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Stem cell biology

Pharmacological activation of nitric oxide signaling promotes human hematopoietic stem cell homing and engraftment

Leukemia volume 35, pages 229–234 (2021)Cite this article

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Hematopoietic cell transplantation (HCT), dependent on hematopoietic stem cells (HSC), is widely used for treatment of many hematological and nonhematological disorders [1]. Successful clinical outcome of HCT predominantly relies on adequate homing and long-term engraftment of HSC into the bone marrow (BM). Enhancing the efficacy of HSC homing and engraftment could have a relevant impact on improving HCT and patient survival, especially when limiting numbers of HSCs are available, as in using umbilical cord blood (CB) or poorly mobilized peripheral blood [2,3,4]. Although efforts have been devoted to developing potential means to enhance HSC engraftment, including boosting HSC expansion [5, 6], enhancing HSC homing [7, 8], mitigating extra physiologic oxygen shock/stress [9], or generating HSCs by reprogramming [10, 11], it is not yet clear which procedures will have the most clinical efficacy, and there is still an urgent need in clinical practice for simple and efficacious methods to enhance HSC engraftment.

Nitric oxide (NO) is a gaseous molecule which acts as a signal molecule in mammalian cells, and plays important roles in a variety of physiological regulations, such as synaptic plasticity, endothelial cell relaxation, and immune responses [12, 13]. NO can freely diffuse across the cellular membrane and activate a cytoplasm enzyme, soluble guanylyl cyclase (sGC), to produce cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). cGMP acts as an important secondary messenger and activates cGMP-dependent protein kinase (PKG) to regulate a broad spectrum of downstream processes. In hematopoietic system, NO signaling is necessary for proper differentiation of HSC and lineage commitment involving multiple signaling pathways [14]. Besides, NO signaling is required in vascular niche for HSC generation and production during embryogenesis [15], implicating potential beneficial effects of NO signaling for HSC biology and HCT. However, potential roles of NO and cGMP in regulating HSC homing and engraftment remain to be determined.

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Fig. 1: Pharmacological activation of NO signaling pathway promotes CB HSC engraftment.
Fig. 2: Activation of NO signaling pathway increases surface CXCR4 expression and HSC homing.

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Acknowledgements

We are indebted to all members of Broxmeyer lab for helpful discussions and assistance. We thank personnel from the in vivo Therapeutics Core and Flow Cytometry Core of the Indiana University School of Medicine for assistance during experiments, which was supported in part by U54 DK106846. The bioinformatics analysis was performed by the Collaborative Core for Cancer Bioinformatics (C3B) shared by IU Simon Cancer Center (P30CA082709) and Purdue University Center for Cancer Research (P30CA023168) with support from the Walther Cancer Foundation. This work was supported by US Public Health Service Grants to HEB from the NIH (R35HL139599, R01HL056416, R01HL112669, R01DK109188, U54 DK106846), Indiana University CCEH Pilot and Feasibility Grant and Fudan University Start-up Research Grant to XH, the National Key R&D Program of China Stem Cell and Translation Research (2019YFA0111800) to BG. We also thank the support from Indiana University Precision Health Initiative (PHI).

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Author notes

  1. These authors contributed equally: Danhua Xu, Min Yang

Authors and Affiliations

  1. Zhongshan-Xuhui Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Danhua Xu & Xinxin Huang

  2. Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China

    Min Yang

  3. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Maegan Capitano & Hal E. Broxmeyer

  4. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Bin Guo

  5. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Sheng Liu & Jun Wan

  6. The Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Jun Wan

  7. School of Informatics and Computing, Indiana University–Purdue University Indianapolis, Indianapolis, IN, 46202, USA

    Jun Wan

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  1. Danhua Xu
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Contributions

DX, MY, and XH designed and performed experiments, and conducted data analysis. MC and BG participated in designing and preparation of experiments, helped with manuscript preparation. SL and JW performed bioinformatics analysis of RNA sequencing data. XH and HEB conceived this study, guided the research, and wrote the paper.

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Correspondence to Hal E. Broxmeyer or Xinxin Huang.

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Xu, D., Yang, M., Capitano, M. et al. Pharmacological activation of nitric oxide signaling promotes human hematopoietic stem cell homing and engraftment. Leukemia 35, 229–234 (2021). https://doi.org/10.1038/s41375-020-0787-z

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