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Functional organic cation transporters mediate osteogenic response to metformin in human umbilical cord mesenchymal stromal cells

  • Author Footnotes
    * These authors contributed equally to this work.
    Faisal E. Al Jofi
    Footnotes
    * These authors contributed equally to this work.
    Affiliations
    Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA

    Department of Preventive Dental Science, Division of Periodontics, Imam Abdulrahman Bin Faisal University, College of Dentistry, Dammam, Saudi Arabia
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  • Author Footnotes
    * These authors contributed equally to this work.
    Tao Ma
    Footnotes
    * These authors contributed equally to this work.
    Affiliations
    Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA
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  • Dong Guo
    Affiliations
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA
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  • Monica P. Schneider
    Affiliations
    Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Maryland, Baltimore, Maryland, USA
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  • Yan Shu
    Affiliations
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA

    Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA
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  • Hockin H.K. Xu
    Affiliations
    Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA

    Biomaterials and Tissue Engineering Division, Department of Advanced Oral Sciences and Therapeutics, School of Dentistry, University of Maryland, Baltimore, Maryland, USA

    Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, University of Maryland, Baltimore, Maryland, USA
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  • Abraham Schneider
    Correspondence
    Correspondence: Abraham Schneider, DDS, PhD, Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 West Baltimore Street, Room 7265, Baltimore, MD 21201, USA.
    Affiliations
    Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA

    Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA
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  • Author Footnotes
    * These authors contributed equally to this work.
Published:March 16, 2018DOI:https://doi.org/10.1016/j.jcyt.2018.02.369

      Abstract

      Background

      Compelling evidence indicates that metformin, a low-cost and safe orally administered biguanide prescribed to millions of type 2 diabetics worldwide, induces the osteoblastic differentiation of mesenchymal stromal cells (MSCs) through the 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway. As a highly hydrophilic cationic compound, metformin uptake is facilitated by cell membrane organic cation transporters (OCTs) of the solute carrier 22A gene family. We hypothesized that to effectively enhance osteogenic differentiation, and ultimately bone regeneration, metformin must gain access into functional OCT-expressing MSCs.

      Methods

      Data was obtained through immunoblotting, cellular uptake, mineralization and gene expression assays.

      Results

      We demonstrate for the first time that functional OCTs are expressed in human-derived MSCs from umbilical cord Wharton's jelly, an inexhaustible source of nonembryonic MSCs with proven osteogenic potential. A clinically relevant concentration of metformin led to AMPK activation, enhanced mineralized nodule formation and increased expression of the osteogenic transcription factor Runt-related transcription factor 2 (RUNX2). Indeed, targeting OCT function through pharmacological and genetic approaches markedly blunted these responses.

      Conclusions

      Our findings indicate that functional OCT expression in UC-MSCs is a biological prerequisite that facilitates the intracellular uptake of metformin to induce an osteogenic effect. Future pre-clinical studies are warranted to investigate whether the expression of functional OCTs may serve as a potential biomarker to predict osteogenic responses to metformin.

      Key Words

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