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The negative effect of prolonged somatotrophic/insulin signaling on an adult bone marrow-residing population of pluripotent very small embryonic-like stem cells (VSELs)

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Abstract

It is well known that attenuated insulin/insulin-like growth factor signaling (IIS) has a positive effect on longevity in several animal species, including mice. Here, we demonstrate that a population of murine pluripotent very small embryonic-like stem cells (VSELs) that reside in bone marrow (BM) is protected from premature depletion during aging by intrinsic parental gene imprinting mechanisms and the level of circulating insulin-like growth factor-I (IGF-I). Accordingly, an increase in the circulating level of IGF-I, as seen in short-lived bovine growth hormone (bGH)-expressing transgenic mice, which age prematurely, as well as in wild-type animals injected for 2 months with bGH, leads to accelerated depletion of VSELs from bone marrow (BM). In contrast, long-living GHR-null or Ames dwarf mice, which have very low levels of circulating IGF-I, exhibit a significantly higher number of VSELs in BM than their littermates at the same age. However, the number of VSELs in these animals decreases after GH or IGF-I treatment. These changes in the level of plasma-circulating IGF-I corroborate with changes in the genomic imprinting status of crucial genes involved in IIS, such as Igf-2-H19, RasGRF1, and Ig2R. Thus, we propose that a chronic increase in IIS contributes to aging by premature depletion of pluripotent VSELs in adult tissues.

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Acknowledgements

This work was supported by NIH R01 DK074720, EU structural funds, Innovative Economy Operational Program POIG.01.01.01-00-109/09-01, and the Henry M. and Stella M. Hoenig Endowment to MZR; by NIH P20RR018733 from the National Center for Research Resources to MK; NIH P01 AG031736 to AB; and NIH AG032290, KBN grant N N401 042638, and U19 AG023122 to MM.

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Authors and Affiliations

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

    Magda Kucia, Riu Liu, Dong-Myung Shin, Janina Ratajczak, Katarzyna Mierzejewska & Mariusz Z. Ratajczak

  2. Department of Physiology, Pomeranian Medical University, Szczecin, Poland

    Magda Kucia, Janina Ratajczak & Mariusz Z. Ratajczak

  3. Burnett School of Biomedical Sciences College of Medicine, Institute of Human Genetics, University of Central Florida, Orlando, FL, USA

    Michal Masternak

  4. Edison Biotechnology Institute and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, OH, USA

    John J. Kopchick

  5. Department of Internal Medicine, School of Medicine, Southern Illinois University, Springfield, IL, USA

    Michal Masternak, Adam Spong & Andrzej Bartke

  6. Institute for Human Genetics Polish Academy of Sciences, Poznan, Poland

    Michal Masternak, Adam Spong & Andrzej Bartke

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  1. Magda Kucia
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  2. Michal Masternak
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  3. Riu Liu
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  4. Dong-Myung Shin
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  10. Mariusz Z. Ratajczak
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Correspondence to Mariusz Z. Ratajczak.

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Supplementary Figure 1

COBRA assay for Igf2-H19 and RasGRF1 DMRs in the response to prolonged GH treatment. Panel A. COBRA assay of Igf2-H19 DMR1 (upper panel) and RasGRF1 DMR (lower panel) by BstUI restriction enzyme cleavage in the indicated cells isolated from six-month- (left) and one-year-old (right) bGH transgenic (bGH-TG) mice and their control wt littermates (bGH-wt). Panels B and C. COBRA assay of Igf2-H19 DMR1 by BstUI restriction enzyme cleavage of the indicated cells isolated from (Panel B) two-year-old Ames dwarf (Prop1df/df, left panel) and Laron dwarf (GHR––, right panel) mice and their control heterozygote (Prop1df/+ or GHR+/–) littermates. Panel C Ames dwarf mice were injected with porcine GH (pGH) at the age of 2 weeks (left) or 6 months (right) for 6 weeks. As a control, same-age mice were treated with saline. The unmethylated DNA (dashed arrow) was not cleaved, in contrast to methylated DNA (solid arrow), because of a sequence change at the site recognized by a restriction enzyme after bisulfite reaction. *non-specific PCR product. (PPT 452 kb)

Supplementary Table I

Peripheral blood parameters in male 6-month and 1-year-old normal and bGH transgenic mice (n=10) (DOC 37 kb)

Supplementary Table II

Peripheral blood parameters in male 2-month old GHR-/- and GHR-/- after exposure to IGF-1 (n=10). (DOC 31 kb)

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Kucia, M., Masternak, M., Liu, R. et al. The negative effect of prolonged somatotrophic/insulin signaling on an adult bone marrow-residing population of pluripotent very small embryonic-like stem cells (VSELs). AGE 35, 315–330 (2013). https://doi.org/10.1007/s11357-011-9364-8

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