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Pineal Gland Hormone Melatonin Inhibits Migration of Hematopoietic Stem/Progenitor Cells (HSPCs) by Downregulating Nlrp3 Inflammasome and Upregulating Heme Oxygenase-1 (HO-1) Activity

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Abstract

Hematopoietic stem progenitor cells (HSPCs) follow the diurnal circulation rhythm in peripheral blood (PB) with nadir during late night and peak at early morning hours. The level of these cells in PB correlates with activation of innate immunity pathways, including complement cascade (ComC) that drives activation of Nlrp3 inflammasome. To support this, mice both in defective ComC activation as well as Nlrp3 inflammasome do not show typical changes in the diurnal level of circulating HSPCs. Migration of HSPCs is also impaired at the intracellular level by the anti-inflammatory enzyme heme oxygenase-1 (HO-1) which is an inhibitor of Nlrp3 inflammasome. It is also well known that circadian rhythm mediates PB level of melatonin released from the pineal gland. Since trafficking of HSPCs is driven by innate immunity-induced sterile inflammation and melatonin has an anti-inflammatory effect, we hypothesized that melatonin could negatively impact the release of HSPCs from BM into PB by inhibiting Nlrp3 inflammasome activation. We provide an evidence that melatonin being a ‘’sleep regulating pineal hormone’’ directly inhibits migration of HSPCs both in vitro migration assays and in vivo during pharmacological mobilization. This correlated with inhibition of cholesterol synthesis required for a proper membrane lipid raft (MLRs) formation and an increase in expression of HO-1—an inhibitor of Nlrp3 inflammasome. Since melatonin is a commonly used drug, this should be considered while preparing a patient for the procedure of HSPCs mobilization. More importantly, our studies shed more mechanistic light on a role of melatonin in the diurnal circulation of HSPCs.

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Detailed data are available upon reasonable request.

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Funding

This work was supported by the National Science Centre, Poland OPUS grant UMO-2021/41/B/NZ3/01589 to MZR and National Science Centre, Poland OPUS grant UMO- 2022/45/B/NZ3/00476 to MK. AT was supported by NIH T32 HL134644 Training Grant to MZR.

This work was also supported by the Stella and Henry Hoenig Endowment to MZR.

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Authors and Affiliations

  1. Stem Cell Institute at Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA

    Ahmed Abdelbaset-Ismail, Arjun Thapa, Janina Ratajczak & Mariusz Z. Ratajczak

  2. Surgery, Anesthesiology, and Radiology Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt

    Ahmed Abdelbaset-Ismail

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

    Katarzyna Brzezniakiewicz-Janus & Mariusz Z. Ratajczak

  4. Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland

    Magda Kucia & Mariusz Z. Ratajczak

Authors
  1. Ahmed Abdelbaset-Ismail
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  2. Katarzyna Brzezniakiewicz-Janus
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  3. Arjun Thapa
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  4. Janina Ratajczak
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  5. Magda Kucia
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  6. Mariusz Z. Ratajczak
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Contributions

MZR, KBJ– conceived idea and designed experiments.

AA, JR. MK – performed experiments.

MZR wrote paper and all the authors provided comments and approved manuscript.

Corresponding author

Correspondence to Mariusz Z. Ratajczak.

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Ethical Approval

This study was performed in accordance with the guidelines of the Animal Care and Use Committee of the University of Louisville School of Medicine and with the Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services, Publication No. NIH 86–23).

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Abdelbaset-Ismail, A., Brzezniakiewicz-Janus, K., Thapa, A. et al. Pineal Gland Hormone Melatonin Inhibits Migration of Hematopoietic Stem/Progenitor Cells (HSPCs) by Downregulating Nlrp3 Inflammasome and Upregulating Heme Oxygenase-1 (HO-1) Activity. Stem Cell Rev and Rep 20, 237–246 (2024). https://doi.org/10.1007/s12015-023-10638-7

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