basílio Manuel Salzmann Wolfgang Strohmaier Günther Krumpl Alex Farr Veronika Sexl Michael Freissmuth Eva Zebedin-Brandl Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation Frontiers in Pharmacology CD34+ HSPCs cord blood stem cell transplantation drug repurposing engraftment efficiency bone marrow reconstitution |
| title | Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation |
| title_full | Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation |
| title_fullStr | Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation |
| title_full_unstemmed | Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation |
| title_short | Repurposing the prostaglandin analogue treprostinil and the calcium-sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation |
| title_sort | repurposing the prostaglandin analogue treprostinil and the calcium sensing receptor modulator cinacalcet to revive cord blood as an alternate source of hematopoietic stem and progenitor cells for transplantation |
| topic | CD34+ HSPCs cord blood stem cell transplantation drug repurposing engraftment efficiency bone marrow reconstitution |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1444311/full |
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