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The NADPH‐Production Enzyme Isocitrate Dehydrogenase Maintains Quiescence in Hair Follicle Stem Cells
Author(s) -
Ambrus Aaron Michael,
Lemons Johanna,
Raitman Irene,
Krishnan Nithya,
Jelinek David,
Suh Eric,
Remillard Matthew,
Shilo Noya,
Haley Erin,
Sun Lova,
Xiao Roy,
Flores Aimee,
Wang David,
White Andrew,
Lowry William,
Coller Hilary
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1260.5
Subject(s) - hair follicle , stem cell , isocitrate dehydrogenase , biology , reactive oxygen species , glutathione , microbiology and biotechnology , oxidative stress , chemistry , biochemistry , enzyme
NADPH is a critical metabolite that is important for regenerating reduced glutathione from oxidized glutathione and eliminating reactive oxygen species (ROS). Metabolic flux and microarray experiments in fibroblasts demonstrated that NADPH‐producing enzymes, glucose‐6‐phosphate dehydrogenase (G6PD), isocitrate dehydrogenase (IDH), and the upstream transcription factor NRF2, are all activated in quiescent compared with proliferating fibroblasts. We demonstrated that G6PD and NRF2 are functionally important for quiescence by showing that inhibition of G6PD or NRF2 results in oxidative stress and apoptosis specifically in quiescent fibroblasts. Flow cytometry experiments demonstrated that ROS in quiescent cells can be derived from mitochondrial superoxide that results from increased mitochondrial activity in the serum‐starved compared with proliferating fibroblasts, as well as an increase in reactive nitrogen species that arise from peroxisomes. To understand the physiological role of NADPH‐production pathways, we examined their potential activity in mouse skin. Consistent with our findings in quiescent fibroblasts, in situ metabolic activity assays revealed higher potential activity for G6PD and IDH in non‐dividing cells. Of particular interest was the high IDH potential in quiescent hair follicle stem cells. Staining of live mouse skin with monochlorobimane showed higher reactivity, consistent with higher levels of reduced glutathione, in hair follicle stem cells. Inhibition of IDH activity in healthy mouse skin with two different inhibitors resulted in progression in the hair follicle cycle from a quiescent to proliferative state suggesting that the high IDH activity observed in hair follicle stem cells may contribute to the maintenance of these stem cells in a quiescent state. Going forward, our focus is on understanding the role of IDH in the maintenance of stem cells as opposed to proliferating, committed progenitor cells. Support or Funding Information H.A.C. was the Milton E. Cassel scholar of the Rita Allen Foundation. This work was supported by NIGMS Center of Excellence grant P50 GM071508, two grants from the Cancer Institute of New Jersey, the New Jersey Commission on Cancer Research, National Cancer Institute 1RC1 CA147961‐01, a Focused Funding Grant to H.A.C. from the Johnson & Johnson Foundation and a grant from the PhRMA Foundation to H.A.C, and XXXX to W.E.L. J.M.S. was supported by NIH training grant T32 HG003284. E.M.H. acknowledges a Bowen Fellowship from Princeton University and the New Jersey Commission on Cancer Research. E.J.S. acknowledges support from the National Science Foundation.