Competitive inhibition of IL-2/IL-2R has a dual effect on HSC ex vivo expansion and IL-2R (CD25) content
Copyright © 2022 Elsevier B.V. All rights reserved..
Interleukin-2 (IL-2) and its receptor play a pivotal role in the regulation of immune response and possess both immune-regulatory and immune-stimulatory functions. As a cytokine of lymphoid cells, the role of IL-2 has been revealed in hematopoietic stem cell (HSC) maintenance and proper hematopoiesis. Here, we investigated that small molecule Ro 26-4550 trifluoroacetate (Ro) mediated competitive inhibition of IL-2 and its receptor alpha subunit (IL-2Rα) throughout ex vivo culture. Ro treatment induced murine and human ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). Ro treated HSPCs sustained self-renewal ability and low apoptotic activity. As a competitive inhibitor of IL-2/IL-2Rα interaction, Ro small molecule induced human HSPCs to entry into cell cycle. The proliferation of bone marrow mesenchymal stem cells (MSC) and fibroblasts were also highly increased post treatment. Besides, Ro treatment enhanced IL-2Rα (CD25) expression independent of IL-2 administration in human mPB-derived HSPCs and BM-derived HSPCs. Increased IL-2Rα (CD25) expression in BM-HSPCs was associated with the increase in the CD4+CD25+ T cell population. Xenotransplantation of immunodeficient mice with ex vivo expanded human CD34+ cells after Ro treatment revealed an efficient multi-lineage reconstitution in the recipient. These findings shed light on the role of IL-2/IL-2Rα interaction in HSC expansion, in vivo and in vitro HSC self-renewal ability and repopulation capacity as well as a possible mean for the induction of CD25 expressing cells in hematopoietic compartments.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:110 |
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| Enthalten in: |
International immunopharmacology - 110(2022) vom: 10. Sept., Seite 109035 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Uslu, Merve [VerfasserIn] |
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| Links: |
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| Themen: |
Antigens, CD34 |
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| Anmerkungen: |
Date Completed 17.08.2022 Date Revised 17.08.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.intimp.2022.109035 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Interleukin-2 (IL-2) and its receptor play a pivotal role in the regulation of immune response and possess both immune-regulatory and immune-stimulatory functions. As a cytokine of lymphoid cells, the role of IL-2 has been revealed in hematopoietic stem cell (HSC) maintenance and proper hematopoiesis. Here, we investigated that small molecule Ro 26-4550 trifluoroacetate (Ro) mediated competitive inhibition of IL-2 and its receptor alpha subunit (IL-2Rα) throughout ex vivo culture. Ro treatment induced murine and human ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). Ro treated HSPCs sustained self-renewal ability and low apoptotic activity. As a competitive inhibitor of IL-2/IL-2Rα interaction, Ro small molecule induced human HSPCs to entry into cell cycle. The proliferation of bone marrow mesenchymal stem cells (MSC) and fibroblasts were also highly increased post treatment. Besides, Ro treatment enhanced IL-2Rα (CD25) expression independent of IL-2 administration in human mPB-derived HSPCs and BM-derived HSPCs. Increased IL-2Rα (CD25) expression in BM-HSPCs was associated with the increase in the CD4+CD25+ T cell population. Xenotransplantation of immunodeficient mice with ex vivo expanded human CD34+ cells after Ro treatment revealed an efficient multi-lineage reconstitution in the recipient. These findings shed light on the role of IL-2/IL-2Rα interaction in HSC expansion, in vivo and in vitro HSC self-renewal ability and repopulation capacity as well as a possible mean for the induction of CD25 expressing cells in hematopoietic compartments | ||
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