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STEM CELL BIOLOGY

The P2X4 purinergic receptor has emerged as a potent regulator of hematopoietic stem/progenitor cell mobilization and homing—a novel view of P2X4 and P2X7 receptor interaction in orchestrating stem cell trafficking

Leukemia volume 36, pages 248–256 (2022)Cite this article

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Abstract

Recent evidence indicates that extracellular adenosine triphosphate (eATP), as a major mediator of purinergic signaling, plays an important role in regulating the mobilization and homing of hematopoietic stem progenitor cells (HSPCs). In our previous work we demonstrated that eATP activates the P2X7 ion channel receptor in HSPCs and that its deficiency impairs stem cell trafficking. To learn more about the role of the P2X purinergic receptor family in hematopoiesis, we phenotyped murine and human HSPCs with respect to the seven P2X receptors and observed that, these cells also highly express P2X4 receptors, which shows ~50% sequence similarity to P2X7 subtypes, but that P2X4 cells are more sensitive to eATP and signal much more rapidly. Using the selective P2X4 receptor antagonist PSB12054 as well as P2X4-KO mice, we found that the P2X4 receptor, similar to P2X7 receptor, promotes trafficking of HSPCs in that its deficiency leads to impaired chemotaxis of HSPCs in response to a stromal-derived factor 1 (SDF-1) gradient, less effective pharmacological mobilization, and defective homing and engraftment of HSPCs after transplantation into myeloablated hosts. This correlated with a decrease in SDF-1 expression in the BM microenvironment. Overall, our results confirm the proposed cooperative dependence of both receptors in response to eATP signaling. In G-CSF-induced mobilization, a lack of one receptor is not compensated by the presence of the other one, which supports their mutual dependence in regulating HSPC trafficking.

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Fig. 1: Impact of ATP on short- and long-term engraftment of HSPCs in WT mice.
Fig. 2: Impact of P2X4 deficiency on the chemotactic activity of murine BMMNCs.
Fig. 3: The impact of P2X4 inhibition on HSPC mobilization.
Fig. 4: The impact of P2X4 and P2X7 antagonists on short- and long-term engraftment of HSPCs in WT mice.
Fig. 5: Early homing and engraftment of P2X4-KO and WT BMMNC and expression of mRNA for SDF-1, CXCR4 and components of Nlrp3 inflammasome in  P2X4-KO and WT BMMNC.

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Acknowledgements

This work was supported by NIH grants 2R01 DK074720, Stella and Henry Hoenig Endowment, and the Polish National Center OPUS grants UMO-2018/29/B/NZ4/01470 to MZR. AT was supported by NIH T32 HL134644 Training Grant to MZR. MA is recipient of the Scholarship for Young Researchers (No. 343/E-393/STYP/13/2018) funded by the Ministry of Science and Higher Education. HU was supported by São Paulo Research Foundation (Project No. 2018/07366-4).

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Author notes

  1. These authors contributed equally: Mateusz Adamiak and Kamila Bujko.

Authors and Affiliations

  1. Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    Mateusz Adamiak, Kamila Bujko, Arjun Thapa, Valentina Pensato, Janina Ratajczak, Magda Kucia & Mariusz Z. Ratajczak

  2. Department of Regenerative Medicine Medical University of Warsaw, Warsaw, Poland

    Mateusz Adamiak, Kamila Bujko, Magda Kucia & Mariusz Z. Ratajczak

  3. Department of Hematology, University of Zielona Gora, Hospital Gorzow Wlkp., Zielona Gora, Poland

    Katarzyna Brzezniakiewicz-Janus & Mariusz Z. Ratajczak

  4. Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA, USA

    Daryl L. Davies

  5. Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil

    Henning Ulrich

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Adamiak, M., Bujko, K., Thapa, A. et al. The P2X4 purinergic receptor has emerged as a potent regulator of hematopoietic stem/progenitor cell mobilization and homing—a novel view of P2X4 and P2X7 receptor interaction in orchestrating stem cell trafficking. Leukemia 36, 248–256 (2022). https://doi.org/10.1038/s41375-021-01352-9

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