Somatic stem cell activity is necessary to replenish lost tissue-specific cells. Hematopoietic, muscle and intestinal stem cell activity declines from adulthood to old age. Consequently, stem cell aging may reduce tissue homeostasis and limit lifespan. Identifying mechanisms to revert or attenuate stem cell aging may therefore offer new strategies to clinically intervene in age-related disorders. The current paradigm holds that hematopoietic stem cell (HSC) aging is not reversible by short-term interventions. Challenging this paradigm, we found that HSCs from aged animals that underwent G-CSF- induced mobilization are phenotypically young with respect to tissue homeostasis and lymphoid differentiation. We hypothesize that the aged stem cell phenotype is not fixed, and that stem cell function is rejuvenated by mobilization. To this end, we will investigate the extent to which mobilized HSCs in aged animals resemble functionally young stem cells and we will directly test whether aged HSCs are rejuvenated upon mobilization. A detailed understanding of the mechanisms that result in the accumulation of phenotypically young HSCs in peripheral blood upon G-CSF mobilization in aged animals are important first steps towards possible translational applications of our findings. PROJECT NARRATIVE Stem cell aging may reduce tissue homeostasis and consequently limit lifespan. Identifying mechanisms that revert or attenuate stem cell aging has therefore enormous therapeutic implications. We found that HSCs from aged animals that underwent G-CSF-induced mobilization are phenotypically young and propose to identify the mechanism that results in functionally young stem cells in aged animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK077762-02
Application #
7588773
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Wright, Daniel G
Project Start
2008-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2009
Total Cost
$225,000
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Leins, Hanna; Mulaw, Medhanie; Eiwen, Karina et al. (2018) Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood 132:565-576
Kumar, Sachin; Geiger, Hartmut (2017) HSC Niche Biology and HSC Expansion Ex Vivo. Trends Mol Med 23:799-819
Guidi, Novella; Sacma, Mehmet; Ständker, Ludger et al. (2017) Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J 36:840-853
Guidi, Novella; Geiger, Hartmut (2017) Rejuvenation of aged hematopoietic stem cells. Semin Hematol 54:51-55
Akunuru, Shailaja; Geiger, Hartmut (2016) Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells. Trends Mol Med 22:701-712
Moehrle, Bettina M; Geiger, Hartmut (2016) Aging of hematopoietic stem cells: DNA damage and mutations? Exp Hematol 44:895-901
Denkinger, Michael D; Leins, Hanna; Schirmbeck, Reinhold et al. (2015) HSC Aging and Senescent Immune Remodeling. Trends Immunol 36:815-824
Moehrle, Bettina M; Nattamai, Kalpana; Brown, Andreas et al. (2015) Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs. Cell Rep 13:2412-2424
Geiger, Hartmut; Zheng, Yi (2013) Cdc42 and aging of hematopoietic stem cells. Curr Opin Hematol 20:295-300
Geiger, Hartmut; de Haan, Gerald; Florian, M Carolina (2013) The ageing haematopoietic stem cell compartment. Nat Rev Immunol 13:376-89

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