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Aging-Related Reduced Expression of CXCR4 on Bone Marrow Mesenchymal Stromal Cells Contributes to Hematopoietic Stem and Progenitor Cell Defects

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Abstract

Aging impairs the regenerative potential of hematopoietic stem cells (HSC) and skews differentiation towards the myeloid lineage. The bone marrow (BM) microenvironment has recently been suggested to influence HSC aging, however the mechanisms whereby BM stromal cells mediate this effect is unknown. Here we show that aging-associated decreased expression of CXCR4 expression on BM mesenchymal stem cells (MSC) plays a crucial role in the development of the hematopoietic stem and progenitor cells (HSPC) aging phenotype. The BM MSC from old mice was sufficient to drive a premature aging phenotype of young HSPC when cultured together ex vivo. The impaired ability of old MSC to support HSPC function is associated with reduced expression of CXCR4 on BM MSC of old mice. Deletion of the CXCR4 gene in young MSC accelerates an aging phenotype in these cells characterized by increased production of reactive oxygen species (ROS), DNA damage, senescence, and reduced proliferation. Culture of HSPC from young mice with CXCR4 deficient MSC also from young mice led to a premature aging phenotype in the young HSPC, as evidenced by reduced hematopoietic regeneration and enhanced myeloid differentiation. Mechanistically, CXCR4 signaling prevents BM MSC dysfunction by suppressing oxidative stress, as treatment of old or CXCR4 deficient MSC with N-acetyl-L-cysteine (NAC), improved their niche supporting activity, and attenuated the HSPC aging phenotype. Our studies suggest that age-associated reduction in CXCR4 expression on BM MSC impairs hematopoietic niche activity with increased ROS production, driving an HSC aging phenotype. Thus, modulation of the SDF-1/CXCR4 axis in MSC may lead to novel interventions to alleviate the age-associated decline in immune/hematopoietic function.

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Acknowledgements

This study is supported by US Public Health Service grants AG046246 (LMP, MAK and CMO), HL096305 (LMP), and a CCEH pilot grant (PS). Old mouse colony maintenance is supported by Department of the Army grants PR140433 (LP, CMO), PR140896 (CMO), and PR141527 (CMO). Flow cytometry was performed in the Flow Cytometry Resource Core Facility of the IU Simon Cancer Center (NCI P30 CA082709).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States

    Pratibha Singh & Louis M. Pelus

  2. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States

    Pratibha Singh, Christie M. Orschell & Louis M. Pelus

  3. Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, United States

    Melissa A. Kacena

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  1. Pratibha Singh
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  2. Melissa A. Kacena
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  4. Louis M. Pelus
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Contributions

P.S. designed the study, executed the experiments, analyzed and interpreted data and wrote the manuscript, C.M.O and M.A.K. provided old mice, assisted with experimental design and data interpretation and critically read and edited the manuscript, and L.M.P. participated in study design, data interpretation, and wrote the manuscript.

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Correspondence to Pratibha Singh.

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Singh, P., Kacena, M.A., Orschell, C.M. et al. Aging-Related Reduced Expression of CXCR4 on Bone Marrow Mesenchymal Stromal Cells Contributes to Hematopoietic Stem and Progenitor Cell Defects. Stem Cell Rev and Rep 16, 684–692 (2020). https://doi.org/10.1007/s12015-020-09974-9

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