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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1444311
This article is part of the Research Topic Mobilization of hematopoietic cells from the bone marrow to the peripheral blood: Challenges and new therapeutic targets View all 5 articles

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

Provisionally accepted
Julia Zehenter Julia Zehenter 1Michaela Prchal-Murphy Michaela Prchal-Murphy 2Eva Maria Koenig Eva Maria Koenig 1Karoline Kollmann Karoline Kollmann 2Madeleine Themanns Madeleine Themanns 1Behnaz Afrastheh Behnaz Afrastheh 1Jose Basilio Jose Basilio 1Manuel Salzmann Manuel Salzmann 1Wolfgang Strohmaier Wolfgang Strohmaier 3Guenther Krumpl Guenther Krumpl 4Alex Farr Alex Farr 1Veronika Sexl Veronika Sexl 5Michael Freissmuth Michael Freissmuth 1Eva Maria Zebedin-Brandl Eva Maria Zebedin-Brandl 1*
  • 1 Medical University of Vienna, Vienna, Austria
  • 2 University of Veterinary Medicine Vienna, Vienna, Vienna, Austria
  • 3 Independent researcher, Austria, Vienna, Austria
  • 4 Independent researcher, Vienna, Austria
  • 5 University of Innsbruck, Innsbruck, Tyrol, Austria

The final, formatted version of the article will be published soon.

    The 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.Methods: A 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.Results: When 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 confirmed synergism, demonstrating enhanced migration, adhesion, and cell differentiation in the sequential presence of treprostinil and cinacalcet.Augmenting 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.

    Keywords: CD34 + HSPCs, cord blood, Stem Cell Transplantation, drug repurposing, Engraftment efficiency, bone marrow reconstitution, differentiation

    Received: 05 Jun 2024; Accepted: 05 Dec 2024.

    Copyright: © 2024 Zehenter, Prchal-Murphy, Koenig, Kollmann, Themanns, Afrastheh, Basilio, Salzmann, Strohmaier, Krumpl, Farr, Sexl, Freissmuth and Zebedin-Brandl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Eva Maria Zebedin-Brandl, Medical University of Vienna, Vienna, Austria

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